−Removed: We are a T-cell reprogramming company dedicated to the mastery of T cells to cure patients with solid tumors.
−Removed: We believe the key to effective cell therapy is the deep and profound understanding of the identity, fate and function of cells to create living medicines.
−Removed: We take a systematic, interrogative, cell biology-driven approach to overcome what we view as the two major barriers to successful Adoptive Cell Therapy (ACT) – (1) T-cell exhaustion and (2) lack of durable stemness – through the application of our proprietary ex vivo genetic and epigenetic reprogramming technologies, Gen-R™ and Epi-R™.
−Removed: Our technologies are designed to be applied in a target and modality agnostic manner to chimeric antigen receptor (CAR), tumor-infiltrating lymphocytes (TIL) and T-cell receptor (TCR) therapies to fundamentally improve the properties of T cells needed to eradicate solid tumors.
−Removed: We believe our autologous T-cell therapies will generate improved, durable clinical outcomes that are potentially curative for patients with solid tumors.
−Removed: We are building a multi-modality product pipeline across several solid tumor indications with high unmet needs.
−Removed: We are advancing a product pipeline of promising living cell product candidates across multiple ACT modalities that incorporate our Gen-R and Epi-R technology platforms.
+Added: We are a clinical-stage cell therapy company advancing a pipeline of product candidates for patients with solid tumors utilizing our proprietary ex vivo genetic and epigenetic T‑cell reprogramming technologies.
+Added: Our investigational therapies use the patient’s own cells as the starting point to generate highly tumor-reactive, longer-lasting functional T cells with enhanced ability to defeat solid tumors.
+Added: Our innovative reprogramming technologies address what we believe are the primary barriers that limit consistent and long-lasting responses to T‑cell therapy in solid tumors:
+Added: T‑cell exhaustion and lack of durable stemness.
+Added: Our technologies are designed to generate T cells with the ability to persist and self‑renew while driving durable tumor cytotoxicity, even in the setting of an immunosuppressive tumor microenvironment.
+Added: The goal is for our technologies to provide patients with T cells that are potent and long-lasting enough to achieve durable antitumor responses.
+Added: Furthermore, our technologies can be applied in a target agnostic manner to multiple T‑cell modalities, including chimeric antigen receptor (CAR), tumor-infiltrating lymphocytes (TIL) and T‑cell receptor (TCR) therapies.
+Added: We apply our technologies with the aim to develop T‑cell therapies with improved durable clinical outcomes.
+Added: Our growing pipeline of promising cell product candidates targets solid tumor indications with large unmet needs that are collectively responsible for approximately 180,000 deaths in the US annually.
Each of our programs provide opportunities to expand into additional indications beyond the patient populations we are initially targeting.
−Removed: Our lead product candidates are summarized in the table below:
−Removed: Our goal is to utilize our proprietary technology platforms to develop curative ACT for patients with solid tumors.
+Added: Our product candidates are summarized in the Table 1 below:
+Added: Lyell’s Pipeline
+Added: Our goal is to develop innovative therapies for patients with solid tumors based on our proprietary T‑cell reprogramming technologies, which generate tumor-reactive, long-lasting functional T cells that resist exhaustion and maintain the ability to self-renew and persist to drive durable tumor cytotoxicity.
Key components of our business strategy to achieve this goal include:
−Removed: • Leverage our proprietary, cell reprogramming technology platforms to fundamentally improve T-cell efficacy and eradicate solid tumors.
−Removed: — We seek to develop T-cell therapies that eradicate solid tumors by addressing the major barriers to ACT efficacy, including overcoming exhaustion of T cells and creating T cells with properties of durable stemness.
−Removed: Our pipeline of therapeutic candidates includes four programs designed to outlast and eradicate solid tumors utilizing our two lead proprietary T-cell reprogramming technologies:
−Removed: Gen-R and Epi-R.
−Removed: • Rapidly advance our deep multi-modality pipeline of product candidates.
−Removed: — Our technology platforms are designed to be applied in a target and modality agnostic manner to CAR, TIL and TCR cell therapies.
−Removed: We believe our autologous T-cell therapies will generate improved, durable clinical outcomes that are potentially curative for
−Removed: patients with solid tumors.
−Removed: Two INDs for our product candidates have been cleared by the U.S.
−Removed: Food and Drug Administration (FDA), and we anticipate filing two additional INDs by the end of 2022/early 2023.
−Removed: • Continually innovate to develop and advance disruptive, next generation platform technologies for cell-based therapy.
−Removed: — We are committed to continuing to discover, develop and advance disruptive technologies that have the potential to revolutionize ACT and its promise to cure patients with solid tumors.
−Removed: For example, we believe our T-cell rejuvenation platform technology may represent the next frontier of epigenetic reprogramming for cell‑based therapy.
−Removed: • Maintain proprietary state of the art manufacturing infrastructure and capabilities to control all aspects of cell product preparations.
−Removed: — We have and will continue to invest in manufacturing to mitigate the risks the field has seen, including challenges in managing production, supply chain, patient specimen chain of custody and quality control.
−Removed: Controlling manufacturing also enables us to protect proprietary aspects of Gen-R and Epi-R, and rapidly incorporate new innovations.
−Removed: LyFE™, our multi-product manufacturing facility, which can produce plasmid, lentivirus and cells, has been commissioned and qualified in compliance with U.S.
−Removed: Food and Drug Administration’s Current Good Manufacturing Practices (cGMP).
−Removed: • Implement digital technologies and cloud solutions to accelerate and enhance our science and operations.
−Removed: — High-performance cloud computing, scalable cloud storage, robotic and artificial intelligence, coupled with our collaboration with Amazon Web Services (AWS), enable real time monitoring of our manufacturing process and ability to incorporate deep insights into our research, manufacturing and clinical development efforts.
−Removed: This approach is being leveraged to inform our next generation cell therapies.
−Removed: • Aggressively generate, secure and defend intellectual property on our differentiated technology platforms and product candidates.
−Removed: — We have developed and secured intellectual property, including know-how, through our internal research efforts, licensing agreements and collaborations.
−Removed: We rigorously analyze, file and protect our intellectual property.
−Removed: Our Technology Platforms
−Removed: ACT has demonstrated profound results in some patients suffering from hematologic tumors, but solid tumors are more complex and have evolved multiple mechanisms to evade and ultimately overcome the immune system.
−Removed: This has limited the use of ACTs in non-hematologic settings.
−Removed: We believe T-cell exhaustion and lack of durable stemness are the two primary barriers limiting the efficacy of ACT in solid tumors.
−Removed: We have developed two proprietary reprogramming technology platforms to address these two major barriers.
−Removed: Gen-R is designed to overcome loss of T-cell function attributable to an exhausted state, and Epi-R is designed to create T-cell populations with properties of durable stemness.
−Removed: T cells with properties of durable stemness are able to proliferate, persist and self-renew, as well as generate differentiated effector cell progenies to provide durable anti-tumor functionality.
−Removed: Gen-R for Overcoming T-Cell Exhaustion.
−Removed: Gen-R is our proprietary ex vivo genetic reprogramming technology to overcome T-cell exhaustion, which results from transcriptional and epigenetic changes that occur as T cells differentiate into a dysfunctional state.
−Removed: Our scientific co-founders discovered T-cell exhaustion occurs more frequently in solid tumors than in hematologic cancers where CAR T cells have demonstrated efficacy.
−Removed: The discovery of Gen-R came from the realization that chronic antigen stimulation, or when the T cell is always “on,” combined with an immunosuppressive solid tumor microenvironment (TME), likely promotes the development of T-cell exhaustion.
−Removed: Our scientific co-founder Dr.
−Removed: Crystal Mackall identified a strategy to prevent T cells from becoming exhausted utilizing ex vivo genetic reprogramming to overcome the problem of T-cell exhaustion.
−Removed: Mackall developed a GD2-targeted CAR T cell that is always turned on and quickly exhausts.
−Removed: This model system drove the CAR T cells to have the hallmark phenotypic, functional, transcriptomic and epigenetic abnormalities described in cancer and chronic viral infections where T cells become exhausted.
−Removed: Compared to normal CD19-targeted CAR T cells that are not always “on,” the GD2 CAR T cells demonstrated elevated expression of cell surface exhaustion-associated markers such as PD-1, TIM-3, LAG3 and CD39, and these T cells had decreased function as measured by secretion of IL-2 compared with T cells expressing the CD19 CAR.
−Removed: All T cell differentiation states, including exhaustion, are characterized by distinct chromatin structure (open versus closed).
−Removed: Generally, open chromatin structures allow for transcription factor binding while closed structures inhibit transcription factor binding.
−Removed: To determine if the GD2 model could enable the understanding of the biology of exhaustion, the GD2 and CD19 CAR T cells were examined for their chromatin structure to evaluate which transcription factor binding sites were accessible in the functional versus the exhausted states.
−Removed: The exhausted GD2 CAR T cells had a genome-wide restructuring of chromatin accessibility compared to the CD19 CAR T cells, and the greatest change was the increased
−Removed: availability of binding sites to the AP-1/ bZIP family and IRF4 transcription factors.
−Removed: These transcription factors include JUNB, JUND, BATF, BATF3, FOSL1, FOSL2 and IRF4.
−Removed: It is notable that c-JUN, a protein which, when dysregulated, has been shown to play a crucial role in T-cell exhaustion, can bind directly to inhibitory bZIP members, potentially limiting its availability for binding to FOS, which is the necessary AP-1 complex for T-cell effector function.
−Removed: Mackall evaluated the levels of each of these transcription factors to see whether there were differences between CD19 and GD2 CAR T cells.
−Removed: What was seen was an increase in the level of several of these proteins including JUNB, BATF3 and IRF4 in GD2 CAR T cells compared to CD19 CAR T cells.
−Removed: Furthermore, in the GD2 CAR T cells c-JUN was shown to be complexed with inhibitory factors such as JUNB, IRF4, BATF and BATF3.
−Removed: We believe these data are suggestive of reduced availability of c-JUN to bind to FOS (its activating partner) which is required for T-cell activation.
−Removed: Mackall then hypothesized that overexpression of c-JUN in the GD2 CAR T cell, would enable the reconstitution of activating c-JUN/FOS heterodimers and shift the balance to activating versus suppressive protein complexes, and prevent the T cells from becoming exhausted.
−Removed: Indeed, overexpression of c-JUN in the GD2 CAR T cells led to tumor eradication in vivo in preclinical models as compared to the mice treated with GD2 CAR T cells that did not overexpress c-JUN.
−Removed: Our scientific co-founder Dr.
−Removed: Stanley Riddell further tested the hypothesis in a rigorous solid tumor model of non-small cell lung cancer (NSCLC) (Figure 1).
−Removed: He utilized a mouse model that recapitulates the oncogenic driver mutations and immunosuppressive TME of human NSCLC.
−Removed: It has been difficult if not impossible to treat the tumors in these mice with chemotherapy or immunotherapy and this “model” is highly representative of human NSCLC.
−Removed: This model was further designed so that the tumors express ROR1 and, perhaps not surprisingly proved to be resistant to therapy with ROR1 CAR T cells, just as was observed in treating human NSCLC with ROR1 CAR T cells.
−Removed: In contrast, tumor-bearing mice treated with ROR1 CAR T cells that overexpressed c-JUN (Gen-R ROR1 CAR T cells) demonstrated greater infiltration by the T cells into the tumor, enhanced function of those T cells and tumor regression in 50% of the mice, further confirming the results obtained by Dr.
−Removed: Mackall in HER2 and other cancer models.
−Removed: These results are in contrast to the 100% tumor progression observed in mice treated with ROR1 CAR without overexpression of c-JUN.
−Removed: Once again, this model illustrated that when T cells enter solid tumors, they exhaust and become ineffective unless the T cells resist exhaustion with Gen-R.
−Removed: ROR1 CAR T cell overexpressing c-JUN (Gen-R ROR1 CAR T cells) demonstrated efficacy in mice with NSCLC
−Removed: Epi-R - Reprogramming Cells to Create Durable Stemness.
−Removed: Epi-R is our proprietary ex vivo epigenetic reprogramming technology to create a novel population of T cells with durable stemness.
−Removed: T cells with properties of durable stemness are able to proliferate, persist and self-renew, as well as generate differentiated effector cell progenies to provide durable anti-tumor functionality.
−Removed: Emerging research has made clear that effective cellular immunotherapy requires T-cell populations with stem‑like characteristics that are capable of both self-renewal and generation of differentiated effector cell progenies to produce clinical responses.
−Removed: The presence of T-cell populations with these attributes correlates with responses to cancer immunotherapy, including TIL ACT and immune checkpoint blockade (ICB) therapy.
−Removed: We believe durable stemness is required for meaningful long-term efficacy against solid tumors.
−Removed: Durable stemness relates to the ability of T cells to maintain their stemness until the tumor is eradicated, that is, they have the ability to proliferate, persist and self-renew, as well as generate differentiated effector cell progenies to provide durable anti‑tumor
−Removed: functionality, despite continued persistent signals from the tumor.
−Removed: We believe that as these cells proliferate, they generate progeny cells that can both differentiate into polyfunctional effector cells, and/or re-populate the population of less differentiated T cell states, thereby maintaining stemness.
−Removed: Epi-R is designed to intentionally and reproducibly generate populations of T cells that have this property of durable stemness.
−Removed: Furthermore, relating specifically to TIL, application of Epi-R has generated T cell preparations that exhibit increased polyclonality, i.e., the retention of a broad repertoire of relevant TCR clonotypes.
−Removed: We believe our scientists have been able to intentionally and reproducibly produce T cell populations with durable stemness using Epi-R.
−Removed: The resulting Epi-R T cell populations have in vitro and preclinical in vivo properties that suggest that they are significantly more potent than those generated by standard approaches to manufacturing T cells for ACT.
−Removed: Standard approaches likely generate ill-defined mixes of cells in various states of differentiation, most of which lack the properties to be effective against solid tumors.
−Removed: To be curative, we believe T cells with durable stemness properties are needed.
−Removed: Our work has built upon the groundbreaking science conducted at the National Cancer Institute (NCI) by the laboratory of Dr.
−Removed: Nick Restifo and then actuated at Lyell by him and his colleagues.
−Removed: We believe that we can reliably produce a population of T cells that have the requisite properties to be effective against tumor cells, that can be characterized by genomic, proteomic and transcriptomic features, and that may ultimately be responsible for clinical effectiveness in ACT.
−Removed: These T cells have enhanced proliferative capacities, as well as the ability to engraft, persist and destroy tumor masses.
−Removed: Our ultimate goal is to characterize, identify, optimize and consistently produce these cells through our proprietary Epi-R technology, which comprises a protocol involving proprietary media, and well-defined cell activation and expansion protocols and customized cytokine combinations.
−Removed: We expect to develop other versions of the protocol in the future to further advance this technology.
−Removed: Epi-R triggers metabolic pathways that cause T cells to have properties of durable stemness.
−Removed: The origins of Epi-R came from Dr.
−Removed: Restifo’s work at the NCI, where he demonstrated that T cells grown in media with high concentrations of potassium were more stem-like and functional.
−Removed: These were the first clues that it might be possible to reprogram cells to be more stem-like and functional.
−Removed: Cells grown with high potassium in the media were 40-100x more potent in vivo against established tumors compared with controls and demonstrated significantly enhanced abilities to infiltrate tumors, with tumor-infiltrating T cells exhibiting enhanced resistance to exhaustion as measured by markers such as TIM3.
−Removed: This work demonstrated that the high potassium resulted in changes in the epigenome of the T cells and that this epigenetic reprogramming was likely responsible for the persistence of functional changes in the T-cell population, even after return to standard media or infusion in vivo .
−Removed: Lyell has further advanced and optimized these epigenetic reprogramming strategies to produce the Epi-R T-cell populations with the properties we seek, measured both phenotypically and functionally.
−Removed: We have expanded beyond the work at the NCI on hyperkalemia to execute multivariate, high dimensional experiments that improve upon what was previously published to create Epi-R protocols.
−Removed: Most importantly, in addition to elevated potassium, we have extensively reformulated the media, and optimized cytokines, growth factors, activation methods and other components related to cell culture, activation and expansion.
−Removed: These modifications were required to optimize phenotypic and in vitro and in vivo functions of the resulting T-cell populations.
−Removed: In addition, we have advanced these research scale efforts and developed clinical scale production capabilities for Epi-R.
−Removed: Our Epi-R technology allows us to generate T-cell therapy products that retain increased characteristics of stemness that have been clinically linked with effective antitumor immunotherapies.
−Removed: These qualities preserve stemness while also enhancing the functional ability of our cells to recognize and destroy tumor cells, what we term durable stemness.
−Removed: Epi-R fine-tunes the chromatin structure of the T cells, which results in a new transcriptional profiles of T cells to yield a novel cell population that is distinct from those produced by standard expansion processes, with increased expression of a distinct population of cells expressing key genes linked with T cell engraftment, expansion, in vivo persistence and function.
−Removed: Trajectory analyses of Epi-R T-cell populations demonstrate that both stem-like and effector populations are maintained in the face of persistent activation, proliferation and multiple cycles of tumor killing, supporting a durable ability to self-renew.
−Removed: As predicted, clinical scale production of Epi-R cells show that they maintain all of these properties, thus addressing one of the challenges in ACT product production – how to maintain functionality of T cells during expansion.
−Removed: Our Epi-R T cell populations have increased durable functionality against tumors in vitro and in vivo , with increased ability to eradicate established tumors in realistic animal models of human cancer.
−Removed: Applying Epi-R to TIL expansion, we have been able to generate TIL products that exhibit increased polyclonality and retention of key TCR clonotypes in cells grown to clinically meaningful numbers.
−Removed: Our Epi-R TIL are able to effectively recognize and respond to autologous tumor cell lines by secreting key inflammatory cytokines and displaying increased ability to kill cancer on a per-cell basis.
−Removed: Epi‑R to create T cells with the qualities associated with clinical antitumor effectiveness, we believe that we have generated an opportunity to eradicate solid cancers.
−Removed: The Next Frontier:
−Removed: Epigenetic Rejuvenation of T Cells
−Removed: We believe that Epi-R – the epigenetic reprogramming of T cells to create Epi-R cell populations with durable stemness – holds great potential.
−Removed: New science is emerging that provides insight into additional opportunities to capture the potential of T cells enhanced with the required properties to cure cancer.
−Removed: There are two key cellular parameters as cells develop and differentiate over the life of an organism:
−Removed: cellular identity and age.
−Removed: The decline in function with aging is stereotypical in many cells;
−Removed: it has been well characterized in T cells.
−Removed: Aging of adult stem cells is thought to play a central role in determining the effect of aging on organismal function.
−Removed: Each T cell clonotype can be renewed from a stem cell-like state, but self-renewal, proliferation, function, persistence and antitumor activity are thought to be impacted by aging.
+Added: • Efficiently advance our diverse pipeline of product candidates — We believe our autologous T‑cell therapies will deliver improved, durable clinical outcomes for patients with solid tumors.
+Added: We have two wholly owned product candidates in two distinct T‑cell modalities, CAR T cell and TIL, currently in Phase 1 development targeting indications with unmet medical needs in large commercial opportunities.
+Added: We anticipate having initial clinical data for both programs in 2024 and filing a new Investigational New Drug (IND) application for our third wholly-owned product candidate in the first half of 2024.
+Added: • Leverage our proprietary, cell reprogramming technology platforms to create highly tumor-reactive, longer‑lasting functional T cells with enhanced ability to defeat solid tumors — We seek to develop T‑cell therapies to defeat solid tumors by addressing the major barriers to successful cell therapy in solid tumors, including overcoming exhaustion of T cells and creating populations of T cells with properties of durable stemness.
+Added: Our pipeline of therapeutic candidates includes programs designed to outlast and eradicate solid tumors utilizing our proprietary, stackable genetic and epigenetic T‑cell reprogramming technologies:
+Added: c-Jun overexpression, NR4A3 knockout, Epi‑R TM and Stim‑R TM .
+Added: • Continually innovate to develop and advance novel, breakthrough technologies for cell therapy — We are committed to continuing to discover, develop and advance disruptive technologies that have the potential to revolutionize cell therapy and its promise to improve the lives of patients with solid tumors.
+Added: For example, our new NR4A3 gene knockout and Stim‑R reprogramming technologies are designed to further improve the potency and durability of T cells.
+Added: These novel technologies are being utilized in our new CAR T-cell product candidate, LYL119, in addition to c-Jun overexpression and Epi‑R, with the goal of creating even greater benefit to patients with cancer.
+Added: • Maintain proprietary state‑of‑the‑art infrastructure and capabilities to control all aspects of cell product manufacturing — We have and will continue to invest in manufacturing with the goal to reliably produce the highest quality cell therapy products for patients.
+Added: This is achieved through implementing consistent processes and mitigating risks, including risks arising from the challenges of managing production, supply chain, patient specimen chain of custody and quality.
+Added: We have built and operate a wholly-owned manufacturing facility, LyFE™, which is a multi-product manufacturing center that can produce plasmid, lentiviral vector and cell products.
+Added: LyFE has been commissioned and qualified in compliance with U.S.
+Added: Food and Drug Administration’s Current Good Manufacturing Practices (cGMP) and is manufacturing cell product for our clinical trials.
+Added: We expect maintaining our own manufacturing facility to not only enable us to implement consistent processes and manage risk, but also to protect proprietary aspects of our reprogramming technologies, support seamless collaboration across research, development and manufacturing, access more detailed and timely product characterization information and rapidly incorporate new innovations.
+Added: Our technology infrastructure enables real‑time monitoring of our manufacturing process and the ability to incorporate insights into our research, manufacturing and clinical development efforts.
+Added: • Generate, secure and defend intellectual property on our differentiated technology platforms and product candidates — We have developed and secured intellectual property, including know-how, through our internal research efforts, licensing agreements and collaborations.
+Added: We rigorously analyze, file and protect our intellectual property in an ongoing manner.
+Added: Our Reprogramming Technologies
+Added: Cell therapy has demonstrated profound results in some patients suffering from hematologic malignancies, but solid tumors are more complex and have evolved multiple mechanisms to evade and ultimately resist clearance by the immune system.
+Added: This has limited the use of cell therapy in solid tumors.
+Added: Based on clinical data and other scientific evidence, we believe T‑cell exhaustion and lack of durable stemness , which include the ability of T cells to persist and self-renew to drive durable tumor cytotoxicity, are two apical barriers limiting the efficacy of cell therapy in solid tumors.
+Added: We have developed proprietary, stackable genetic and epigenetic reprogramming technologies to address these two major barriers.
+Added: Our reprogramming technologies are designed to generate potent T cells with durable cytotoxic function, irrespective of target and irrespective of whether they are delivered as CAR, TIL or TCR therapies.
+Added: We have generated T cells that have demonstrated in nonclinical studies the ability to sustain cancer cell killing in murine models of solid tumors and an increased ability to maintain stemness to drive more durable tumor cytotoxicity.
+Added: T‑cell exhaustion describes a dysfunctional cellular state characterized by increased expression of cell surface markers such as PD-1, TIM-3, and LAG-3, and importantly the functional inability to respond to antigen and elimination of target cells.
+Added: A clinical study previously conducted by one of our founders, Stanley Riddell, M.D., Professor in Immunology, Burke O’Reilly Family Endowed Chair in Immunotherapy, Fred Hutchinson Cancer Center, illustrated the different fates of CAR T cells in solid tumors versus hematologic malignancies and identified T-cell exhaustion as a key barrier to successful cell therapy in the solid tumor microenvironment.
+Added: In this study, conceptually depicted in Figure 1, autologous ROR1-targeted CAR T cells infused into patients with chronic lymphocytic leukemia underwent rapid expansion and retained T‑cell effector functions, leading to tumor cell clearance and clinical responses.
+Added: However, when CAR T cells generated with the same method are infused into patients with solid tumor such as triple-negative breast cancer (TNBC) or non-small cell lung cancer (NSCLC), these T cells often failed to expand adequately, rapidly developed
+Added: cell surface markers of T‑cell exhaustion and adopted a dysfunctional state.
+Added: The outcome of these studies clearly demonstrated that T‑cell exhaustion is a major barrier to successful cell therapy in solid tumors.
+Added: Solid tumors drive T cells down a path to exhaustion.
+Added: Durable stemness describes the quality of a population of T cells to persist through self-renewal, as well as generate differentiated effector cell progenies to provide durable tumor cytotoxicity.
+Added: Emerging research has shown that effective immunotherapy requires T‑cell populations with stem‑like characteristics to produce clinical responses, where the presence of stem-like T cells correlates with solid tumor responses to cancer immunotherapy in the setting of solid tumors, including TIL and immune checkpoint blockade therapy (Sade-Feldman et al., Cell , Nov.
+Added: Krishna et al., Science , Dec.
+Added: Genetic reprogramming technologies :
+Added: Our two proprietary ex vivo genetic reprogramming technologies are c‑Jun overexpression and NR4A3 gene knockout.
+Added: c-Jun and NR4A3 are involved in the regulation of the activator protein 1 (AP-1) transcription factor pathway, which plays a key role in T‑cell effector function.
+Added: These complementary reprogramming technologies function within this critical biological pathway to endow resistance to T‑cell exhaustion.
+Added: Overexpression of c-Jun is based on the work of Lyell co-founder, Crystal Mackall, M.D., the Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine at Stanford University and Founding Director of the Stanford Center for Cancer Cell Therapy.
+Added: Mackall discovered that exhausted T cells have an imbalance in the AP‑1 family of transcription factors, and that correcting for this imbalance by overexpression of c-Jun enables T cells to resist exhaustion, infiltrate solid tumors and maintain their functionality and potency.
+Added: This work was fully described in a Nature publication in 2019 (Lynn et al., Nature , Dec.
+Added: Our second genetic reprogramming technology, NR4A3 gene knockout, builds on the approach of reprogramming of the AP-1 transcription factor pathway to delay exhaustion and improve antitumor function.
+Added: We and others have previously observed that the NR4A family of transcription factors is upregulated in exhausted T cells and may contribute to T‑cell exhaustion in part by restricting the activity of AP-1.
+Added: We hypothesize that disruption of NR4A3 expression, along with c-Jun overexpression, can further unleash the potential for maximal c-Jun activity and endow greater functional resistance to exhaustion.
+Added: Our nonclinical data suggest the combination of these two technologies, NR4A3 gene knockout and c-Jun overexpression, can act in a complementary fashion and have the potential to further improve the potency and durability of our CAR therapy.
+Added: Epigenetic reprogramming technologies:
+Added: Our two proprietary ex vivo epigenetic reprogramming technologies are Epi‑R and Stim‑R.
+Added: These novel manufacturing technologies generate product candidates with more stem-like cells and with greater potency during ex vivo T‑cell expansion.
+Added: Epi‑R is our proprietary ex vivo epigenetic reprogramming technology that intentionally and reproducibly generates a population of T cells with durable stemness.
+Added: T cells with properties of durable stemness have an increased ability to self-renew and persist to drive durable tumor cytotoxicity.
+Added: This technology is built upon the groundbreaking science conducted at the National Cancer Institute (NCI), where it was demonstrated that products with more stem-like and functional T cells can be achieved by altering the metabolic state of the cells during expansion
+Added: (Vodnala et al., Science , Mar.
+Added: Key NCI scientists conducting this research subsequently joined Lyell where they advanced this research substantially to create the Epi‑R manufacturing protocol, which intentionally produces T‑cell populations with desirable stem-like properties that can be measured both phenotypically and functionally.
+Added: This novel Epi‑R protocol includes proprietary media, well-defined cell activation and expansion processes, as well as customized cytokine combinations.
+Added: Lyell’s Epi‑R protocol enables manufacturing of T‑cell therapy product candidates that are highly potent against cancer cells but also retain characteristics of stemness, which have been clinically associated with effective antitumor immunotherapies (Figure 2).
+Added: Furthermore, relating specifically to TIL, the application of Epi‑R has generated T‑cell populations that exhibit a high degree of polyclonality, i.e., the retention of a broad repertoire of TCR clonotypes that may react to a broader set of tumor antigens, thus improving the potential of our TIL therapy to counteract the heterogeneous nature of solid tumors.
+Added: Additionally, we are able to reliably and reproducibly manufacture our TIL products from a variety of solid tumors, including those that have been traditionally hard to manufacture such as from checkpoint refractory malignant melanoma, NSCLC and colorectal cancer (CRC).
+Added: Lyell’s proprietary Epi-R protocol produces T-cell populations with long-lived stem-like characteristics.
+Added: This protocol is used in both our LYL797 CAR T cell product candidate and in our LYL845 TIL product candidate as shown below.
+Added: Our second epigenetic reprogramming technology, Stim‑R, is a proprietary synthetic cell mimetic that mediates more precise and natural T‑cell activation in the manufacturing process.
+Added: Current manufacturing platforms typically utilize antibody-conjugated beads that were developed decades ago for expanding T cells.
+Added: This standard approach does not provide precise control over the strength or duration of the signaling that drives T‑cell expansion ex vivo .
+Added: Our Stim‑R platform optimizes signaling parameters during T‑cell activation using degradable lipid-coated silica rods that can be functionalized to regulate cell activation more closely mimicking natural T‑cell stimulation.
+Added: This technology allows for greater control over the duration, intensity and type of signals delivered during cell expansion and manufacturing, resulting in the generation of more potent T‑cell products.
+Added: T‑cell rejuvenation technologies:
We and others have documented the impact of aging on T‑cell function, which begins to decline after puberty, and at an increasingly accelerated rate after age 65.
−Removed: Morbidity and mortality from cancer also increases with age.
−Removed: We are therefore working to advance a third platform technology that focuses on rejuvenation of antitumor T cells.
−Removed: The most transformative examples of cell reprogramming have been demonstrated by Shinya Yamanaka, who proved through his Nobel Prize-winning work the ability to reprogram and dedifferentiate somatic cells into induced pluripotent stem cells utilizing four transcription factors (OCT3/4, SOX2, KLF4 and c-MYC;
−Removed: or OSKM), termed the Yamanaka factors.
−Removed: These factors regulate the developmental signaling network necessary for embryonic cell pluripotency.
−Removed: These iPSCs are remarkable in two ways:
−Removed: they are fully de-differentiated and they are rejuvenated to age zero, the age of cells immediately post-fertilization.
−Removed: Recently, numerous labs have made a leap in cellular reprogramming, called partial reprogramming.
−Removed: By carefully controlling cell exposure to OSKM, scientists have been able to retain the functionality of cells while avoiding the impacts of aging.
−Removed: Rejuvenation can be measured by the reacquisition of youthful properties like enhanced stem cell proliferation and by newly discovered molecular clocks, which measure the intrinsic cellular epigenetic changes associated with aging.
−Removed: These intrinsic ‘clocks’ can be measured by DNA methylation patterns.
−Removed: We have early data for the first time with T cells illustrating the ability to “turn back” the epigenetic clock in a process called cell rejuvenation, without changing the cell’s identity as would occur in de-differentiation.
−Removed: This cell rejuvenation process utilizes transient expression of OSKM, and/or other reprogramming factors.
−Removed: Our data illustrates that when we express the reprogramming factors in a T-cell population for a prolonged amount of time, T cells lose their identity and start to acquire markers associated with mesenchymal and embryonic stem cells.
−Removed: During this process, cells acquire the expression of stage-specific embryonic antigen-4 (SSEA-4) and begin to attach to the cell culture substrate.
−Removed: We are developing a method to revert the initial changes caused by reprogramming to maintain T-cell identity while reducing the epigenetic age of the cells.
+Added: Morbidity and mortality from cancer also increase with age.
+Added: Thus, we are working to advance another novel reprogramming technology that focuses on rejuvenation of antitumor T cells.
+Added: We are developing a method to maintain T‑cell identity while reducing the epigenetic age of the cells.
This technology is currently in the research stage.
−Removed: Targeting Cancer Cells:
−Removed: ACT Modalities and Their Limited Efficacy Against Solid Tumors to Date
−Removed: Most of the activity in ACT for cancer has focused on ways to provide the requisite specificity of the T cells to cancer:
−Removed: identifying appropriate tumor-specific targets, evaluating their frequency on cancers versus healthy tissues and evaluating the best ways to traffic immune cells to them and attack the cancer.
−Removed: There are three main modalities to achieve target specificity in ACT today:
−Removed: CARs, TCRs and TILs, and, unfortunately, with very few exceptions, they have not meaningfully improved clinical outcomes in patients suffering from solid tumor cancers.
−Removed: Chimeric antigen receptors are artificial cell surface receptors that are genetically engineered into T cells and comprise a chimeric protein that contains an extracellular binding domain specific to a surface molecule on tumor cells linked to an intracellular activation domain that turns the T cells “on” to kill target tumor cells when the antibody portion binds to the tumor cell target.
−Removed: CAR-based ACT has shown efficacy in some cancers, including durable complete remissions.
−Removed: The greatest clinical benefit has been demonstrated in B cell malignancies where the adoptive transfer of autologous T cells engineered with a CAR targeting CD19 has been shown to induce complete remission in 40 – 90% of patients resulting in the approval of five CD19 CAR T cell therapies.
−Removed: However, CAR T cells have thus far demonstrated limited efficacy in solid tumors.
−Removed: Furthermore, the identification of targets with sufficient differential expression between tumor and normal tissues has limited the broader development of CAR T-cell therapies in solid tumors.
−Removed: Tumor infiltrating lymphocytes are T cells that have entered and reside within the tumor.
−Removed: They are polyclonal in nature, i.e., they are able to recognize multiple tumor neoantigens.
−Removed: A TIL-based ACT approach isolates and expands TILs from tumor masses and reinfuses the expanded cells into the patient.
−Removed: The polyclonality of TILs is a major advantage to address the heterogeneity and antigen loss challenges of solid tumors.
−Removed: The risk of normal tissue toxicity is mitigated because the targets for these T cells are directed against neoantigens that arise from the accumulation of mutations in genes unique to the cancer.
−Removed: While a handful of clinical trials, primarily academic, have demonstrated TILs may generate durable responses in certain tumor types such as melanoma, they have shown limited efficacy in patients with other prevalent solid tumor cancers.
−Removed: Regardless, most patients treated with TIL therapy do not respond to treatment, and most patients who do respond eventually relapse.
−Removed: T cell receptors are directed against fragments of intracellular proteins that are presented by the human leukocyte antigen (HLA) complex on the surface of target cells.
−Removed: T cells can be engineered with a cloned TCR that mono-specifically directs the T cell to recognize a neoantigen that arises from the tumor’s mutated proteins or to recognize an aberrant or overexpressed self-protein.
−Removed: TCRs specific for neoantigens have the advantage of being tumor specific, meaning that normal tissues do not express these neoantigens thereby reducing the risk of normal tissue toxicity.
−Removed: TCR-based ACT has been utilized clinically to treat a limited number of cancers.
−Removed: Although there has been some clinical success in treating cancer patients with TCR-engineered T cell products, most patients infused with these cells do not experience durable, complete responses to therapy.
−Removed: We are advancing a product pipeline of promising living cell product candidates across multiple ACT modalities that incorporate our Gen-R and Epi-R technology platforms.
−Removed: Each of our programs provide opportunities to expand into additional indications beyond the patient populations we are initially targeting.
−Removed: Our lead product candidates are summarized in the table below:
−Removed: Our ROR1 Targeted CAR T-Cell Product Candidate for the Treatment of Multiple Solid Tumor Indications
−Removed: We are applying our Gen-R and Epi-R technology platforms to our lead CAR T-cell product candidate, LYL797, which is expected to be an IV administered CAR T-cell product targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1).
−Removed: LYL797 contains a CAR with a 4-1BB/CD3z co-stimulatory domain, an optimized spacer and a single-chain variable fragment (scFy) derived from an R12 rabbit monoclonal antibody that recognizes and binds with high specificity to human ROR1.
−Removed: LYL797 also incorporates Gen-R and a proprietary optimized version of human EGFR (EGFR opt ) used
−Removed: for tracking of the CAR T cells in the peripheral blood.
+Added: We have generated data illustrating the ability to “turn back” the epigenetic clock in a process called cellular rejuvenation, without changing the T‑cell’s identity as would occur in the setting of induced pluripotent stem cell-derived T cells.
+Added: Our Clinical Programs
+Added: We are advancing a diverse pipeline of CAR T cell and TIL product candidates that incorporate our stackable reprogramming technologies designed to generate potent T cells with durable cytotoxic function, irrespective of target and irrespective of whether they are delivered as CAR T, TIL or TCR T therapies.
+Added: Each of our programs currently target
+Added: cancers with large unmet need and provide opportunity to expand into additional indications.
+Added: We have deployed our technologies in our pipeline in the following manner to provide rapid clinical proof-of-concept (Table 1):
+Added: • LYL797 incorporates our c-Jun and Epi‑R technologies and is undergoing evaluation in a Phase 1 clinical trial enrolling patients with relapsed/refractory TNBC or NSCLC.
+Added: • LYL119 incorporates our c-Jun, NR4A3, Epi‑R and Stim‑R technologies and is currently in preclinical development.
+Added: • LYL845 incorporates our Epi‑R technology and is undergoing evaluation in a Phase 1 clinical trial including patients with advanced melanoma, relapsed/refractory NSCLC or CRC.
+Added: A genetically and epigenetically reprogrammed ROR1 CAR T‑cell product candidate designed for differentiated potency and durability targeting multiple solid tumor indications.
+Added: We are applying our c-Jun and Epi‑R technologies to our lead CAR T‑cell product candidate, LYL797, which is expected to be an intravenously‑administered CAR T‑cell product targeting the receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein.
+Added: ROR1 is a fetal protein expressed during embryogenesis and is believed to be important in cell migration, polarity and survival.
+Added: It is expressed in several cancer types, including TNBC, NSCLC, ovarian cancer and chronic lymphocytic leukemia, and is generally associated with a poor prognosis.
+Added: LYL797 (Figure 3) contains a CAR with a 4-1BB/CD3ζ intracellular domain, a transmembrane domain, an optimized spacer domain and a single-chain variable fragment (scFv) derived from an R12 rabbit monoclonal antibody that recognizes and binds with high specificity to human ROR1.
+Added: LYL797 also incorporates c-Jun and a proprietary optimized truncated version of human EGFR (EGFR opt ) used for tracking the CAR T cells in the peripheral blood post treatment and can also be used as a safety measure with the administration of cetuximab, if needed.
LYL797 is manufactured utilizing our proprietary Epi‑R technology.
−Removed: We are initially developing LYL797 for the treatment of ROR1 + triple-negative breast cancer (TNBC) and NSCLC.
−Removed: ROR1 expression is associated with poor prognosis.
−Removed: Significant subsets of patients with common cancers express ROR1, including TNBC (~60%) and NSCLC (~40%), two of the highest ROR1 expressing indications.
−Removed: If successful, we anticipate expanding into other ROR1 + cancers with a lower incidence of ROR1 expression, including potentially HR + breast cancer, ovarian and other solid tumors.
−Removed: In December 2021 we announced FDA clearance of our Investigational New Drug (IND) application for LYL797.
−Removed: With the opening of a clinical trial site in March 2022, we have initiated our Phase 1 clinical trial designed to evaluate the safety and anti-tumor activity of LYL797 in patients with ROR1+ TNBC or NSCLC.
−Removed: We plan to share initial data from the trial when we have a meaningful number of patients and an indication of clinical effect, which we expect to occur in 2023.
−Removed: Rationale for ROR1
−Removed: We have selected ROR1 as our initial target because it is highly expressed in certain solid tumor types and clinical data has been generated using ROR1 CAR T cells that demonstrate exhaustion and thus serve as a good vehicle to test our Gen-R technology.
−Removed: Data from multiple third-party clinical trials of ROR1 targeted therapies in hematologic and solid tumor cancers suggest that targeting ROR1 was well tolerated at active dose levels with no on-target, off-tumor toxicity observed despite ROR1 expression in a number of normal tissues.
−Removed: Target Indications
−Removed: Patients with solid tumors, including TNBC, NSCLC, ovarian cancer or HR+ breast cancer, often face a poor prognosis and low rates of long-term survival.
−Removed: Although patients may benefit initially from radiation therapy, chemotherapy, surgery and more advanced alternatives such as ICB, immunotherapies or targeted therapies, most patients eventually relapse.
−Removed: After becoming resistant to initial lines of therapy, patients are limited to palliative care, experimental therapies in clinical trials or chemotherapy regimens that are often highly toxic and largely ineffective.
−Removed: Patients are further challenged by high rates of late-stage diagnosis, when tumors have metastasized.
−Removed: Despite recent advances in therapeutic development, for most patients diagnosed with solid tumors, a significant unmet medical need exists and long-term survival rates remain low.
−Removed: ROR1 has been reported to be expressed in many other solid tumors beyond breast, lung and ovarian, including prostate, stomach, endometrial and pancreatic, providing multiple opportunities for indication expansion.
−Removed: Many of these indications are unaddressed or under-addressed with currently approved therapeutics;
−Removed: further, patients with ROR1 expression tend to experience poorer outcomes on these treatments and poorer prognosis.
−Removed: These indications represent a significant unmet need and a substantial opportunity.
−Removed: Preclinical Data
−Removed: We have conducted a number of preclinical in vitro and in vivo experiments of LYL797 against ROR1 + solid tumors.
−Removed: These studies have demonstrated that LYL797, which incorporates Gen-R and Epi-R, maintains stem-like phenotypes and can resist exhaustion while inhibiting tumor growth in models of tumor cells expressing ROR1.
−Removed: Gen-R and Epi-R, in combination with ROR1-targeted CAR T cells, have been evaluated preclinically in in vitro and in vivo models.
−Removed: In the studies depicted below, we exposed ROR1 + Gen-R CAR T cells (ROR-1 + Gen-R) and other ROR1 CAR T cells without Gen-R (the Control) to chronic stimulation by repeated exposure to ROR1 + NSCLC tumor cells, with fresh tumor cells introduced every two days.
−Removed: After seven days of chronic stimulation, we assessed cytolytic ability and cytokine release from the T cells.
−Removed: In all donors, the ROR1 + Gen-R T cells demonstrated improved maintenance of cytotoxicity against ROR1 + tumor cells while producing increased levels of cytotoxic cytokines, such as IFNɣ.
−Removed: This suggests persistence of activity and thus lack of exhaustion in ROR1 + Gen-R versus the Control T cells (Figure 2).
−Removed: In vitro experiment demonstrated superior ability of ROR1 + Gen-R T cells to resist T cell exhaustion.
−Removed: In this experiment we repeatedly stimulated T cells from three different donors with ROR1 + lung cancer cells (cell lines A549 and H1975).
−Removed: After four rounds of stimulation over seven days, we tracked tumor killing kinetics by measuring reduction of tumor cells over time.
−Removed: Shown here are results comparing ROR1 + Gen-R T cells (Gen-R, in green), to the Control T cells (the Control, in red), and to T cells without a ROR1 CAR (Mock, in black).
−Removed: In both the left and middle columns (against two lung tumor cancer cell lines—A549 and H1795), the green line is below the red and black lines, indicating that more
−Removed: tumor killing occurred with ROR1 + Gen-R T cells.
−Removed: In addition, as shown in the right panel, at 24 hours after the fourth round of stimulation, the ROR1 + Gen-R T cells produced more of the killing-associated cytokines IFN ɣ and IL-2.
−Removed: In in vivo experiments the ROR1 + Gen-R T cells achieved superior tumor growth inhibition relative to the Control in murine models of ROR1 + lung cancer.
−Removed: Importantly, as shown in the figure below, the Control T cells were administered at a sub-therapeutic dose and did not result in complete tumor eradication, while the ROR1 + Gen-R T cells, when administered intravenously at the same dose, demonstrated near complete inhibition of tumor growth.
−Removed: In vivo study demonstrated inhibition of tumor using ROR1 + Gen-R T cells.
−Removed: In this study, tumor cells from a human ROR1 + lung cancer cell line were implanted into NSG mice.
−Removed: When tumors reached 100mm3, the mice were intravenously injected with ROR1 + Gen-R T cells (Gen-R, in green), the Control T cells (the Control, in red) or T cells without a ROR1 CAR (Mock, in black).
−Removed: The left panel shows results from tracking tumor growth.
−Removed: The black and red lines, Mock and the Control, go up over time, while the green line at the bottom, ROR1 + Gen-R, is nearly flat.
−Removed: At the end of the study (60 days post T cell injection) all of the mice treated with ROR1 + Gen-R T cells were alive and had no meaningful change in body weight.
−Removed: Additional in vitro experiments demonstrate synergistic improvement of CAR T cells by implementing Epi-R in addition to Gen-R (LYL797).
−Removed: When repeatedly exposed to ROR1 + NSCLC tumor cells, with fresh tumor cells introduced every three days, LYL797 showed increases in cytotoxicity, proliferation and secretion of cytokines compared to ROR1 + Gen-R, across all donors.
−Removed: In vitro , application of Epi-R technology resulted in better functional activity of ROR1 + Gen-R T cells.
−Removed: LYL797 T cells (LYL797, in green) and ROR1 + Gen-R T cells (the Control, in red) were repeatedly stimulated every three days with tumor cells from a ROR1 + lung cancer cell line (A549).
−Removed: During the final stimulation, we measured the percent
−Removed: enhancement in tumor cell clearance (cytotoxicity) or the fold increase in proliferation and 24 hour cytokine production of LYL797 T cells compared to ROR1 + Gen-R T cells.
−Removed: Data from four donors is shown.
−Removed: LYL797 T cells showed increases in cytotoxicity, proliferation and secretion of cytokines compared to ROR1 + Gen-R T cells.
−Removed: Our Phase 1 Trial
−Removed: Our Phase 1 clinical trial is designed to evaluate the safety and anti-tumor activity of LYL797 in patients with ROR1+ TNBC or NSCLC.
−Removed: The trial is designed as an open label, dose escalation and expansion trial in patients with relapsed/refractory TNBC or NSCLC who have failed at least two lines of therapy.
−Removed: Once a dose is identified during dose escalation in TNBC, 15 patients with TNBC and 15 patients with NSCLC are expected to be enrolled at the recommended dose.
−Removed: The primary endpoint is safety and tolerability of LYL797.
−Removed: Secondary endpoints include clinical activity based on the evaluation of antitumor activity as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and characterization of the pharmacokinetic profile of LYL797.
+Added: LYL797 construct.
+Added: Phase 1 Clinical Trial
+Added: Our Phase 1 clinical trial (NCT05274451) is designed to evaluate the safety and antitumor activity of LYL797 in patients with ROR1-positive TNBC or NSCLC.
+Added: The trial is designed as an open label, dose escalation and expansion trial in patients with relapsed/refractory TNBC who have failed at least two lines of therapy and patients with relapsed/refractory NSCLC who have failed at least one line of therapy.
+Added: Per protocol, dose expansion at the recommended dose identified during dose escalation is expected to occur in at least 15 patients with TNBC and 15 patients with NSCLC.
+Added: The primary outcome measure assesses the safety and tolerability of LYL797.
+Added: Patients will be monitored for cytokine release syndrome (CRS) and immune effector cell‑associated neurotoxicity syndrome, as well as tissue-specific toxicities in ROR1-expressing organs.
+Added: Secondary outcome measures include clinical activity based on the evaluation of antitumor activity as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and characterization of the pharmacokinetic profile of LYL797.
Exploratory biomarkers of T‑cell function – exhaustion and stemness – will also be assessed.
−Removed: Patients will be monitored for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), as well as tissue specific toxicities in ROR1-expressing organs.
−Removed: As a safety measure, we have included our EGFRopt safety switch in our construct.
−Removed: Thus, cetuximab may be used as a safety intervention, if indicated.
−Removed: LYL797 Phase 1 trial design
−Removed: Our TIL Product Candidate Targeting Multiple Solid Tumor Indications
−Removed: We are applying our Epi-R technology to develop our product candidate, LYL845, which is expected to be an IV administered autologous TIL therapy in multiple solid tumors.
−Removed: TILs have previously shown clinical benefit in patients with melanoma and other solid tumors with high mutation burdens.
−Removed: Published data from third-party TIL trials show that treating metastatic melanoma patients with TILs results in a 50% or greater response rate, with up to half of those responses complete and durable.
−Removed: TIL therapy has also been shown to result in responses in patients with advanced cervical, lung, breast and gastrointestinal cancers, although response rates in these tumor histologies are much lower than that observed in the melanoma setting.
−Removed: TILs target a variety of tumor antigens, but it is thought that the clinical efficacy of TILs is largely driven by specific recognition of mutated tumor neoantigens.
−Removed: Further, broad TIL efficacy has been limited by poor enrichment of tumor-reactive T cells, poor quality and growth potential of expanded T cells, and failure to maintain polyclonality of TILs during production.
−Removed: We have designed LYL845 to incorporate our Epi-R technology that has shown promising improvements in enhancing T cell potency, antitumor activity and increased polyclonality of TILs.
−Removed: We expect to submit an IND to the FDA in the second half of 2022 for LYL845.
+Added: We plan to share initial data from the trial when we have a meaningful number of patients and an indication of clinical effect, which we expect to occur in the first half of 2024.
Target Indications
−Removed: We are initially targeting melanoma, and also plan to include patients with other solid tumors, potentially including NSCLC, colon, head and neck, cervical, breast and pancreatic, which all have a high unmet need based on the current treatment landscapes.
−Removed: Although patients may benefit initially from radiation therapy, chemotherapy, surgery and more advanced alternatives such as checkpoint therapies, immunotherapies or targeted therapies, most patients with these types of cancers eventually relapse.
−Removed: After becoming resistant to initial lines of therapy, patients are limited to palliative care, experimental therapies in clinical trials or chemotherapy regimens that are often highly toxic and largely ineffective.
−Removed: Overall, despite recent advances in therapeutic development, for most patients diagnosed with solid tumors, a significant unmet medical need exists and long-term survival rates remain low.
−Removed: Our Preclinical Data
−Removed: We have conducted a number of preclinical in vitro and in vivo studies supporting the development of LYL845 that suggest TILs enhanced with Epi-R maintain properties of durable stemness, including superior expansion and tumor eradication in both animal studies and autologous experiments, as well as polyclonality.
−Removed: Our Epi-R T cell populations have demonstrated superior expansion in in vivo mouse models.
−Removed: We measured the number of T cells in the mice at various time points and observed as many as 50-fold more T cells in mice injected with Epi-R T cells, as compared to mice injected with T cells expanded in Standard Preparation.
−Removed: We also observed, after 40 days, tumor eradication in 8 out of 9 mice treated with Epi-R T cells versus eradication in only 4 out of 10 mice treated with Standard Preparation.
−Removed: Standard Preparation, as used throughout this document refers to a typical cell preparation that includes TransAct beads, OpTmizer media and IL-2, IL-7 and IL-15 cytokines.
−Removed: Epi-R T cells had improved expansion in vivo as shown in the left panel and had greatly improved antitumor function in mouse models of cancer, as shown on the right.
−Removed: Epi-R T cells eliminated tumors in 8 out of 9 treated mice (note overlapping blue lines in Epi-R tumor killing along the x-axis), compared to 4 out of 10 mice treated with Standard Preparation T cells.
−Removed: In in vitro studies we evaluated Epi-R expanded TIL recognition of autologous melanoma cancer cells.
−Removed: Utilizing a patient melanoma tumor excision, we both extracted and expanded TIL from that specimen in either Standard Preparation or Epi-R, and created a cancer cell line in order to evaluate whether the expanded TIL from that tumor recognize and react to that patient’s own cancer cells.
−Removed: We were able to demonstrate that Epi-R TIL do exhibit enhanced activation, the response is mediated by activated killer CD8 + cells, and they have significantly enhanced tumor cell killing capacity when compared to Standard Preparation.
−Removed: The higher secretion of IL-2, the critical T cell growth factor, is notable.
−Removed: Epi-R TIL had enhanced recognition and activity against autologous melanoma tumor cell line.
−Removed: Asterisks denote significant p-values between groups.
−Removed: The red bars in the graph on the left show that Epi-R T cells from TIL secreted increased levels of IFN ɣ and IL-2 cytokines as compared to Standard Preparation after co-culture with autologous melanoma tumor cells, indicating greater activation and cytotoxicity potential.
−Removed: As a control, when TIL alone were measured without the presence of autologous tumor cells, they did not activate and did not secrete the cytokines.
−Removed: In the bar chart on the right, we demonstrate that production of IFN ɣ secretion dropped significantly when target cells were coated with an antibody to HLA Class I, indicating that the tumor cell recognition was mediated by CD8 + T cells.
−Removed: These cells were also shown to be more effective at tumor cell killing.
−Removed: In the graph below on the left, we show that Epi-R TIL killed autologous tumor cells at a rate of approximately 50% whereas those TIL grown in Standard Preparation killed at a rate of approximately 20%.
−Removed: We also observed, in an experiment to titrate different levels of Epi-R TIL against tumor cells, that a 4:1 effector T cell to tumor cell ratio resulted in complete tumor eradication.
−Removed: Epi-R TIL had improved ability to kill autologous tumor cells.
−Removed: Standard and Epi-R TIL were co-cultured with autologous melanoma tumor cells and their ability to kill tumor was measured after 24 hours (left panel).
−Removed: Altering the ratio of TIL:tumor cells (E/T ratio) can impact TIL ability to kill tumor.
−Removed: Epi-R TIL exhibited increased tumor killing at all E/T ratios, and at a 4:1 ratio Epi-R TIL successfully killed all tumor cells.
−Removed: Epi-R has also demonstrated the ability to preserve the polyclonality of TIL preparations, one of the key advantages of this ACT modality.
−Removed: Quantitatively, polyclonality can be measured by the Simpson Clonality index.
−Removed: The Simpson Clonality Index is a quantitative tool that reflects diversity within a dataset;
−Removed: a low number represents high diversity, while a high number represents low diversity.
−Removed: An index value of 1 would represent a monoclonal population.
−Removed: The Simpson Clonality Index of TIL in the tumor is very low, demonstrating high clonal diversity of the original TILs.
−Removed: In Standard Preparation, the majority of clones giving rise to the desired clonal diversity are lost upon stimulation and expansion as shown by the high Simpson Clonality Index.
−Removed: In contrast, most of the original tumor clonal diversity is maintained in TIL expanded with Epi-R, as shown with a low index score.
−Removed: It is known that T cells migrating through tissues experience arrested migration upon recognition of their target tumor antigen, resulting in their activation and expansion, which is followed by their exhaustion.
−Removed: We quantified the TCRs
−Removed: from TILs and ranked them by the frequency of the clonotypes found.
−Removed: We compared the frequencies of individual TCRs after expansion in Standard Preparation or Epi-R conditions.
−Removed: On the right in the graph below, we show that Epi-R preserved dominant TIL clonotypes found amplified in the tumor;
−Removed: 57% of the TCR Vß sequences corresponded to the top 50 TCRs represented in the original TIL.
−Removed: By sharp contrast, only 2% of the TCR clonotypes expanded in Standard Preparation were represented in the top 50 TCRs found in TIL.
−Removed: Epi-R TIL exhibited increased T cell polyclonality in multiple tumor types as measured by the Simpson Clonality Index (a measure of polyclonality, with high Simpson values indicating low polyclonality).
−Removed: Epi-R TIL exhibited a low Simpson Clonality Index that reflects increased diversity of T-cell TCR repertoire.
−Removed: Epi-R TIL also exhibited retention of original dominant T cell clones.
−Removed: TCR sequencing was performed on Standard Preparation and Epi-R TIL.
−Removed: The relative abundance of TCRs that were observed in starting tumor T cell population was compared with Standard Preparation and Epi-R expanded TILs.
−Removed: Epi-R TILs retained greater proportions of starting TCR repertoire after expansion.
−Removed: Of the top 50 dominant tumor TCRs, 57% are represented in the Epi-R expanded product vs 2% in the Standard Preparation.
−Removed: Our Planned IND Submission and Phase 1 Trial
−Removed: We plan to submit an IND for LYL845 to the FDA in the second half of 2022.
−Removed: We are planning our Phase 1 clinical trial as a dose escalation and expansion study of LYL845 in multiple solid tumor indications.
−Removed: The primary endpoint of our Phase 1 trial is expected to be the safety and tolerability of LYL854.
−Removed: We are initially targeting melanoma, and also plan to include patients with other solid tumors, potentially including NSCLC, colon, head and neck, cervical, breast and pancreatic.
−Removed: We plan to monitor patients for CRS and auto-immunity.
−Removed: We plan to monitor clinical efficacy based on antitumor activity as evaluated by RECIST criteria and characterization of the pharmacokinetic profile of LYL845.
−Removed: LYL845 Phase 1 Trial
−Removed: NY-ESO-1 TCR:
−Removed: Our Lead Program with GSK
−Removed: Our collaborator, GSK, is developing an NY-ESO-1 TCR T cell product candidate, NY-ESO-1 c259 , currently in pivotal development.
−Removed: Our collaboration explores the potential enhancement of that product candidate though the application of our Gen-R and Epi-R platform technologies, with a goal to improve the depth and durability of clinical responses.
−Removed: While we are currently evaluating Gen-R and Epi-R in separate preclinical and clinical programs, together these programs could represent a single future product opportunity for GSK utilizing one or both of our platform technologies.
−Removed: We are responsible for preclinical activities for both programs and GSK is responsible for executing the clinical trials and commercialization, if approved, of a future product.
−Removed: We anticipate that initial clinical trials will be conducted in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS).
−Removed: Positive results from the initial patient cohorts could support additional combinations and expansions into additional NY-ESO-1+ tumor types, including those with lower levels of target antigen, such as NSCLC.
−Removed: In January 2022, we announced FDA clearance of our IND for LYL132 (NY-ESO-1 + Epi-R).
−Removed: The planned Phase 1 trial is designed to assess LYL132 in patients with NY-ESO-1+ advanced SS or myxoid/round cell liposarcoma (MRCLS).
−Removed: Lyell holds the product IND and will manufacture LYL132 in its LyFE™ Manufacturing Center and GSK will conduct the Phase 1 trial.
−Removed: GSK has communicated to us that due to updated manufacturing timing, the IND submission to the FDA for NY‑ESO-1 + Gen-R is likely to be in late 2022/early 2023.
−Removed: Rationale for NY-ESO-1
−Removed: NY-ESO-1 is a known cancer testis antigen target that has been previously validated in clinical trials.
−Removed: It is expressed in a wide range of solid tumors, including at high levels in some indications;
−Removed: however, it has low or no expression in healthy adult tissues.
−Removed: It is expressed in approximately 80% of SS, neuroblastomas and MRCLS, more than 40% of melanomas and ovarian cancers, and between 20% to 40% of multiple other cancers including bladder, esophageal, hepatocellular, head and neck, ovarian, prostate, myeloma, breast and NSCLC.
−Removed: Patients who could benefit from treatment with NY-ESO-1-targeted therapies are further limited because the NY-ESO-1-antigen is HLA A2-restricted and the therapeutic T cells recognize only certain protein sequences.
+Added: We are initially developing LYL797 for the treatment of ROR1-positive TNBC and NSCLC.
+Added: Significant subsets of patients with common cancers express ROR1, including TNBC (~60%) and NSCLC (~40%), two of the highest ROR1‑expressing solid tumor indications.
+Added: If successful, we may expand into other ROR1-positive cancers with a lower incidence of ROR1 expression, including potentially hormone-receptor positive breast cancer, ovarian and other solid tumors.
+Added: Breast cancer is the second most common cancer in American women.
+Added: Currently, the average risk for a woman in the United States to develop breast cancer is approximately 13%.
+Added: Breast cancers that demonstrate the absence of estrogen receptor and progesterone receptor and no overexpression of HER2 are referred to as TNBC.
+Added: Approximately 10-15% of patients with breast cancer have TNBC and triple negative status tends to be more common in women younger than age 40, who are African American or who have a BRCA1 mutation.
+Added: TNBCs have a high tendency to metastasize, and patients are at a higher risk to relapse compared to other molecular types.
+Added: TNBCs differ from other types of invasive breast cancer in that TNBC tumors grow and spread faster, have limited treatment options and have a worse prognosis.
+Added: In the United States, there are approximately 40,000 new cases of TNBC annually and approximately 22% of breast cancer deaths are from TNBC.
+Added: Once TNBC has spread to distant parts of the body, the 5-year survival rate is only 11.5% despite currently available treatment options.
+Added: Available treatments include surgery, neoadjuvant and adjuvant chemotherapy such as capecitabine or gemcitabine, taxanes, anthracyclines and eribulin, check-point inhibitors such as pembrolizumab, and poly ADP ribose polymerase or PARP inhibitors such as olaparib and talazoparib.
+Added: At recurrence, the antibody-drug conjugate sacituzumab govitecan-hziy may be prescribed.
+Added: Lung cancer is the second most common cancer and is the leading cause of cancer mortality worldwide.
+Added: NSCLC, defined as any type of epithelial lung cancer other than small-cell lung carcinoma, accounts for about 84% of all lung cancers.
+Added: In 2016, the incidence of NSCLC varied widely, ranging from 3 to 57 per 100,000 in Africa and North America respectively, with ~2 million cases diagnosed globally.
+Added: It is estimated that 110,000 deaths from this disease occurred in the United States in 2022.
+Added: For people with localized NSCLC, the overall 5-year survival rate is ~61%.
+Added: For regional NSCLC, the 5-year survival rate is ~35%.
+Added: Based on current data, when cancer metastasizes, the 5-year survival rate is 6% despite surgery, radiation and treatment with multiple currently-approved therapies, including chemotherapy, immunotherapy and targeted drug therapy.
+Added: Nonclinical Data
+Added: We have conducted extensive nonclinical in vitro and in vivo studies supporting development of LYL797.
+Added: Nonclinical studies of ROR1 CAR T cells that overexpress c-Jun have demonstrated tumor reduction, enhanced cytokine production and tumor infiltration in an aggressive NSCLC syngeneic animal model (Figure 4).
+Added: CAR T cells generated with our Epi‑R manufacturing protocol exhibit enhanced durability and cytotoxicity (Figure 5).
+Added: Additionally, in a nonclinical xenograft tumor model, LYL797, combining c-Jun overexpression and Epi‑R, demonstrated prolonged survival in a xenograft NSCLC animal model (Figure 6).
+Added: During the past year, we have presented these and other nonclinical findings at scientific and medical conferences, including in April, at the American Association of Cancer Research Annual Meeting.
+Added: Our scientific co-founder, Stanley Riddell, M.D., first tested the hypothesis that overexpression of c-Jun could improve T‑cell function in a rigorous solid tumor model of NSCLC (Figure 4).
+Added: Riddell and colleagues utilized a transgenic mouse model with inducible oncogenic driver mutations KRASG12D and p53 deletion.
+Added: Once triggered, these mice developed tumors de novo that recapitulate an immunosuppressive tumor microenvironment, akin to human NSCLC.
+Added: Previous studies have shown that this aggressive tumor model does not respond to chemotherapy or PD-L1 immunotherapy.
+Added: In our study, we observed that this aggressive tumor model is also resistant to treatment with ROR1 CAR T cells, just as was observed in treating human NSCLC with ROR1 CAR T cells.
+Added: In contrast, tumor-bearing mice treated with ROR1 CAR T cells that overexpressed c-Jun demonstrated greater infiltration by the T cells into the tumor, enhanced function of those T cells and tumor regression or stabilization in 50% of the mice versus the 100% tumor progression observed in mice treated with ROR1 CAR without overexpression of c-Jun.
+Added: Nonclinical efficacy demonstrated with c-Jun overexpressing ROR1 CAR T cells in aggressive NSCLC model.
+Added: We have also demonstrated that CAR T cells generated with Epi‑R are able to kill tumor cells over time in an experiment where the CAR T cells are repeatedly challenged to kill tumor cells over multiple rounds (Figure 5).
+Added: In this experiment, CAR T cells are co-cultured with ROR1-positive tumor cells, and tumor cell killing can be assessed and quantified by measurement of decreasing fluorescence.
+Added: CAR T cells were repeatedly challenged with tumor cells over multiple rounds to assess the durability of tumor cell killing.
+Added: Cells generated through standard expansion protocols gradually lose their functionality by the third round and are significantly less effective in killing tumor cells by the fourth round of tumor cell killing.
+Added: In contrast, cells generated with the Epi‑R protocol continue to kill tumor cells.
+Added: Importantly, the Epi‑R cells are no longer in the Epi‑R protocol, suggesting that the stem-like attribute derived from the epigenetic reprogramming is sustained after the manufacturing protocol and for the duration of the experiment.
+Added: The Epi‑R protocol produces populations of T cells with durable cytotoxicity.
+Added: In May, at the American Society of Gene and Cell Therapy Annual Meeting, we presented a study that assessed in vivo functional activity of LYL797 (ROR1 CAR T cells with c-Jun and Epi‑R) compared to conventional ROR1 CAR T cells in an established human ROR1-positive H1975 mouse xenograft model.
+Added: In this study, LYL797 demonstrated improved expansion in the peripheral blood of tumor-bearing animals and control of tumor growth, which led to prolonged survival (Figure 6).
+Added: Taken together, these nonclinical data characterize LYL797 and demonstrate that ROR1-targeted CAR T cells reprogrammed with c-Jun and Epi-R can overcome barriers of T-cell exhaustion and lack of durable stemness.
+Added: LYL797 prolongs survival in NSCLC (H1975) xenograft model.
+Added: A novel epigenetically reprogrammed TIL product candidate designed for differentiated potency and durability targeting multiple solid tumor indications.
+Added: We are applying our epigenetic reprogramming technology, Epi‑R, to develop LYL845, which is expected to be an intravenously‑administered autologous TIL therapy for multiple solid tumors.
+Added: Our Epi‑R protocol comprises proprietary media, optimized cytokine compositions and well-defined cell activation and expansion protocols used during our manufacturing process.
+Added: TIL have previously shown clinical benefit in patients with advanced melanoma and other solid tumors with high mutational burden.
+Added: Published data from third-party TIL trials show that treating metastatic melanoma patients with TIL can result in complete and durable responses.
+Added: Response rates to TIL therapy in patients with other advanced solid tumors such as lung, colorectal and breast are much lower than that observed in advanced melanoma.
+Added: Broad TIL efficacy has been limited by poor enrichment of tumor-reactive T cells and the poor quality and limited growth potential of expanded T cells.
+Added: Failure to maintain polyclonality of TIL during production may also limit their ability to eradicate cancer cells given the inherent heterogeneous nature of solid tumors.
+Added: LYL845 incorporates our Epi‑R technology that has shown promising improvements in enhancing T-cell potency, antitumor activity and increased polyclonality of TIL in nonclinical experiments.
+Added: Phase 1 Clinical Trial
+Added: Our Phase 1 clinical trial (NCT05573035) is designed to evaluate the safety and antitumor activity of LYL845 in patients with advanced melanoma, NSCLC and CRC.
+Added: If successful, we expect to expand into additional indications.
+Added: The trial is designed as an open label, dose escalation and expansion trial in patients with relapsed and/or refractory metastatic or locally advanced solid tumors.
+Added: Per protocol, dose expansion at the recommended dose identified during dose escalation is expected to occur in at least 15 patients with advanced melanoma, 15 patients with NSCLC and 15 patients with CRC.
+Added: The primary outcome measure assesses the safety and tolerability of LYL845.
+Added: Secondary outcome measures include clinical activity based on the evaluation of antitumor activity as evaluated by RECIST criteria and characterization of the pharmacokinetic profile of LYL845.
+Added: Evaluation of T-cell expansion, phenotype, clonal diversity and persistence will also be assessed.
+Added: Patients will be monitored for CRS and auto-immunity.
+Added: We plan to share initial data from the trial when we have a meaningful number of patients and an indication of clinical effect, which we expect to occur in 2024.
Target Indications
−Removed: We are initially targeting SS, MRCLS and NSCLC, which all have a high unmet need based on the current treatment landscapes.
−Removed: SS and MRCLS, in particular, have limited treatment alternatives, and are largely treated with a combination of surgery and chemotherapy, but with significant rates of metastases and low 5-year survival rates in metastatic cases.
−Removed: While NSCLC has more treatment alternatives, it still has low five-year survival rates and due to its prevalence causes upwards of 130,000 deaths in the United States per year.
−Removed: In addition to the unmet need in these cancers, NY-ESO-1 expression is high in all three, 80+% in MRCLRS and SS as well as up to 25% in NSCLC, further supporting our development plans.
−Removed: Preclinical Data
−Removed: We have separately tested both platform technologies with GSK’s NY-ESO-1 TCR.
−Removed: We are currently conducting preclinical studies for NY-ESO-1 TCR with Gen-R (NY-ESO-1 + Gen-R) and NY-ESO-1 TCR with Epi-R (NY-ESO-1 + Epi-R), compared to GSK’s baseline NY-ESO-1 TCR (the Control).
−Removed: Preclinical in vitro and in vivo experiments of NY-ESO-1 + Epi-R (LYL132) have demonstrated that LYL132 has T cells with qualities consistent with T-cell stemness, including enhanced metabolic fitness and proliferation.
−Removed: We believe these qualities could be associated with improved clinical responses that could further improve first generation approaches.
−Removed: We have conducted a series of in vitro and in vivo experiments that show NY-ESO-1 + Gen-R T cells resisted exhaustion and had increased production of cytokines associated with tumor killing, improved sensitivity to lower levels of NY-ESO-1 surface expression and improved tumor cell killing compared to the Control, both initially and after persistent exposure to NY-ESO-1 + tumor cells.
−Removed: We believe these findings could translate into improved outcomes in the clinical setting.
−Removed: We exposed NY-ESO-1 + Gen-R T cells to NY-ESO-1 + solid tumor cell lines and measured IFNɣ and IL-2, cytokines associated with tumor killing.
−Removed: We observed a more than two-fold increase in secretion of those cytokines with NY-ESO-1 + Gen-R compared to the Control in two of three donors.
−Removed: We also exposed T cells to increasing concentrations of NY-ESO-1 on solid tumor cells and showed that NY-ESO-1 + Gen-R were significantly more sensitive than the Control to low levels of NY-ESO-1 (Figure 12).
−Removed: In vitro experiments showed that NY-ESO-1 + Gen-R had increased antitumor cytokines (left panel) and increased antigen sensitivity (right panel) compared to the Control.
−Removed: In the experiment on the left, T cells were exposed to NY-ESO-1 + tumor cells and IFNɣ and IL-2 production were measured.
−Removed: The figure shows that NY- ESO- 1 + Gen-R (TCR + Gen-R, green curves) produced higher and increasing amounts of those cytokines compared to the Control (red curves).
−Removed: In the experiment on the right, T cells were exposed to increasing concentrations of NY-ESO-1 peptide presented by T2 cells, where EC50 and EC90 are measures of maximal antigen concentration needed for response.
−Removed: The right panel shows that NY-ESO-1 + Gen-R (green dots) were more sensitive to low levels of NY-ESO-1 compared to the Control (red dots).
−Removed: Mock T cells, without NY-ESO-1 TCR or Gen-R, are shown in the black curves.
−Removed: Results for EC50 were significant, with p values between groups shown.
−Removed: Additionally, NY-ESO-1 + Gen-R T cells demonstrated a stronger, faster and sustained durability to kill solid tumor cells versus the Control (Figure 13).
−Removed: This result was observed across five donors and two NY-ESO-1+ solid tumor cell lines.
−Removed: NY-ESO-1 + Gen-R T cells (TCR + Gen-R, green curves) demonstrated superior ability to kill NY-ESO-1 + solid tumor cells compared to the Control.
−Removed: The figure shows T cell killing efficiency against two different NY-ESO-1 + cell lines, measured by tracking kinetics of tumor cell clearance over time.
−Removed: The green curves illustrate the clearance of tumor cells by the NY-ESO-1 + Gen-R;
−Removed: the red curves illustrate the same for the Control.
−Removed: Mock T cells, without NY-ESO-1 TCR or Gen-R, are shown in the black curves.
−Removed: In the right panel, the red curve goes upward over time as the TCR T cells without Gen-R lost their antitumor activity, while the green curve goes downward, showing that NY-ESO-1 + Gen-R T cells maintained their antitumor activity.
−Removed: Experiment performed with five donors;
−Removed: representative donor shown.
−Removed: To test for T cell exhaustion, we exposed NY-ESO-1 + Gen-R to NY-ESO-1 + solid tumor cells repetitively.
−Removed: After persistent antigen exposure, NY-ESO-1 + Gen-R continued to kill NY-ESO-1 + tumor cells and secrete cytokines associated with tumor killing, while the Control T cells lost this ability (Figure 14).
−Removed: In addition, a significantly lower proportion of NY-ESO-1 + Gen-R expressed markers of exhaustion.
−Removed: These results suggest that NY-ESO-1 + Gen-R T cells resisted exhaustion after persistent antigen exposure compared to the Control.
−Removed: NY-ESO-1 + Gen-R T cells (TCR + Gen-R, green line) showed enhanced long-term tumor killing activity.
−Removed: In a serial re-stimulation assay, where the T cells were exposed to fresh NY-ESO-1 + tumor cells four times, NY-ESO-1 + Gen-R T cells maintained the ability to kill NY-ESO-1 + tumor cells and to secrete cytokines over time, whereas the Control cells (red line) exhibited signs of exhaustion, as illustrated by loss of killing activity and cytokine secretion.
−Removed: The green curves in the left panel and the green dots in the right panel show that the NY-ESO-1 + Gen-R T cells were able to kill NY-ESO-1 + tumor cells and secrete high amounts of cytokines before (Day 0) and after (Day 14) four rounds of NY-ESO-1 antigen exposure, whereas the Control T cells showed signs of exhaustion, as illustrated by loss of ability to kill and secrete cytokines (red curves and red dots).
−Removed: Mock T cells, without NY-ESO-1 TCR or Gen-R, are shown in the black curves.
−Removed: Significant p values between groups are shown.
+Added: We are initially developing LYL845 for advanced melanoma, NSCLC and CRC.
+Added: Based on our success with those, we plan to include patients with other solid tumors, potentially including head and neck, cervical, breast and pancreatic cancer.
+Added: Although patients with these cancers may benefit initially from radiation therapy, chemotherapy, surgery, and more advanced alternatives such as checkpoint therapies, immunotherapies or targeted therapies, most patients with these types of cancers eventually relapse.
+Added: After becoming resistant to initial lines of therapy, patients are limited to palliative care, experimental therapies in clinical trials or chemotherapy regimens that are often highly toxic and largely ineffective.
+Added: Overall, despite recent advances in therapeutic development, for most patients diagnosed with advanced solid tumors, long-term survival rates remain low.
+Added: Melanoma of the skin is among the most common cancers in the United States behind breast, prostate, lung and CRC.
+Added: It is one of the most common cancers in young adults and especially in young women.
+Added: It is estimated there are over 100,000 new cases of melanoma diagnosed in the United States per year.
+Added: Melanoma arises due to genetic mutations in melanocytes, the pigment producing cells, which can be found in the skin, eye, inner ear and leptomeninges, and represents
+Added: the most aggressive and the deadliest form of skin cancer.
+Added: Although melanoma accounts for only ~1% of all dermatologic cancers, it is responsible for ~80% of deaths from skin cancer.
+Added: Only ~14% of patients with advanced melanoma survive for five years.
+Added: Available treatment options include surgery, radiation therapy, immunotherapy (PD-1 inhibitors), chemotherapy and targeted therapies (MEK and BRAF inhibitors).
+Added: A description of NSCLC can be found above in the section describing the Phase 1 clinical trial for LYL797.
+Added: Colorectal cancer is the third leading cause of cancer-related deaths in both men and women in the United States.
+Added: Most colorectal cancers are a type of tumor called adenocarcinoma, which is cancer of the cells that line the inside tissue of the colon and rectum.
+Added: In 2022, it was estimated that there were approximately 150,000 new cases of CRC in the United States with an estimated cause of approximately 53,000 deaths each year.
+Added: For patients diagnosed with metastatic disease, the 5-year survival rate is 14%.
+Added: Approximately 25% of patients have metastatic disease at diagnosis, and about 50% of patients with colorectal cancer will eventually develop metastases.
+Added: Over 35% of the patients with a new diagnosis of CRC will die within five years.
+Added: Currently available treatments include surgery, radiation therapy, chemotherapy, immunotherapy and targeted therapy (vascular endothelial growth factor, epidermal growth factor receptor, BRAF, NTRK, HER2 and kinase inhibitors).
+Added: Nonclinical Data
+Added: We have conducted nonclinical studies supporting the development of LYL845.
+Added: These studies have demonstrated that TIL generated with our Epi‑R technology have phenotypes (stemness markers and cytotoxic T cells) associated with clinical responses in published literature and preserved polyclonal tumor reactive cells.
+Added: In addition, using Epi‑R allows us to expand TIL in not only immunologically hot tumors such as melanoma, but also immunologically colder tumors such as NSCLC and CRC.
+Added: During the past year, we have presented these findings at scientific and medical conferences.
+Added: These presentations are summarized below:
+Added: In November, at the 2022 Annual Meeting of the Society for Immunotherapy of Cancer (SITC), we presented data that demonstrated the ability of our Epi‑R technology to successfully and reliably expand TIL across three tumor types as compared to the standard (control) process.
+Added: In this study, expanding TIL with Epi‑R technology resulted in a 100% success rate (at least 10B cells) vs.
+Added: 58% with control, including across twelve more difficult-to-expand tumor samples collected from checkpoint inhibitor refractory melanoma, NSCLC and CRC patients (Figure 7).
+Added: Further, in this study Epi‑R technology yielded a product (LYL845) with qualities that have been linked with antitumor functionality and improved outcomes in previous TIL clinical trials, including a greater proportion of CD8+ cytotoxic T cells and enrichment of T cells with stem-like profiles (Figure 8), and better metabolic fitness compared to control TIL.
+Added: Our Epi‑R protocol more consistently successfully expands TIL from immunologically cold solid tumors vs.
+Added: standard expansion processes.
+Added: LYL845 is enriched for cells with characteristics associated with improved clinical outcomes (Krishna et al., Science, Dec.
+Added: We also presented at the 2022 meeting of SITC comprehensive analyses of transcriptomic profiles, polyclonality and prediction of tumor reactive T cell clones in our LYL845 product candidate.
+Added: In particular, our bioinformatic analyses demonstrated that LYL845 products expanded using Epi‑R technology at clinical scale were highly polyclonal and preserved approximately 94% of the predicted tumor reactive clones (Figure 9).
+Added: Further, preserved putative tumor reactive clones in LYL845 products have increased stemness and reduced exhaustion-associated genes compared to TIL products derived from the standard process.
+Added: Moreover, the tumor-specific reactivity of LYL845 was confirmed by demonstrating dose-dependent antitumor cytolytic activity and cytokine secretion in tumor cell specific co-culture assays.
+Added: LYL845 TIL preserve ~94% of predicted tumor reactive clones to enable targeting of heterogeneous solid tumors.
+Added: An innovative ROR1 CAR T-cell product candidate designed for enhanced cytotoxicity.
+Added: A key pillar of our strategy is to continually innovate to develop and advance novel, breakthrough technologies that address key barriers to successful cell therapy for solid tumors.
+Added: We have advanced a new genetic reprogramming
+Added: technology, NR4A3 knockout, and a new epigenetic reprogramming technology, Stim‑R, that are being applied in our new CAR T-cell product candidate, LYL119.
+Added: These technologies are stackable and complementary to c-Jun and Epi‑R and are designed to further improve the antitumor potency and durability of T cells.
+Added: LYL119 is being advanced with the goal of potentially creating even greater benefit for patients with ROR1-positive solid tumors.
+Added: An IND application is expected to be submitted for LYL119 in the first half of 2024.
+Added: Nonclinical Data
+Added: In November at the 2022 meeting of SITC, we presented nonclinical data demonstrating that our NR4A3 knockout and Stim‑R technologies further enhance survival in vivo in a murine H1975 xenograft tumor model at a reduced CAR T‑cell dose.
+Added: We presented data demonstrating that the combination of our two genetic reprogramming technologies, NR4A3 gene knockout and c-Jun overexpression, enhances the functional activity of ROR1 CAR T cells as shown by higher levels of cytokine production, increased CAR T‑cell persistence and reduced surface expression of inhibitory receptors after repetitive antigen stimulation, as well as significant improvement in tumor control in vivo (Figure 10).
+Added: In a separate abstract, we also presented nonclinical data demonstrating that Stim‑R generates potent CAR T‑cell products with increased cell proliferation and persistence in vivo , as well as improved tumor control (Figure 11).
+Added: Combining c-Jun overexpression with NR4A3 knockout enables T cells to further resist exhaustion and prolongs survival.
+Added: Stim‑R ROR1 CAR T cells demonstrate improved potency and prolongs survival.
Our Manufacturing Capabilities
−Removed: We believe it is critically important to own, control and continuously monitor all aspects of the cell therapy manufacturing process in order to mitigate risks the field has seen, including challenges in managing production, supply chain, patient specimen chain of custody and quality control.
−Removed: We made a strategic decision to invest in building our own manufacturing facility to control our supply chain, maximize efficiencies in cell product production time, cost and quality, and have the ability to rapidly incorporate disruptive advancements and new innovations.
−Removed: Controlling manufacturing also enables us to protect proprietary aspects of our Gen-R and Epi-R technology platforms.
+Added: We believe it is critically important to own, control and continuously monitor all aspects of the cell therapy manufacturing process to mitigate risks, including challenges in managing production, supply chain, patient specimen chain of custody and quality control.
+Added: We made a strategic decision to invest in building our own manufacturing facility to control our supply chain, maximize efficiencies in cell product production time, optimize cost and quality, and have the ability to rapidly incorporate disruptive advancements and new innovations.
+Added: Controlling manufacturing also enables us to protect proprietary aspects of our reprogramming technologies.
We view our manufacturing team and capabilities as a significant competitive advantage.
−Removed: Our LyFE manufacturing center is approximately 73,000 square feet and comprises laboratories, offices and manufacturing suites.
−Removed: LyFE has a flexible and modular design allowing us to produce plasmid, viral vector and T cell product to control and de-risk the sequence and timing of production of the major components of our supply chain related to our product candidates.
+Added: Our LyFE manufacturing center located in Bothell, Washington is approximately 73,000 square feet and is comprised of manufacturing suites, laboratories and offices.
+Added: LyFE is commissioned and designed to be in compliance with U.S.
+Added: and European Union cGMP standards and has a flexible and modular design enabling CAR T cell, TIL, TCR T cell and GMP viral vector production to control and de-risk the manufacturing sequence and timing of the major components of our supply chain.
+Added: Owning our own facility encourages seamless collaboration across research, process development and manufacturing for high-quality reproducibility at manufacturing scale.
+Added: We are currently producing clinical supply for our Phase 1 trials at LyFE.
At full staffing and capacity, we expect to be able to manufacture approximately 500 infusions per year depending on product candidate mix.
−Removed: At this time, we believe this capacity is sufficient to support our pipeline programs through pivotal trials and, if approved, early commercialization.
−Removed: Since becoming operational in April 2021, the LyFE manufacturing center has completed successful engineering runs at scale in support of our current and planned clinical trials.
−Removed: In December 2021, we announced that LyFE is commissioned and qualified in compliance with the FDA’s cGMP requirements.
−Removed: LyFE is designed to produce cell products at scale for our current and planned clinical trials across our CAR, TIL and TCR programs.
+Added: At this time, we believe this capacity is sufficient to support our pipeline programs into pivotal trials and, if approved, early commercialization.
The pharmaceutical industry is highly competitive and dynamic, owing to rapidly advancing technologies.
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Some of these companies may have substantially greater financial and other resources than we have, such as larger research and development staff and well-established marketing and sales forces, or may operate in jurisdictions where lower standards of evidence are required to bring products to market.
−Removed: There are a number of companies developing CAR T cells, TCR T cells or TIL-based immune-oncology therapies for the treatment of solid tumors including Achilles Therapeutics plc, Adaptimmune Therapeutics Plc., Bristol Myers Squibb Co., Gilead Sciences Inc., Instil Bio Inc., Intima Bioscience Inc., Iovance Biotherapeutics Inc., the Janssen Pharmaceutical Companies of Johnson & Johnson, Nanjing Legend Biotech, Nurix Therapeutics Inc., Oncternal Therapeutics Inc., Precigen Inc.
−Removed: and TILT Biotherapeutics Ltd.
−Removed: Among companies developing cell therapies for solid tumors, we believe we are substantially differentiated by our technology platforms, knowledge, experience, scientific personnel and robust intellectual property portfolio.
+Added: T‑cell therapies for the treatment of solid tumors are being developed by a number of companies, including but not limited to Adaptimmune Therapeutics plc, ArsenalBio, AstraZeneca plc, Bristol Myers Squibb Co.,
+Added: Gilead Sciences Inc., Immunocore Holdings plc, Iovance Biotherapeutics Inc., the Janssen Pharmaceutical Companies of Johnson & Johnson, Nanjing Legend Biotech, Novartis AG, Nurix Therapeutics Inc., Precigen Inc.
+Added: and Turnstone Biologics.
+Added: We are also aware that other companies are developing therapies in modalities such as monoclonal antibodies and antibody drug conjugates for cancers that express ROR1, such as Merck & Co., Inc.
+Added: Among companies developing cell therapies for solid tumors, we believe we are substantially differentiated by our reprogramming technologies, knowledge, experience, scientific personnel and robust intellectual property portfolio.
We believe the key competitive factors affecting the success of any of our product candidates will include efficacy, safety, accessibility, price and cost of manufacturing.
−Removed: Collaboration, License and Success Payment Agreements
+Added: License, Collaboration and Success Payment Agreements
Fred Hutch License Agreement and Success Payment Agreement
−Removed: In December 2018, we entered into a license agreement with Fred Hutchinson Cancer Research Center (Fred Hutch) that grants us an exclusive, worldwide, sublicensable license under certain patent rights, and a non-exclusive, worldwide, sublicensable license under certain technology, to research, develop, manufacture, improve and commercialize products and processes covered by such patent rights or incorporating such technology for all fields of use utilizing CARs and/or TCRs.
−Removed: This agreement was amended in June 2019, September 2019, January 2020, and August 2020.
+Added: In December 2018, we entered into a license agreement with Fred Hutchinson Cancer Center (Fred Hutch) (as amended in June 2019, September 2019, January 2020, and August 2020) that grants us a worldwide, sublicensable license under certain patent rights (exclusive) and certain technology (non-exclusive), to research, develop and commercialize products and processes for all fields of use utilizing CARs and/or TCRs.
We paid Fred Hutch an upfront payment of $150,000.
In connection with the license agreement, we entered into a letter agreement with Fred Hutch pursuant to which we issued to Fred Hutch 1,075,000 shares of our common stock.
−Removed: We also entered into a letter agreement with Fred Hutch in December 2018 under which we agreed to make success payments to Fred Hutch, payable in cash or publicly traded equity at our discretion.
−Removed: These success payments are based on increases in the per share fair market value of our Series A convertible preferred stock or any security into which such stock has been converted or for which it has been exchanged during the success payment period, which is a period of time that begins on the date of our letter agreement with Fred Hutch and ends on the earlier of:
+Added: The license agreement will expire, on a product-by-product and country-by-country basis, on the later of (a) the expiration of the last to expire valid claim of the patents rights covering such product in such country and (b) ten (10) years after the date of the first commercial sale of such product in such country.
+Added: We may terminate the agreement at will in its entirety or with respect to any patent.
+Added: Fred Hutch has the right to terminate the agreement in the event of our uncured breach.
+Added: We also entered into a letter agreement with Fred Hutch in December 2018 under which we agreed to make success payments to Fred Hutch, payable in cash or publicly tradable equity at our discretion.
+Added: These success payments are based on increases in the per share fair market value of our common stock (as all our Series A convertible preferred stock were converted into an equivalent number of shares of our common stock upon the closing of our initial public offering) during the success payment period, which is a period of time that begins on the date of our letter agreement with Fred Hutch and ends on the earlier of:
(a) the ninth anniversary of that date and (b) the earlier of (i) the date on which we sell, lease, transfer or exclusively license all or substantially all of our assets to another company and (ii) the date on which we merge or consolidate with or into another entity (other than a merger in which our pre-merger stockholders own a majority of the shares of the surviving entity).
−Removed: Upon the closing of our initial public offering, all shares of Series A convertible preferred stock then outstanding converted into an equivalent number of shares of our common stock.
Success payments will be owed (if applicable) after measurement of the value of our common stock in connection with the following valuation dates during the success payment period:
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Any success payment will generally be made within 45 days after the applicable valuation date, except that in the case of a merger or sale of all of our company’s assets, the success payment will be made on the earlier of the 90 th day following the transaction or the first date that transaction proceeds are paid to any of our stockholders.
−Removed: In the case of (1), (2) and (3), the value of our common stock will be determined by the average trading price of a share of our common stock over the consecutive 90-day period preceding the
−Removed: date the success payment is made;
+Added: In the case of (1), (2) and (3), the value of our common stock will be determined by the average trading price of a share of our common stock over the consecutive 90-day period preceding the date the success payment is made;
the value will otherwise be determined either, in the case of a merger or stock sale, by the consideration paid in the transaction for each share of our stock or the stock of the acquiring entity (or their parent or affiliate).
The amount of a success payment is determined based on whether the value of our common stock meets or exceeds certain specified threshold values ascending from $18.29 per share to $91.44 per share, in each case subject to adjustment for any stock dividend, stock split, combination of shares or other similar events.
−Removed: Each threshold is associated with a success payment, ascending from $10.0 million at $18.29 per share to $200.0 million at $91.44 per share, payable if such threshold is reached.
+Added: Each threshold is associated with a success payment, ascending from $10.0 million at $18.29 per share to a cumulative total of $200.0 million at $91.44 per share, payable if such threshold is reached.
Any previous success payments made to Fred Hutch are credited against the success payment owed as of any valuation date, so that Fred Hutch does not receive multiple success payments in connection with the same threshold.
The success payments paid to Fred Hutch will not exceed, in aggregate, $200.0 million, which would be owed only when the value of the common stock reaches $91.44 per share.
+Added: To date, no success payments have been incurred as the per share fair value of our common stock was below the price required for payment.
Stanford License Agreement and Success Payment Agreement
−Removed: In January 2019, we entered into a license agreement with The Board of Trustees of the Leland Stanford Junior University (Stanford) that grants us an exclusive, worldwide, sublicensable license under certain patent rights, and a non-exclusive, worldwide, sublicensable license under certain other patent rights and technology, to make, have made, use, offer to sell, sell, import or otherwise offer to dispose of products and processes covered by such patent rights or incorporating such technology for all fields of use utilizing CARs and/or TCRs.
−Removed: The patents and patent applications covered by this agreement are directed to compositions and methods of treating related to preventing, reversing, inhibiting, reducing or modulating T cell exhaustion and compositions and methods related to engineered cell surface receptors including CARs.
+Added: In January 2019, we entered into a license agreement with The Board of Trustees of the Leland Stanford Junior University (Stanford) that grants us a worldwide, sublicensable license under certain patent rights (exclusive), and certain other patent rights and technology (non-exclusive), to research, develop and commercialize products and processes for all fields of use utilizing CARs and/or TCRs.
We also have the right to add certain Stanford patent applications covering certain inventions that are improvements to the existing patents and patent applications, as well as a right of first negotiation for other patent applications covering inventions made in the principal investigator’s lab that relate to and are necessary or useful for utilizing CARs and/or TCRs.
−Removed: We are obligated to use commercially reasonable efforts to develop, manufacture and sell licensed products and to develop markets for licensed products.
We paid Stanford an upfront payment of $400,000.
−Removed: We are required to pay Stanford an annual maintenance fee in the mid tens of thousands on the second anniversary of entering into this agreement, and each anniversary thereafter until the date of the first commercial sale of a licensed product.
+Added: In connection with the license agreement, we entered into a letter agreement in January 2019 with Stanford pursuant to which we issued to Stanford 910,000 shares of our common stock.
+Added: We are required to pay Stanford an annual maintenance fee in the mid tens of thousands of dollars on the second anniversary of entering into this agreement, and each anniversary thereafter until the date of the first commercial sale of a licensed product.
We are obligated to pay Stanford up to a maximum of $3.7 million per target upon achievement of certain specified clinical and regulatory milestones.
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If we seek to challenge the validity of any of the licensed patents, during the pendency of such action our royalty rate will increase, and if the outcome of such challenge finds that patent is both valid and infringed our royalty rate will increase further.
−Removed: We are also required to pay Stanford (a) royalties in the mid-teens percentage of the payments that we receive from sublicensees of the rights solely licensed to us by Stanford, or (b) if sublicensed with other intellectual property, on a tiered basis in the low six figures up to $300,000.
+Added: We are also required to pay Stanford (a) royalties in the mid-teens percentage of the payments that we receive from sublicensees of the rights solely licensed to us by Stanford, or (b) sublicensing fees if sublicensed with other intellectual property on a tiered basis up to $300,000.
The license agreement will expire, on a licensed product-by-licensed product and country-by-country basis, on the expiration of the last to expire valid claim of the licensed patents rights covering such licensed product in such country.
1 unchanged sentence
Stanford has the right to terminate the agreement in the event of our uncured breach.
−Removed: In connection with the license agreement, we entered into a letter agreement in January 2019 with Stanford pursuant to which we issued to Stanford 910,000 shares of our common stock.
−Removed: We also entered into a letter agreement with Stanford in October 2020, under which we agreed to make success payments to Stanford, payable in cash or publicly traded equity at our discretion.
−Removed: These success payments are based on increases in the per share fair market value of our Series A convertible preferred stock or any security into which such stock has been converted or for which it has been exchanged during the success payment period, which is a period of time that begins on the date of our letter agreement with Stanford and ends on the earlier of:
+Added: We also entered into a letter agreement with Stanford in October 2020, under which we agreed to make success payments to Stanford, payable in cash or publicly tradable equity at our discretion.
+Added: These success payments are based on increases in the per share fair market value of our common stock (as all our Series A convertible preferred stock were converted into an equivalent number of shares of our common stock upon the closing of our initial public offering) during the success payment period, which is a period of time that begins on the date of our letter agreement with Stanford and ends on the earlier of:
(a) the ninth anniversary of that date and (b) the earlier of (i) the date on which we sell, lease, transfer or exclusively license all or substantially all of our assets to another company and (ii) the date on which we merge or consolidate with or into another entity (other than a merger in which our pre-merger stockholders own a majority of the shares of the surviving entity).
−Removed: Upon the closing of our initial public offering, all shares of Series A convertible preferred stock then outstanding converted into an equivalent number of shares of our common stock.
Success payments will be owed (if applicable) after measurement of the value of our common stock in connection with the following valuation dates during the success payment period:
−Removed: (1) the date of the
−Removed: first anniversary of our initial public offering;
+Added: (1) the date of the first anniversary of our initial public offering;
(2) the second anniversary of such date;
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The amount of a success payment is determined based on whether the value of our common stock meets or exceeds certain specified threshold values ascending from $18.29 per share to $91.44 per share, in each case subject to adjustment for any stock dividend, stock split, combination of shares or other similar events.
−Removed: Each threshold is associated with a success payment, ascending from $10.0 million at $18.29 per share to $200.0 million at $91.44 per share, payable if such threshold is reached.
+Added: Each threshold is associated with a success payment, ascending from $10.0 million at $18.29 per share to a cumulative total of $200.0 million at $91.44 per share, payable if such threshold is reached.
Any previous success payments made to Stanford are credited against the success payment owed as of any valuation date, so that Stanford does not receive multiple success payments in connection with the same threshold.
The success payments paid to Stanford will not exceed, in aggregate, $200.0 million, which would be owed only when the value of the common stock reaches $91.44 per share.
+Added: To date, no success payments have been incurred as the per share fair value of our common stock was below the price required for payment.
GSK Collaboration and License Agreement
−Removed: In May 2019, we entered into a collaboration and license agreement with GSK that became effective on July 7, 2019 and was amended in June 2020 and December 2021.
−Removed: Under the GSK Agreement, we agreed to work collaboratively with GSK to research and develop certain T cell therapies incorporating our technology platforms or other cell therapy innovations as applied to CARs or TCRs under distinct collaboration programs.
−Removed: The GSK Agreement could include T cell therapies for up to a total of nine CAR or TCR targets, and GSK may select these CAR or TCR targets for collaboration during a specified period, subject to certain restrictions.
−Removed: Under the GSK Agreement, we granted GSK an option, for each Lyell cell therapy innovation that was the subject of a collaboration program under the GSK Agreement, to obtain an exclusive, worldwide license to develop and commercialize that Lyell cell therapy innovations as part of a TCR or CAR cell therapy for the specific target, for human diagnostic and therapeutic uses, except that we retain rights for the China territory for T cell therapies directed to targets that were within GSK’s pipeline and met certain criteria prior to inclusion in the GSK Agreement.
−Removed: We also retain rights to the Lyell cell therapy innovations for other products and targets.
−Removed: For potential T cell therapies that are the subject of collaboration programs under the GSK Agreement, we are responsible for certain research and development activities, at our cost, up to GSK’s option point.
−Removed: The GSK option point is prior to IND filing for therapies to targets that were within GSK’s pipeline and met certain criteria prior to inclusion in the GSK Agreement and, for other targets, the GSK option point is after results of a specific clinical trial.
−Removed: At the GSK option point, together with GSK we must engage in an option process for a specified period of time, at the end of which GSK may exercise its option.
−Removed: Generally, each party is responsible for its own cost and expense to conduct each collaboration program.
−Removed: Upon any such option exercise, GSK will be responsible for further development, at GSK’s cost.
−Removed: In April 2021, GSK exercised its option to the NY-ESO-1 TCR with Gen-R program.
−Removed: As a result of such option exercise, we will transition to GSK responsibility for future research and development of this program at its cost and expense.
−Removed: For a specified time period, we are prohibited from working with third parties to develop or commercialize CAR or TCR T cell therapies, except (a) in China for non-GSK programs, (b) with entities such as research institutions, contractors and clinical sites that are not granted commercial rights, (c) for companies with supporting tools and (d) in programs for which the therapy targets one of the targets excluded from the GSK Agreement.
−Removed: Currently five targets are excluded, and we may exclude three additional targets during a specified period.
−Removed: In addition, there is a target-based exclusivity for so long as GSK is paying royalties on a product to that target.
−Removed: We received an upfront payment of $45.0 million from GSK under the GSK Agreement.
−Removed: In addition to the upfront payment, we are eligible to receive up to two one-time payments, totaling up to approximately $200.0 million in aggregate for technology validation of Lyell’s cell therapy innovations.
−Removed: For each cell therapy target for which there has been a joint collaboration program, Lyell also could receive up to approximately $400.0 million in aggregate in development and sales
−Removed: milestones if the target is already within GSK’s pipeline and meets certain criteria, up to approximately $900.0 million in aggregate in development and sales milestones for all other targets and tiered royalties on a per-product basis ranging from low to high single digits for targets that are already within GSK’s pipeline and meet certain criteria, or from high single digits to low teens for all other targets.
−Removed: Milestones are paid once per target, even if there is more than one Lyell innovation applied to a T cell therapy directed to that target.
−Removed: The GSK Agreement will expire on a product-by-product and country-by-country basis upon the latest of (a) the expiration of the last valid claim of the last to expire licensed patent covering such product in such country, (b) the expiration of all regulatory exclusivity for such product in such country or (c) a specified period after the first commercial sale of such product in such country.
−Removed: GSK may terminate the GSK Agreement in its entirety or on a collaboration program-by-collaboration program basis for convenience or in its entirety upon a change of control of Lyell by a GSK competitor.
−Removed: Each party may terminate the GSK Agreement in its entirety or with respect to a collaboration program in the event of an uncured material breach by the other party or in its entirety for the other party’s insolvency.
−Removed: We may terminate the GSK Agreement in the event of a patent challenge by GSK or specified third parties.
−Removed: In December 2021, we entered into a Second Amendment to Collaboration and License Agreement (Collaboration Amendment) with GSK.
−Removed: The Collaboration Amendment amends the terms of the GSK Agreement.
−Removed: Pursuant to the Collaboration Amendment, among other things, we will manufacture the NY-ESO-1 + Epi-R TCR cell therapy product candidate for an initial planned Phase 1 clinical trial (Epi-R Trial) at our manufacturing facility in Bothell, Washington.
−Removed: GSK will conduct the Epi-R Trial under its First Time in Humans Master Protocol for NY-ESO-1 (FTIH Protocol) pursuant to a clinical plan agreed to by us and GSK.
−Removed: We are responsible for submitting the IND for this product candidate with the FDA, and GSK is responsible for filing its updated FTIH Protocol and for regulatory interactions with FDA related to that protocol.
−Removed: Each party bears its own costs associated with its responsibilities under the GSK Agreement.
−Removed: The Collaboration Amendment further specifies that we are eligible (i) to receive milestone payments for any use of an Anti-Exhaustion Component in connection with a collaboration target, whether or not there was a specific research program and (ii) for one set of milestone and royalty payments with respect to a collaboration target, even if the approved product uses more than one Anti-Exhaustion Component.
−Removed: The Collaboration Amendment also modifies the scope of license grants in the GSK Agreement to conform to the modified responsibilities under the Collaboration Amendment and specifies that Lyell owns improvements to the Epi-R and Gen-R technologies.
−Removed: National Cancer Institute (NCI) License Agreement
−Removed: In December 2020, we entered into a license agreement with NCI that grants us a worldwide license to certain patent rights, and intellectual property rights related to certain know-how, to develop, make and commercialize licensed products and practice licensed processes for the treatment of human cancers, which license is (A) exclusive with respect to certain licensed patents for use in the field of (1) companion diagnostics for our T cell therapy products, (2) adoptive T cell therapy products generated from autologously derived, induced pluripotent stem cells or (3) adoptive T cell therapy products isolated from autologously-derived and allogeneic-derived peripheral blood;
−Removed: (B) non-exclusive with respect to all licensed patents for use in the field of (4) autologous and allogeneic, adoptive T cell therapy products;
−Removed: and (C) non-exclusive with respect to the licensed know-how for use in the fields of (1) through (4).
−Removed: The licensed patents and licensed know-how covered are directed, in part, to thymic emigrant cells, hematopoietic progenitor cells, thymic organoid from human pluripotent stem cells, T cells, T memory stem cells and their use for the treatment of cancer in humans.
−Removed: We may grant sublicenses under our license with NCI’s written approval and, if the rights we are sublicensing are non-exclusive, they must be sublicensed in combination with certain other intellectual property.
−Removed: On or before the seventh anniversary of the agreement, it is the intention of NCI and us to enter into an amendment to the agreement, which amendment is intended to narrow our exclusive license for certain licensed patents to a defined list of cancer indications that meet certain criteria.
−Removed: Such amendment would also extend the term of our exclusive license to such licensed patents so that it would continue beyond such seventh anniversary until the expiration of the last to expire of such licensed patents.
−Removed: We are obligated to use commercially reasonable efforts to develop, manufacture and sell licensed products and to adhere to an agreed-upon clinical development plan and performance milestones.
−Removed: We paid NCI an upfront payment of $100,000.
−Removed: We have paid a prorated annual maintenance payment to NCI in the mid four figures and we also agreed to pay NCI future annual maintenance payments in the high five figures, which payments may be credited against earned royalties.
−Removed: We may be obligated to pay NCI up to a maximum of $3.1 million upon achievement of certain specified clinical and regulatory milestones.
−Removed: We may also be obligated to pay NCI a maximum of $12.0 million collectively for all licensed products upon our achievement of certain commercial milestones.
−Removed: In addition, the license agreement provides that we are required to pay NCI low single-digit royalties on annual net sales of the licensed products.
−Removed: The license agreement will expire on the expiration of the last to expire valid claim of the licensed patents.
−Removed: We may terminate the agreement at will, in its entirety, or on a patent-by-patent and country-by-country basis.
−Removed: NCI has the right to terminate the agreement in the event of our uncured breach or to terminate or modify the agreement, at NCI’s option, for our failure to meet certain diligence obligations, in the event of certain false statements or omissions by us, for our violation of certain laws, for our material breach of a covenant in this agreement, if we fail to maintain reasonable availability of licensed products or licensed processes, if we cannot meet certain health and safety needs or if we cannot reasonably justify a failure to comply with certain production requirements.
+Added: In 2019, we entered into a collaboration and license agreement with GlaxoSmithKline (GSK) that became effective on July 7, 2019 and was amended in June 2020 and December 2021 (GSK Agreement) for potential T‑cell therapies that apply our platform technologies and cell therapy innovations with T‑cell receptors (TCRs) or chimeric antigen receptors (CARs) under distinct collaboration programs.
+Added: The GSK Agreement defined two initial collaboration targets, CD19 and NY-ESO-1, and allowed GSK to nominate seven additional targets through July 2024.
+Added: After agreeing on the programs for those targets, we were expected to perform research and development services for each agreed program up until a defined point (GSK Option Point), at which time GSK would decide whether or not to exercise an option to obtain a license from us (License Option) and take over the future development and commercialization.
+Added: For the LYL331 program (NY-ESO-1 TCR with c-Jun), GSK exercised the License Option in April 2021 and assumed sole responsibility for future development and commercialization of the program at its own cost and expense.
+Added: No IND for LYL331 was submitted to the U.S.
+Added: Food and Drug Administration (FDA).
+Added: For the LYL132 program (NY-ESO-1 TCR with Epi‑R), we filed an IND application, which cleared in January 2022, though no patients were treated.
+Added: The program targeting CD19 was a research effort.
+Added: No additional targets were nominated over the term of the GSK Agreement.
+Added: GSK terminated the GSK Agreement effective December 24, 2022 and Lyell has discontinued any further work on these programs.
+Added: We received a non-refundable upfront payment of $45.0 million under the GSK Agreement.
+Added: In connection with the GSK Agreement, in May 2019, we also entered into a stock purchase agreement with GSK (GSK Stock Purchase Agreement), pursuant to which we agreed to sell 30,253,189 shares of Series AA convertible preferred stock at a price of $6.78 per share, which was above the issuance date estimated fair value of $4.84 per share.
+Added: The difference between the per share values resulted in $58.6 million additional deemed consideration, bringing the total upfront payment of the GSK Agreement to $103.6 million.
Intellectual Property
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We have in-licensed and procured, and filed for numerous patent applications, which include claims directed to compositions, methods of use, processes, dosing and formulations, and possess substantial know-how and trade secrets relating to the development and commercialization of our cell engineering technology platforms and related product candidates, including related manufacturing processes and protocols.
−Removed: Our intellectual property strategy is designed to provide multi-layered protection covering our core technologies, such as Epi-R, Gen-R and cell rejuvenation, as well as various aspects of our product candidates.
+Added: Our intellectual property strategy is designed to provide multi-layered protection covering our T‑cell reprogramming technologies, including but not limited to c-Jun, NR4A3, Epi‑R and Stim‑R, as well as various aspects of our product candidates.
For all patent applications, we determine claiming strategy on a case-by-case basis.
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Notwithstanding these efforts, we cannot be sure that any patents will be granted with respect to any patent application we have licensed or filed or may license or file in the future, and we cannot be sure that any patents we have licensed or patents that may be licensed or granted to us in the future will not be challenged, invalidated or circumvented or that such patents will be commercially useful in protecting our technologies.
−Removed: As of March 1, 2022, our in-licensed and owned patent portfolio consists of over 30 issued patents and 135 pending patent applications that we have licensed and over 40 pending patent applications that we own.
−Removed: Our portfolio covers various aspects of our core technologies including Epi-R, Gen-R and cell rejuvenation as well as our product candidates.
+Added: As of February 1, 2023, our in-licensed and owned patent portfolio consists of over 40 issued patents and over 135 pending patent applications that we have licensed and over 100 pending patent applications that we own.
+Added: Our portfolio
+Added: covers various aspects of our T‑cell reprogramming technologies, c-Jun, NR4A3, Epi‑R and Stim‑R, as well as our product candidates.
The patents and patent applications in our portfolio are held primarily in the United States, Europe, Canada, Japan and Australia.
−Removed: For information related to our in-licensed intellectual property, see the subsection titled under “—Collaboration, License and Success Payment Agreements.”
+Added: For information related to our in-licensed intellectual property, see the subsection titled under “—License, Collaboration and Success Payment Agreements.”
Individual patents extend for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance and the legal term of patents in the countries in which they are obtained.
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In addition, in certain instances, the patent term of a U.S.
−Removed: patent that covers an FDA-approved drug may also be eligible for extension to recapture a portion of the term effectively lost as a result of clinical trials and the FDA regulatory review period, such extension is referred to as patent term extension (PTE).
+Added: patent that covers an FDA‑approved drug may also be eligible for extension to recapture a portion of the term effectively lost as a result of clinical trials and the FDA regulatory review period, such extension is referred to as patent term extension.
The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval.
Similar provisions are available in Europe and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug.
−Removed: However there is no guarantee that the applicable authorities,
−Removed: including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.
+Added: However, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.
The duration of patents outside of the United States varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest nonprovisional filing date.
The actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.
−Removed: As of March 1, 2022, our registered trademark portfolio currently contains approximately 135 registered trademarks and pending trademark applications, consisting of approximately 10 pending trademark applications in the United States, approximately 105 foreign pending trademark applications in Argentina, Australia, Brazil, Canada, China, Colombia, Costa Rica, European Union, Hong Kong, India, Israel, Japan, Mexico, New Zealand, Oman, South Korea, Russia, Singapore, South Africa, Switzerland, UAE and Venezuela;
−Removed: and approximately 20 trademark registrations in the following countries through national filings:
−Removed: Australia, Brazil, China, European Union, Hong Kong, India, Israel, Japan, Mexico, New Zealand, Republic of Korea, Switzerland and the United Kingdom.
+Added: As of February 1, 2023, our registered trademark portfolio currently contains over 165 registered trademarks and pending trademark applications, consisting of approximately 9 pending trademark applications in the United States, over 80 foreign pending trademark applications in Argentina, Brazil, Canada, China, Hong Kong, India, Israel, Mexico, Oman, South Korea, Russia, Singapore, South Africa, the United Arab Emirates and Venezuela;
+Added: and over 75 trademark registrations in the following countries through national filings:
+Added: Australia, Brazil, China, Colombia, Costa Rica, European Union, Hong Kong, India, Israel, Japan, Mexico, New Zealand, Oman, Russia, South Korea, Switzerland, the United Arab Emirates, the United Kingdom and Venezuela.
We may also rely, in some circumstances, on trade secrets to protect our technology.
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We intend to either build a commercial infrastructure to support sales of any approved products or outsource this function to third parties.
−Removed: We intend to continue evaluating opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of LYL797 or LYL845.
+Added: We intend to evaluate opportunities to work with partners that enhance our capabilities with respect to the development and commercialization of LYL797, LYL845, LYL119 and any other product candidates we may develop.
In addition, we intend to commercialize our product candidates, if approved, in key markets either alone or with partners to maximize the worldwide commercial potential of our programs.
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The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of biologics such as those we are developing.
−Removed: We, along with third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct trials or seek approval or licensure of our product candidates.
+Added: with third-party contractors, will be required to navigate the various nonclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct trials or seek approval or licensure of our product candidates.
The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.
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The process required by the FDA before biologics may be marketed in the United States generally involves the following:
−Removed: • completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s Good Laboratory Practice requirements (GLP);
−Removed: • submission to the FDA of an IND, which must become effective before clinical trials may begin;
+Added: • completion of nonclinical laboratory tests and animal studies performed in accordance with the FDA’s Good Laboratory Practice requirements (GLP);
+Added: • submission to the FDA of an IND application, which must become effective before clinical trials may begin;
• approval by an Institutional Review Board (IRB) or ethics committee at each clinical site before the trial is commenced;
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• a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;
−Removed: • satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency and, if applicable, to assess compliance with the FDA’s cGTPs requirements for the use of human cellular and tissue products, and of selected clinical investigation sites to assess compliance with GCPs;
+Added: • satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency and, if applicable, to assess compliance with the FDA’s current Good Tissue Practices (cGTPs) requirements for the use of human cellular and tissue products, and of selected clinical investigation sites to assess compliance with GCPs;
• potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the BLA;
• FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the United States.
−Removed: Before testing any biological product candidate in humans, the product candidate enters the preclinical testing stage.
−Removed: Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies to assess the potential safety and activity of the product candidate.
−Removed: The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs.
+Added: Before testing any biological product candidate in humans, the product candidate enters the nonclinical testing stage.
+Added: Nonclinical tests, also referred to as preclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies to assess the potential safety and activity of the product candidate.
+Added: The conduct of the nonclinical tests must comply with federal regulations and requirements including GLPs.
Prior to beginning the first clinical trial with a product candidate in the United States, we must submit an IND to the FDA.
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Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
−Removed: In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of IBCs as set forth in the NIH Guidelines for Research Involving Recombinant DNA Molecules (the NIH Guidelines).
−Removed: Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an Institutional Biosafety Committee (IBC), a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.
+Added: In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of an Institutional Biosafety Committee (IBC) as set forth in the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules (the NIH Guidelines).
+Added: Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees
+Added: research utilizing recombinant or synthetic nucleic acid molecules at that institution.
The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.
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A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
−Removed: Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.
+Added: Furthermore, an IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.
Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.
−Removed: Some studies also include
−Removed: oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.
+Added: Some studies also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.
There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.
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Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.
−Removed: The BLA must include all relevant data available from preclinical and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.
+Added: The BLA must include all relevant data available from nonclinical and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.
Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including trials initiated by independent investigators.
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The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP and adequate to assure consistent production of the product within required specifications.
−Removed: For a product candidate that is also a human cellular or tissue product, the FDA also will not approve the application if the
−Removed: manufacturer is not in compliance with cGTPs.
−Removed: These are FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues and cellular and tissue-based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion or transfer into a human recipient.
+Added: For a product candidate that is also a human cellular or tissue product, the FDA also will not approve the application if the manufacturer is not in compliance with cGTPs.
+Added: These are FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues and cellular and tissue-based products (HCT/Ps), which are human cells or tissue intended for implantation, transplant, infusion or transfer into a human recipient.
The primary intent of the GTP requirements is to ensure that cell and tissue-based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable disease.
1 unchanged sentence
Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.
−Removed: If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information.
+Added: If the FDA determines that the application, manufacturing process or manufacturing facilities, or data collected from clinical trial sites are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information.
Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
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Fast track designation applies to the combination of the product and the specific indication for which it is being studied.
−Removed: The sponsor of a new biologic may request that the FDA designate the biologic as a fast track product at any time during the clinical development of the product.
+Added: The sponsor of a new biologic may request that the FDA designate the biologic as a
+Added: fast track product at any time during the clinical development of the product.
The sponsor of a fast track product has opportunities for more frequent interactions with the applicable FDA review team during product development and, once a BLA is submitted, the product candidate may be eligible for priority review.
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In the United States, orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.
−Removed: In addition, if a product that has orphan drug designation subsequently receives the first FDA approval for a particular drug or biologic for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities
−Removed: of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
+Added: In addition, if a product that has orphan drug designation subsequently receives the first FDA approval for a particular drug or biologic for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.
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Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties.
−Removed: FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical hold, warning or untitled letters, product recalls, product
−Removed: seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits or civil or criminal penalties.
+Added: FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical hold, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits or civil or criminal penalties.
Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested and approved by the FDA.
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Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.
−Removed: In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.
−Removed: During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.
+Added: In addition, the approval of a biosimilar product may not be made effective by the FDA until twelve (12) years from the date on which the reference product was first licensed.
+Added: During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own nonclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.
The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.
3 unchanged sentences
This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.
−Removed: The BPCIA is complex and continues to be interpreted and implemented by the FDA.
+Added: The BPCIA is complex and continues to be interpreted
+Added: and implemented by the FDA.
In addition, government proposals have sought to reduce the 12-year reference product exclusivity period.
8 unchanged sentences
Once the CTA is approved in accordance with the applicable requirements, clinical trial development may proceed.
−Removed: requirements and process governing the conduct of clinical trials, are to a significant extent harmonized at the European Union-level but could vary from country to country.
+Added: The requirements and process governing the conduct of clinical trials are to a significant extent harmonized at the European Union-level but could vary from country to country.
In all cases, the clinical trials are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
−Removed: The way clinical trials are conducted in the European Union will undergo a major change when the Clinical Trial Regulation (Regulation (EU) 536/2014) comes into application, probably in 2022.
+Added: The way clinical trials are conducted in the European Union underwent a major change when the Clinical Trial Regulation (Regulation (EU) 536/2014) came into application in January 2022.
The Regulation harmonizes the assessment and supervision processes for clinical trials throughout the European Union via a Clinical Trials Information System, which will contain a centralized European Union portal and database.
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and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the European Union, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation (EC) 847/2000.
−Removed: Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.
+Added: Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing
+Added: authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.
The application for orphan drug designation must be submitted before the application for marketing authorization.
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All ATMPs must obtain a marketing authorization from the EMA and are regulated through the centralized authorization procedure.
−Removed: Regulation (EC) No 1394/2007 (the ATMP Regulation) provides specific incentives to accelerate the development of such products, including fee reductions for scientific advice, an ATMP classification procedure (for all developers) and a certification procedure for quality and preclinical data (for SMEs only).
+Added: Regulation (EC) No 1394/2007 (the ATMP Regulation) provides specific incentives to accelerate the development of such products, including fee reductions for scientific advice, an ATMP classification procedure (for all developers) and a certification procedure for quality and nonclinical data (for SMEs only).
If tissues and cells are being used as starting materials in a medicinal product we may also need to comply with the requirements of Directive 2004/23/EC (the European Tissues and Cells Directive) covering standards for donation, procurement and testing, processing, preservation, storage and distribution of human tissues and cells, as well as its technical implementing directives;
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Other Healthcare Laws
−Removed: Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business and may constrain the financial arrangements and relationships through which we research, sell, market and distribute any products for which we obtain marketing approval.
+Added: Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business and may
+Added: constrain the financial arrangements and relationships through which we research, sell, market and distribute any products for which we obtain marketing approval.
Such laws include, without limitation, federal and state anti-kickback, fraud and abuse, false claims, data privacy and security, price reporting and physician and other health care provider transparency laws and regulations.
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There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.
−Removed: The exceptions and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify
−Removed: for an exception or safe harbor but the exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.
+Added: The exceptions and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended to induce prescribing, purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor but the exceptions and safe harbors are drawn narrowly and require strict compliance in order to offer protection.
Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute.
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Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.
−Removed: Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals and certain ownership and investment interests held by these healthcare providers and their immediate family members.
−Removed: Beginning in 2022, applicable manufacturers also will be required to report information regarding its payments and other transfers of value to physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified registered nurse anesthetists and certified nurse midwives during the previous year.
+Added: Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) annually report information related to certain payments or other transfers of value made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other health care professionals (such as physician assistants and nurse practitioners) and teaching hospitals and certain ownership and investment interests held by these physicians and their immediate family members.
We may also be subject to data privacy and security regulations by both the federal government and the states in which we conduct our business.
−Removed: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and its implementing regulations, impose requirements on covered entities, including certain healthcare providers, health plans, healthcare clearinghouses and their respective business associates that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as their covered subcontractors relating to the privacy, security and transmission of individually identifiable health information.
+Added: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and its implementing regulations, impose requirements on covered entities, including certain healthcare providers, health plans, healthcare clearinghouses and their respective business associates that create, receive,
+Added: maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as their covered subcontractors relating to the privacy, security and transmission of individually identifiable health information.
Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.
2 unchanged sentences
In order to distribute products commercially, we must comply with state laws that require the registration of manufacturers and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state.
−Removed: Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in
−Removed: the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.
+Added: Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.
Several states have enacted legislation requiring pharmaceutical companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, track and report gifts, compensation and other remuneration made to physicians and other healthcare providers, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.
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There have been executive, judicial and Congressional challenges to certain aspects of the ACA.
−Removed: For example, the Tax Act was enacted, which includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On December 14, 2018, a U.S.
−Removed: District Court Judge in the Northern District of Texas ruled that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.
−Removed: Additionally, on December 18, 2019, the U.S.
−Removed: Court of Appeals for the 5th Circuit ruled that that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.
−Removed: On June 17, 2021, the U.S.
+Added: For example, the Tax Act was enacted, which includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On June 17, 2021, the U.S.
Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.
−Removed: Thus, the ACA will remain in effect in its current form.
President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.
The executive order also instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.
−Removed: It is unclear how the Supreme Court ruling, other such litigation and the healthcare reform measures of the Biden administration will impact the ACA and our business.
+Added: Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (IRA) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.
+Added: The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost through a newly established manufacturer discount program.
+Added: It is possible that the ACA will be subject to judicial or Congressional challenges in the future.
+Added: It is unclear how any such additional challenges and healthcare reform measures of the Biden administration will impact the ACA and our business.
Other legislative changes have also been proposed and adopted in the United States since the ACA was enacted.
−Removed: On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013.
−Removed: However, COVID-19 relief legislation suspended the 2% Medicare sequester from May 1, 2020 through December 31, 2021.
+Added: On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which began in 2013 and will remain in effect through 2031.
+Added: However, COVID-19 relief legislation suspended the 2% Medicare sequester from May 1, 2020 through March 31, 2022.
+Added: Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.
In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
There has been heightened governmental scrutiny recently over the manner in which pharmaceutical companies set prices for their marketed products, which has resulted in several Congressional inquiries and proposed federal legislation, as well as state efforts, designed to, among other things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
−Removed: The likelihood of success of these and other measures initiated by the former Trump administration is uncertain, particularly in light of the Biden administration.
+Added: In addition, the IRA, among other things, (1) directs HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
+Added: These provisions will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.
+Added: It is currently unclear how the IRA will be implemented, but it is likely to have a significant impact on the pharmaceutical industry.
+Added: Further, the Biden administration released an additional executive order on October 14, 2022, directing HHS to submit a report within ninety (90) days on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.
+Added: It is unclear whether this executive order or similar policy initiatives will be implemented in the future.
At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
29 unchanged sentences
While the CJEU upheld the adequacy, subject to certain conditions, of the standard contractual clauses (a standard form of contract approved by the European Commission as an adequate personal data transfer mechanism), future regulatory guidance could result in changes to the use of standard contractual clauses.
−Removed: As supervisory authorities issue further guidance on personal data export mechanisms, including circumstances where the standard contractual clauses cannot be used, and/or start taking enforcement action, we could suffer additional costs, complaints and/or regulatory investigations or fines, and/or if we are otherwise unable to transfer personal data between and among countries and regions in which we operate, it could affect the manner in which we provide our services, the geographical location or segregation of our relevant systems and operations, and could adversely affect our financial results.
+Added: As supervisory authorities issue further guidance on personal
+Added: data export mechanisms, including circumstances where the standard contractual clauses cannot be used, and/or start taking enforcement action, we could suffer additional costs, complaints and/or regulatory investigations or fines, and/or if we are otherwise unable to transfer personal data between and among countries and regions in which we operate, it could affect the manner in which we provide our services, the geographical location or segregation of our relevant systems and operations, and could adversely affect our financial results.
Further, the vote in the United Kingdom in favor of exiting the European Union, referred to as Brexit, has created uncertainty with regard to data protection regulation in the United Kingdom.
2 unchanged sentences
Beginning in 2021, the United Kingdom will be a “third country” under the GDPR.
−Removed: In addition, California recently enacted the California Consumer Privacy Act (CCPA), which creates new individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling certain personal data of consumers or households.
+Added: In addition, California enacted the California Consumer Privacy Act (CCPA), which creates new individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling certain personal data of consumers or households.
The CCPA requires covered companies to provide new disclosure to consumers about such companies’ data collection, use and sharing practices, provide such consumers new ways to opt-out of certain sales or transfers of personal information, and provide consumers with additional causes of action.
3 unchanged sentences
In addition, laws in all 50 U.S.
−Removed: states require businesses to provide notice to consumers whose personal information has been disclosed as a result of a data
+Added: states require businesses to provide notice to consumers whose personal information has been disclosed as a result of a data breach.
State laws are changing rapidly and there is discussion in the U.S.
4 unchanged sentences
It will also create a new California data protection agency authorized to issue substantive regulations and could result in increased privacy and information security enforcement.
−Removed: The majority of the provisions will go into effect on January 1, 2023, and additional compliance investment and potential business process changes may be required.
+Added: The majority of the provisions went into effect on January 1, 2023, and additional compliance investment and potential business process changes may be required.
Foreign Corrupt Practices Act
3 unchanged sentences
Employees and Human Capital Management
−Removed: We are a T-cell reprogramming company dedicated to the mastery of T cells to cure patients with solid tumor cancers.
+Added: We are a clinical stage T‑cell reprogramming company dedicated to developing novel cell therapies to improve the lives of people with solid tumor cancers.
We strive to create an environment where everyone can do the best work of their lives, be themselves and thrive personally and professionally.
Our culture is grounded by innovative science and demands excellence.
−Removed: Patients are waiting for new, innovative and effective therapies, and it is this need that drives our sense of urgency to achieve our important mission.
+Added: Patients are waiting for better therapies, and it is this need that drives our sense of urgency to achieve our important mission.
We believe success comes when we and our employees align our core values with our mission to translate our ground-breaking science into medicines with the potential to transform patients’ lives.
6 unchanged sentences
Our Employees
−Removed: We view our employees as a valuable assets in serving our mission.
+Added: We view our employees as valuable assets in serving our mission.
We compete in the highly competitive biotechnology industry, and attracting, retaining and developing a diverse group of talented employees is crucial to our strategy and our ability to compete effectively.
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We face substantial competition among numerous biopharmaceutical companies and academic institutions as well as technology companies for individuals with these skills.
−Removed: As of December 31, 2021, we had 219 employees, 149 of whom were engaged in research and development activities, technical operations and process sciences.
+Added: As of December 31, 2022, we had 274 employees, over 75% of whom were engaged in research and development activities, technical operations and process sciences.
Our employees are highly skilled, and many hold advanced degrees.
6 unchanged sentences
We hold talent discussions regularly, which include promotion cycles across functions and role levels.
−Removed: We are in the process of creating and implementing a comprehensive talent management framework inclusive of role leveling, competencies, training by role level and competencies, development and career planning.
+Added: In 2022, we created a comprehensive talent management framework, which includes role leveling, competencies, training by role level and competencies and development planning.
Since inception, our employee turnover has remained consistently below average for the U.S.
−Removed: life sciences industry generally, as well as for life sciences companies located in Northern California.
+Added: life sciences industry generally, as well as for life sciences companies located in Northern California and the Pacific Northwest.
Given our expanding operations and need to further grow our headcount to support our business, we continually assess employee turnover, recruitment initiatives, compensation and benefits programs, safety in performing critical laboratory work, diversity and other matters relevant to human capital management, and we review results with our board of directors on a periodic basis.
−Removed: Our Compensation & Benefits
+Added: Our Compensation and Benefits
Given the highly competitive nature of our industry and the importance of recruitment and retention to our success, we strive to provide our employees with what we believe is a competitive and comprehensive total rewards package of compensation, benefits and services.
−Removed: This package includes at or competitive market pay, healthcare benefits for employees and family members, a flexible spending account, paid time off benefits, family leave, flexible work schedules, flexible work locations, 401(k) matching and an employee assistance program.
−Removed: In addition, we offer employees the benefit of equity ownership in the company through stock option grants.
−Removed: Our employees are also eligible to participate in an employee stock purchase plan, which offers the opportunity to purchase our common stock at a discount of at least 15%.
−Removed: Our Commitment to Diversity, Belonging, Inclusion & Equity
+Added: This package includes competitive market pay, healthcare benefits for employees and family members, a flexible spending account, paid time off benefits, family leave, flexible work schedules, flexible work locations, 401(k) matching, an employee assistance program and a new wellness program.
+Added: In addition, we offer employees the benefit of equity ownership in the company through stock option grants and restricted stock units.
+Added: Our employees are also eligible to participate in an employee stock purchase plan, which offers the opportunity to purchase our common stock at a discount of 15%.
+Added: Our Commitment to Diversity, Belonging, Inclusion and Equity
We strongly believe in a diverse workplace where all employees can thrive in an inclusive environment free from discrimination, harassment, bias and prejudice.
2 unchanged sentences
Not only is a diverse, equitable and inclusive mindset and culture critical to an engaged and committed workplace, but it is also imperative to understanding and meeting the needs of the patients we seek to help with our medicines.
−Removed: In 2020, with the support of our Chief Executive Officer and executive leadership team, we convened a Diversity, Belonging, Inclusion and Equity (DBIE) working group comprised of a diverse group of employees tasked with designing and implementing specific initiatives to promote greater diversity, belonging, inclusion and equity at Lyell.
+Added: With the support of our executive leadership team, we convened a Diversity, Belonging, Inclusion and Equity (DBIE) working group in 2020 comprised of a diverse group of employees tasked with designing and implementing specific initiatives to promote greater diversity, belonging, inclusion and equity at Lyell.
We also engaged an experienced DBIE consultant to advise us on the design and planning of new DBIE initiatives based on expertise and external benchmarking.
The DBIE working group formalized a DBIE statement, a framework, a tactical plan and advanced a commitment to the importance of DBIE.
−Removed: In 2022, we expect to implement a DBIE speaker series, relevant DBIE training for managers and to expand our recruiting activities to include the use of Textio, a platform that aims to reduce gender bias in role descriptions and postings, and to utilize new recruiting platforms to further diversify candidate pools.
+Added: In 2022, we offered several DBIE speaker events, rolled out Inclusivity@Lyell
+Added: training sessions, utilized Textio to reduce gender bias in role descriptions and postings, and tried several new recruiting sources to further diversify candidate pools.
Although we are proud of our progress to date, we have and will continue to conduct relevant training and provide guidance with respect to best practices of similarly situated companies.
4 unchanged sentences
We review and analyze our compensation decisions for individual employees and our workforce as a whole on at least an annual basis.
−Removed: In 2021, we conducted a pay equity analysis that we believe demonstrated that our compensation practices and structure are equitable.
+Added: In 2022, we engaged an independent external firm to conduct a pay equity analysis, the results of which we believe demonstrated that our compensation practices and structure are equitable.
If we identify employees with unjustified pay gaps that do not align with our pay philosophy, we review and take appropriate action to ensure fidelity between our stated philosophy and actions.
−Removed: Our Efforts to Address the COVID-19 Pandemic
−Removed: Employee safety and well-being is of paramount importance to us in any year and was of particular focus since 2020 in light of the evolving COVID-19 pandemic.
−Removed: In response to the pandemic, we have supported our employees and government efforts to curb the COVID-19 pandemic through safety and communication efforts and investments, which include:
−Removed: • Creating a COVID-19 working group responsible for establishing COVID-19 safety protocols and regularly communicating updates to all employees;
−Removed: • A work from home policy in which work that can be done from home is encouraged and allowed to be done from home;
−Removed: • Decreasing density and increasing physical distancing in our facilities for employees working onsite using scheduling adjustments and flexibility;
−Removed: • Robust cleaning protocols across all locations;
−Removed: • Strict mask requirements for employees, contractors and other onsite vendors;
−Removed: • Requirement that all employees and substantially all other third parties that come onsite be fully vaccinated;
−Removed: • Rigorous procedures to address actual and suspected COVID-19 cases and potential exposure; and
−Removed: • Limitation of all domestic and international non-essential travel for all employees.
−Removed: Additionally, from time to time we have instituted additional programs during the COVID-19 pandemic to support our employees, including wellness days and subsidies to all employees for home office expenses and upgrades.
−Removed: One of our top priorities during the ongoing COVID-19 pandemic remains protecting the health and well-being of our employees, customers, partners and communities.
−Removed: We have closely monitored the COVID-19 pandemic and have strived to follow recommended containment and mitigation measures, including the guidance from the Centers for Disease Control and Prevention ( CDC), Occupational Safety and Health Administration (OSHA), the states of California and Washington (including their state OSHA programs) and applicable counties.
−Removed: For most of the pandemic, essential laboratory, manufacturing and support employees worked in our facilities to continue and progress experiments and manufacturing related activities.
−Removed: We will continue to actively monitor the situation related to the COVID-19 pandemic and may take further actions that alter our operations, including those that may be required by federal, state, or local authorities, or that we determine are in the best interests of our employees and other third parties with whom we do business.
+Added: Employee Safety and COVID-19
+Added: Employee safety and well-being is of paramount importance to us in any year and has been of particular focus since 2020 in light of the evolving and continuing effects of the COVID-19 pandemic.
+Added: In response to the pandemic, we have supported our employees and government efforts to curb the COVID-19 pandemic through safety and communication efforts and investments.
+Added: One of our top priorities is the protection of the health and well-being of our employees, partners and communities.
+Added: While our employees have returned to work in our offices on a flexible-basis, all employees and substantially all other third parties that come onsite are required to be fully vaccinated.
+Added: We continue to maintain rigorous procedures to address actual and suspected COVID-19 cases and potential exposure, including increased cleaning of high touch areas, provision of hand sanitizing stations and limited on-site contract tracing as needed, and we expect to continue such measures for the near foreseeable future.
+Added: We continue to closely monitor the COVID-19 pandemic and have strived to follow recommended containment and mitigation measures, including the guidance from the Centers for Disease Control and Prevention ( CDC), Occupational Safety and Health Administration (OSHA), the states of California and Washington (including their state OSHA programs) and applicable counties.
+Added: Available Information
+Added: Our website address is www.lyell.com.
+Added: We file annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and amendments to reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act.
+Added: The SEC maintains a website at www.sec.gov that contains reports, proxy and information statements and other information that we file with the SEC electronically.
+Added: Copies of our reports on Form 10-K, Forms 10-Q, Forms 8-K, and amendments to those reports may also be obtained, free of charge, electronically on the investor relations page on our website located at ir.lyell.com as soon as reasonably practical after we file such material with, or furnish it to, the SEC.
+Added: We also use the investor relations page on our website as a channel of distribution for important company information.
+Added: Important information, including press releases, analyst presentations and financial information regarding us, as well as corporate governance information, is routinely posted and accessible on the investor relations page on our website.
+Added: Information on or that can be accessed through our website is not part of this Annual Report on Form 10-K, and the inclusion of our website address is an inactive textual reference only.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.