What changed in this filing

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Item 1. Business

2023-03-01 compared with 2022-03-01 · 388 added, 410 removed, 820 unchanged (49% of the section changed)

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• our ability to develop next-generation therapies and vaccines that complement, harness, and amplify the immune system to defeat cancers and infectious diseases;

• our ability to implement and support our SARS-CoV-2 (COVID‑19) vaccine and therapeutic programs;

• any impact of the coronavirus pandemic, or responses to the pandemic, on our business, clinical trials or personnel;

• our ability to obtain funding for our operations, including funding necessary to complete further development and any commercialization of our product candidates;

• our expectations regarding the potential benefits of our strategy and technology;

• our expectations regarding the operation of our product candidates and related benefits;

• our expectations regarding the operation and effectiveness of our product candidates and related benefits;

• our ability to utilize multiple modes to induce cell death;

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• our beliefs regarding the success, cost and timing of our product candidate development activities and current and future clinical trials and studies, including study design and the enrollment of patients;

• the timing of the development and commercialization of our product candidates;

• our expectations regarding our ability to utilize the Phase 1/2 aNK and haNK ® clinical trials data to support the development of our product candidates, including our haNK, taNK, t‑haNK ™ , MSC, and M-ceNK ™ product candidates;

• our expectations regarding the development, application, commercialization, marketing, prospects and use generally of our product candidates, including Anktiva ™ , saRNA, hAd5 and yeast constructs, recombinant sub-unit proteins, endosomal delivery vector (EDV ™ ) constructs, toll-like receptor-activating adjuvants, and aldoxorubicin;

• the timing or likelihood of regulatory filings or other actions and related regulatory authority responses, including any planned investigational new drug (IND), Biologics License Application (BLA) or New Drug Application (NDA) filings including, without limitation, the anticipated timing of filing a BLA for bacillus Calmette-Guérin (BCG) -unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) or pursuit of accelerated regulatory approval pathways or orphan drug status and Breakthrough Therapy designations;

• our expectations regarding the development, application, commercialization, marketing, prospects and use generally of our product candidates, including Anktiva ™ (N-803), saRNA, hAd5 and yeast constructs, recombinant subunit proteins, toll-like receptor-activating adjuvants, and aldoxorubicin;

• the timing or likelihood of regulatory filings or other actions and related regulatory authority responses, including any planned investigational new drug (IND), Biologics License Application (BLA) or New Drug Application (NDA) filings or pursuit of accelerated regulatory approval pathways or orphan drug status and Breakthrough Therapy designations;

• our ability to implement and support our SARS-CoV-2 (COVID‑19) vaccine and therapeutic programs;

• our ability to implement an integrated discovery ecosystem and the operation of that planned ecosystem, including being able to regularly add neoepitopes and subsequently formulate new product candidates;

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• our expectations regarding the timing of enrollment and submission of our clinical trials, and protocols related to such trials;

• our ability to produce an antibody cytokine fusion protein, a DNA, RNA, or recombinant protein vaccine, a toll-like receptor-activating adjuvant, an NK-cell therapy, or a damage-associated molecular patterns (DAMP) inducer therapy;

• our ability to produce an antibody cytokine fusion protein, a DNA, RNA, or recombinant protein vaccine, a toll-like receptor-activating adjuvant, an NK-cell or T-cell therapy, or a damage-associated molecular patterns (DAMP) inducer therapy;

• our beliefs regarding the potential manufacturing and distribution benefits associated with our product candidates, and our ability to scale up the production of our product candidates;

• our plans regarding our manufacturing facilities and our belief that our manufacturing is capable of being conducted in‑house;

• our belief in the potential of our antibody cytokine fusion proteins, DNA, RNA or recombinant protein vaccines, toll-like receptor-activating adjuvants, NK-cell therapy, or DAMP inducer platforms, and the fact that our business is based upon the success individually and collectively of these platforms;

• our belief regarding the magnitude or duration for additional clinical testing of our antibody cytokine fusion proteins, DNA, RNA or recombinant protein vaccines, toll-like receptor-activating adjuvants, NK-cell therapy, or DAMP inducers along with other product candidate families;

• even if we successfully develop and commercialize specific product candidates like our Anktiva or PD-L1 t‑haNK, our ability to develop and commercialize our other product candidates either alone or in combination with other therapeutic agents;

• our belief in the potential of our antibody cytokine fusion proteins, DNA, RNA or recombinant protein vaccines, toll-like receptor-activating adjuvants, NK-cell therapies, or DAMP inducer platforms, and the fact that our business is based upon the success individually and collectively of these platforms;

• our belief regarding the magnitude or duration for additional clinical testing of our antibody cytokine fusion proteins, DNA, RNA or recombinant protein vaccines, toll-like receptor-activating adjuvants, NK-cell therapies, or DAMP inducers along with other product candidate families;

• even if we successfully develop and commercialize specific product candidates like our N-803 or PD-L1 t‑haNK, our ability to develop and commercialize our other product candidates either alone or in combination with other therapeutic agents;

• the ability to obtain and maintain regulatory approval of any of our product candidates, and any related restrictions, limitations and/or warnings in the label of any approved product candidate;

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• the accuracy of our estimates regarding our future revenue, as well as our future operating expenses, capital requirements and needs for additional financing;

• our ability to obtain funding for our operations, including funding necessary to complete further development and any commercialization of our product candidates;

• our ability to obtain, maintain, protect and enforce intellectual property protection for our product candidates and technology and not infringe upon, misappropriate or otherwise violate the intellectual property of others;

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• regulatory developments in the United States (U.S.) and foreign countries;

• the timing of the development and commercialization of our product candidates.

• any impact of the coronavirus pandemic, or responses to the pandemic, on our business, clinical trials or personnel.

Forward-looking statements include statements that are not historical facts and can be identified by terms such as “anticipates,” “believes,” “could,” “seeks,” “estimates,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “projects,” “should,” “will,” “would,” or similar expressions and the negatives of those terms.

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Anktiva, ceNK, Conkwest, GlobeImmune, GlobeImmune (logo), haNK, haNK (Chinese characters), ImmunityBio, NantKwest, NK-92, Outsmart your disease, taNK, Tarmogen, VesAnktiva, and VivaBioCell are trademarks or registered trademarks of ImmunityBio, Inc., its subsidiaries, or its affiliates.

Our product candidates, including N-803, are investigational.

Safety and efficacy have not been established by any agency, including the U.S.

Food and Drug Administration (FDA).

This Annual Report contains references to our trademarks and trademarks belonging to other entities.

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These platforms and their associated product candidates are designed to overcome the limitations of the current standards of care in oncology and infectious diseases, such as checkpoint inhibitors and antiretroviral therapies.

We have established one of the most comprehensive portfolios of immunotherapy and vaccine platforms, which include:

We believe that our innovative approach to orchestrate and combine therapies for optimal immune system response will become a therapeutic foundation across multiple clinical indications.

Food and Drug Administration (FDA) for BCG -unresponsive NMIBC CIS .

B ased on the reported results of the trial, we have initiated discussions with the FDA to file a BLA for Anktiva (to be branded VesAnktiva ™ for intravesical administration) plus BCG for BCG-unresponsive NMIBC CIS.

Additionally, we believe data from multiple clinical trials indicates Anktiva has broad potential to enhance the activity of therapeutic monoclonal antibodies (mAbs), including checkpoint inhibitors (e.g., Keytruda ® ), across a wide range of tumor types.

Our platforms, which include 17 first-in-human therapeutic agents, are being studied in 26 actively recruiting clinical trials—17 of which are in Phase 2 or 3 development—across 13 indications in liquid and solid tumors, including bladder, pancreatic and lung cancers.

Our portfolio includes:

Our platforms include 9 first-in-human therapeutic agents that are currently being studied in 26 clinical trials—17 of which are in Phase 2 or 3 development—across 12 indications in liquid and solid tumors, including bladder, pancreatic and lung cancers.

These are among the most frequent and lethal cancer types for which there are high failure rates for existing standards of care or, in some cases, no available effective treatment.

In infectious disease, our pipeline currently targets such pathogens as the novel strain of the coronavirus (SARS-CoV-2) and human immunodeficiency virus (HIV).

In infectious diseases, our pipeline currently targets such pathogens as the novel strain of the coronavirus (SARS-CoV-2) and human immunodeficiency virus (HIV).

We believe SARS-CoV-2 currently lacks a vaccine that provides long-term protection against the virus, particularly its variants, while HIV affects tens of millions of people globally and currently has no known cure.

We believe that our innovative approach to orchestrate and combine therapies for optimal immune system response will become a therapeutic foundation across multiple clinical indications.

Additionally, we believe that data from multiple clinical trials indicates N-803 has broad potential to enhance the activity of therapeutic monoclonal antibodies (mAbs), including checkpoint inhibitors (e.g., Keytruda), across a wide range of tumor types.

N-803 is currently being studied in 21 clinical trials (both ImmunityBio and investigator-sponsored) across 12 indications.

Although such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval, Anktiva, ImmunityBio’s novel antibody cytokine fusion protein, has received Breakthrough Therapy and Fast Track designations from the FDA in combination with bacillus Calmette- Guérin (BCG) for the treatment of patients with BCG -unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without Ta or T1 disease.

In May 2022, we announced the submission of a Biologics License Application (BLA) to the FDA for our product candidate, Anktiva in combination with BCG for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without Ta or T1 disease .

In July 2022, we announced that the FDA had accepted our BLA for review and set a target Prescription Drug User Fee Act (PDUFA) action date of May 23, 2023.

It is unclear when the FDA will approve our BLA, if at all.

We have established Good Manufacturing Practice (GMP) manufacturing capacity at scale with cutting-edge cell manufacturing expertise and ready-to-scale facilities, as well as extensive and seasoned research and development (R&D), clinical trial, and regulatory operations and development teams.

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To achieve this goal, the key elements of our strategy include:

• advancing the approval and commercialization of our lead antibody cytokine fusion protein, Anktiva, as an integral component of immunotherapy combinations, including those with checkpoint inhibitors;

• advancing the approval and commercialization of our lead antibody cytokine fusion protein, N-803, as an integral component of immunotherapy combinations, including those with checkpoint inhibitors;

• continuously scrutinizing our clinical pipeline and assessing our strategic priorities to maximize opportunities for regulatory approval and to meet unmet medical needs;

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• continuing to prospect, license, and acquire technologies to complement and strengthen our platforms and product candidates, both as single agent and combination therapies, in order to activate and coordinate the innate and adaptive immune system to generate cellular memory against multiple tumor types and infectious diseases;

• optimizing investment in our discovery, development, and manufacturing capabilities for our next-generation targeted antibody cytokine fusion proteins and vaccine candidates, as well as for cell therapies;

• optimizing investment in our discovery, development, and manufacturing capabilities for our next-generation targeted antibody cytokine fusion and recombinant proteins and vaccine candidates, as well as for cell therapies;

• advancing our formulations and delivery mechanisms to make our promising biotechnology product candidates available to the broadest population possible;

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Antibody Cytokine Fusion Proteins

Antibody cytokine fusion proteins such as Anktiva are a novel class of biopharmaceuticals that enhance the therapeutic potential of cytokines, and promote lymphocyte infiltration at a site of disease, improving immune response.

Anktiva (N-803) is a novel interleukin-15 (IL-15) superagonist fusion protein consisting of high-affinity mutant IL-15N72D fused to the IL-15 receptor α sushi subunit and linked to the Fc portion of IgG1 Fc.

The novel antibody cytokine fusion protein specifically increases the activity of two critical aspects of the immune system—NK cells and cytotoxic (tumor cell killing) CD8 T-cells—and exerts its effects via beta gamma, rather than alpha, T-cell receptor binding and avoids regulatory T-cell (T-reg) stimulation that might dampen the pro-immune effect.

Anktiva has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

Multiple Phase 1 and Phase 2 trials in both liquid and solid tumors have been completed through the date of this Annual Report in ov er 700 patients.

Although such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval, Anktiva has been awarded both Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC CIS as well as Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC CIS.

Based on patient data that was submitted with our application to obtain the Breakthrough Therapy designation in BCG-unresponsive NMIBC CIS, Anktiva achieved its primary endpoint of a complete response (CR) rate at any time in the ongoing registrational Phase 2/3 trial.

We believe that other indications with registration potential include BCG unresponsive papillary bladder cancer , lung cancer, pancreatic cancer, glioblastoma multiforme ( GBM) and triple-negative breast cancer (TNBC).

We have initiated discussions with the FDA to file a BLA for Anktiva (to be branded Ves Anktiva for intravesical administration) plus BCG for BCG-unresponsive NMIBC CIS.

In addition to Anktiva, we are developing bi-specific fusion proteins targeting CD20, PD-L1, IL-12, and TGF-ß to further enhance NK and T-cell activation directed to the infectious disease or tumor microenvironment, and to modulate the systemic and local immune response to accelerate immunogenic cell death.

Antibody cytokine fusion proteins such as N-803 are a novel class of biopharmaceuticals that enhance the therapeutic potential of cytokines, and promote lymphocyte infiltration at a site of disease, improving immune response.

N-803 is a novel interleukin-15 (IL-15) superagonist fusion protein consisting of high-affinity mutant IL-15N72D fused to the IL-15 receptor α sushi subunit and linked to the Fc portion of IgG1 Fc.

The novel antibody cytokine fusion protein specifically increases the activity of two critical aspects of the immune system—NK cells and cytotoxic (tumor cell killing) CD8 T-cells—and exerts its effects via enhanced IL-2 receptor binding to the β site resulting in generation of Killer T cells and not the immunosuppressive regulatory T-cell (T-reg) cells.

This superagonist IL-15 activity is the first in class to activate and proliferate NK cells, CD8+ Killer T cells, and Memory T cells.

We believe this fusion protein combined with our natural killer cell therapy platform and our DNA/RNA vector delivery platforms places ImmunityBio at the leading edge to successfully deliver a cancer vaccine for durable complete responses across multiple tumor types.

Although such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval, Anktiva has received Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC CIS with or without Ta or T1 disease as well as Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC CIS.

I n May 2022, we announced the submission of a BLA to the FDA for our product candidate, Anktiva in combination with BCG for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without Ta or T1 disease.

In July 2022, we announced that the FDA had accepted our BLA for review and set a target PDUFA action date of May 23, 2023.

It is unclear when the FDA will approve our BLA, if at all.

We believe that other N-803 indications with registration potential include BCG-unresponsive papillary bladder cancer , lung cancer, pancreatic cancer, and glioblastoma multiforme ( GBM) in oncology and HIV in infectious diseases.

In addition to N-803, we are developing bi-specific fusion proteins targeting CD20, PD-L1, IL-12, and TGF-ß to further enhance NK and T-cell activation directed to the infectious disease or tumor microenvironment, and to modulate the systemic and local immune response to accelerate immunogenic cell death.

Prioritized product candidates in preclinical development include antibody cytokine fusion proteins N-820 (targeting CD20), N-809 (targeting PD-L1), N-812 (delivering IL-12 to necrotic tumor cells), and N-830 (delivering a TGF- ß Trap to necrotic tumor cells).

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These technologies can deliver DNA, self-amplifying RNA (saRNA), and subunit proteins to induce B- and T-cell memory due to the activation of both CD4+ and CD8+ T cells along with antibody (humoral) responses.

We believe a “mix-and-match” strategy (i.e., a heterologous approach combining different vaccine platforms) could provide maximal immune protection against current and future COVID-19 variants such as Delta and Omicron.

In SARS-CoV-2, we believe the focus on targeting a highly mutable S-protein and the associated antigenic drift with limited memory T-cell response is leading to a potential for emergence of resistance to the current generation of vaccines.

A booster vaccine targeting the N protein, which is highly conserved in the coronavirus genus and is one of the most abundant structural proteins in virus-infected cells, could provide maximal immune protection against current and future COVID-19 variants such as Delta and Omicron and their associated sub-lineage variants of concern.

In oncology, we are exploring the delivery of N-803 in combination with hAd5 TAAs like E6/E7, CEA, MUC1, Brachyury, and PSA, which we believe could yield immunological memory.

Our key vaccine delivery technologies include:

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Synthetic RNA technology has quickly emerged for prophylactic and therapeutic vaccines in part because it allows for rapid, scalable, and cell-free manufacturing as evidenced by the adoption of SARS-CoV-2 RNA vaccines.

We believe our saRNA technology (licensed from the Infectious Disease Research Institute (IDRI) both directly and, in the case of SARS-CoV-2, through our joint venture formed with Amyris, Inc.

We believe our saRNA technology (licensed from the Access to Advanced Health Institute (AAHI) (formerly known as the Infectious Disease Research Institute, or IDRI), both directly and, in the case of SARS-CoV-2, through our joint venture formed with Amyris, Inc.

(Amyris) in December 2021) represents a significant improvement over existing RNA technologies.

Our saRNA constructs include a nanostructured lipid carrier (NLC) formulation important for thermal stability and facilitating the substitution of genetic sequences and have demonstrated an ability to vaccinate with multi-valent strains.

The self-replicating capability allows for increased potency by maintaining auto-replicative activity derived from the RNA virus vector, while the self-amplifying capability may increase the duration and breadth of immunity.

Preclinical studies in small animal and non-human primate (NHP) models have shown that the saRNA delivery vehicle results in potent humoral and cell-based immunogenicity.

Phase 1 first-in-human trials of saRNA for COVID-19 are anticipated to begin in the first half of 2022.

Phase 1 first-in-human trials of saRNA for COVID-19 began in 2022 and continues in the first quarter of 2023.

Results to date demonstrated limited adverse events of the saRNA S construct, and the trial is currently evaluating the safety and immunogenicity of our saRNA N construct in a similar dose escalation manner.

Once Phase 1 is complete, the results will be used to inform the Phase 2 design for optimal immunogenicity.

Second-generation adenovirus hAd5 vector

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Our human adenovirus serotype 5 (hAd5) technology has unique deletions in the early 1, (E1), early 2 (E2b) and early 3 (E3) regions (hAd5 [E1-, E2b-, E3-]), which allows it to be effective in the presence of pre-existing adenovirus immunity and lowers the risk of generating de novo vector-directed immunity.

We have several hAd5 product candidates, which have been studied in multiple Phase 1 and 2 clinical trials as potential vaccines for the treatment of SARS-CoV-2 and certain cancers.

Importantly, these product candidates have shown an ability to overcome previous adenovirus immunity in cancer patients and in preclinical models.

The hAd5 technology has also been used with common TAAs to establish memory T cells in multiple clinical trials.

Our SARS-CoV-2 candidate uses a combination of S-Fusion and N-ETSD, our novel constructs of COVID-19 S+N proteins, which has been shown to generate CD4+ and CD8+ T cell mediated immunity and neutralizing antibodies in Phase 1 trials.

Our vaccine candidate is currently being studied in our SISONKE Boost Trial (COVID 4.010) in South Africa now in Phase 3.

Recombinant subunit proteins

Our yeast vaccine platforms have been studied in both oncology and infectious disease.

The Tarmogen platform (licensed from our subsidiary GlobeImmune, Inc.

We have developed several hAd5 product candidates, which have been studied in multiple clinical trials as potential vaccines for the treatment of infectious diseases and certain cancers.

Importantly, these product candidates have shown an ability to overcome previous adenovirus immunity in preclinical models and in cancer patients.

In oncology, we are exploring the delivery of N-803 in combination with hAd5 TAAs like HPV E6/E7, CEA, MUC1, Brachyury, and PSA, which we believe could yield immunological memory.

Recombinant protein platforms

Our yeast vaccine platforms have been studied in both oncology and infectious diseases:

(i) our Tarmogen platform (licensed from our subsidiary GlobeImmune, Inc.

(GlobeImmune)) has been administered to over 400 patients with cancer or infectious diseases in FDA-regulated clinical trials.

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Immunization with this platform elicits CD4+ and CD8+ T cell responses capable of eliminating tumor cells or pathogen-infected cells.

Our recombinant receptor-binding domain (RBD) pichia-based antigen (licensed from the Baylor College of Medicine (BCM), which was developed at the Texas Children’s Hospital Center for Vaccine Development) with 3M-052/Alum adjuvants and related technology (licensed from IDRI and 3M Company (3M) and affiliates) has been shown to provide protection against SARS-CoV-1, SARS-CoV-2 (and variants of concern), and animal coronaviruses.

Phase 1 clinical trials of this subunit protein and 3M-052 adjuvants are anticipated to begin in the first half of 2022.

Bacterial-based endosomal delivery vectors

EDVs are a first-in-class, cyto-immunotherapy platform that utilizes antibody-targeted, bacterially-derived, 400 nm diameter non-living “nanocells” to release high concentrations of super-cytotoxic drugs, molecularly-targeted drugs, or small interfering RNAs (siRNAs)/microRNAs (miRNAs) and can be engineered to activate iNKT cells (see below—Invariant natural killer T cells (iNKT)).

We signed a binding term sheet with EnGeneIC Pty Limited (EnGeneIC) to integrate their patented EDV to explore clinical development in the treatment of COVID-19 and pancreatic cancer.

(ii) our pichia platform was used to produce RBD antigens (licensed from Baylor College of Medicine (BCM) (which was developed at the Texas Children’s Hospital Center for Vaccine Development)), which, when combined with the 3M-052/Alum adjuvants and related technology (licensed from AAHI and 3M Company (3M) and affiliates), had been shown to provide protection against SARS-CoV-1, SARS-CoV-2 (and variants of concern), and animal coronaviruses in preclinical models.

Toll-Like Receptor Activating Adjuvants

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Once activated, these TLRs stimulate danger signals to the immune cells initiating an immune response.

We have licensed adjuvants and related technology from IDRI and 3M Company and its affiliates to incorporate with the vaccine delivery platforms described above and have access to multiple toll receptor activators, including TLR 4, TLR 7, and TLR 8.

We have licensed adjuvants and related technology from AAHI and 3M and its affiliates to incorporate with the vaccine delivery platforms described above and have access to multiple toll receptor activators, including TLR 4, TLR 7, and TLR 8.

The synthetic imidazoquinolinone 3M-052 is structurally similar to resiquimod.

The 3M-052/Alum adjuvant formulation is in Phase 1 trials in the U.S.

with an HIV antigen and has been well-tolerated and highly immunogenic.

A Phase 1 clinical trial for SARS-CoV-2 of this 3M-052 adjuvant in combination with a subunit protein is anticipated to begin in the first half of 2022.

We also plan to use these adjuvants in vaccines for the treatment of tuberculosis, schistosomiasis, and influenza.

with an HIV antigen and has been well-tolerated and immunogenic.

NK Cell Therapy

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These product candidates are intended to be combined with commercially available therapeutic antibodies to effectively target either two different epitopes of the same cancer-specific protein or two entirely different cancer specific proteins.

Key trials studying o ur t-haNK product candidates have been initiated—PD-L1 t-haNK in Phase 1/2 trials in TNBC , and Phase 2 trials in pancreatic and GBM—and CD19 t-haNK has been cleared to commence Phase 1 testing in non-Hodgkin’s lymphoma.

We believe we have a pipeline of other prominent CARs for t-haNK, including HER2 and epidermal growth factor receptor ( EGFR), which are advancing through clinical-enabling studies, among others, which will enable us to potentially address an even broader range of cancers as part of a chemotherapy-free combination regimen.

In March 2021, in collaboration with the National Cancer Institute (NCI), our PD-L1 t-haNK was reported to be a potent cell therapy agent against myeloid-derived suppressor cells (MDSC) and overcome T cell escape in multiple types of resistant tumors (Fabian et al 2020).

In January 2022, we reported on the results of our metastatic pancreatic cancer trial using PD-L1 t-haNK in combination with Anktiva.

These findings, which were reported at the ASCO Gastrointestinal Conference in January 2022, showed a median overall survival of 6.3 months in patients who had progressed after two prior lines of therapy, more than doubling historical survival.

We plan to meet with the FDA in 2022 to discuss a potential path for the approval of combination therapies for pancreatic cancer.

Trials studying o ur t-haNK product candidates were initiated—PD-L1 t-haNK in a Phase 1 trial in triple negative breast cancer ( TNBC) , and a Phase 2 trial in pancreatic cancer—and CD19 t-haNK has been cleared to commence Phase 1 testing.

In collaboration with the National Cancer Institute (NCI), our PD-L1 t-haNK was reported to be a potent cell therapy agent against myeloid-derived suppressor cells (MDSC) and overcome T cell escape in multiple types of resistant tumors (Fabian et al 2020).

Results of the QUILT 88 trial of patients with advanced pancreatic cancer reported at the American Society of Clinical Oncology (ASCO) meeting in June 2022 and updated at ASCO GI in January 2023 showed a median overall survival of 6.3 months (95% CI:

5.0, 7.2 months) in patients who had progressed after two prior lines of therapy, more than doubling historical survival.

We believe we have a pipeline of other prominent CARs for t-haNK, including epidermal growth factor receptor ( EGFR), which is advancing through clinical-enabling studies, which will enable us to potentially address an even broader range of cancers as part of a chemotherapy-free combination regimen.

Autologous and allogenic memory-like cytokine-enhanced NK cells (M-ceNK)

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These cells have been isolated and characterized by their unique cell-surface marker profile and their highly desirable feature of immune-memory, marked by their pronounced anti-cancer activity for weeks to months in duration, which has made these cells a research focus for more than a decade.

We have developed a unique ability to generate a portfolio of distinct M-ceNK cell products through the application of our proprietary GMP-in-a-Box bioreactors and cytokines and our proprietary methods and overall expertise in scale manufacturing of NK cell-based products.

In May 2021, the FDA authorized the company to conduct a first-in-human trial to study the M-ceNK platform in solid tumors (QUILT 3.076).

An initial clinical trial showed that healthy and patient-derived M-ceNK killed NK-resistant tumor cells.

Invariant natural killer T cells

iNKT cells are unique T cells that express an invariant aβ T-cell receptor (TCR) and a number of cell surface molecules in common with NK cells.

Although they comprise less than 1% of peripheral blood mononuclear cells (PBMCs), they are important immunoregulatory cells that can quickly produce large amounts of cytokines.

iNKT cell-derived cytokines and chemokines recruit and activate dendritic cells and can modulate several other cell types, including B cells, CD4+ and CD8+ T cells, NK cells, macrophages and neutrophils.

iNKT cells recognize glycolipid antigens presented by the non-polymorphic major histocompatability complex (MHC) Class I-like molecule, CD1d in contrast to conventional T cells, which primarily recognize peptide antigens presented by MHC molecules.

We entered into a binding term sheet with EnGeneIC to license EDV, which can be engineered to activate iNKT cells, to explore clinical development in the treatment of COVID-19 and pancreatic cancer.

We plan on developing iNKT-cell vaccines, including for the prevention of COVID-19.

EDV is now in Phase 3 clinical trials in Australia.

Through the date of this Annual Report, the initial 2x109 EDV IM dose has shown little to no adverse events (AEs) with what we believe is promising antibody, memory B cell and T cell activity.

In addition to expanding this trial in Australia and the U.S., we are exploring using the EDV technology in combination with our other vaccine constructs for select future trials.

We have developed a unique ability to generate a portfolio of distinct M-ceNK cell products through the application of our proprietary technology and cytokines and our proprietary methods and overall expertise in scale manufacturing of NK cell-based products.

A Phase 1 trial is open and actively enrolling patients in a f irst-in-human trial to study the M-ceNK platform in solid tumors (QUILT 3.076).

Damage-Associated Molecular Patterns Inducers

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DAMPs may play a protective role by alerting the immune system to the existence of dying tumor cells, thereby triggering immunogenic tumor cell death.

Albumin bound chemo modulators and tumor associated antigen regulators target delivery of the chemotherapy agent to the tumor microenvironment, activate tumor killing macrophages and/or enable a tumor suppressive microenvironment.

Albumin-bound immune modulators and tumor associated antigen regulators target delivery of the chemotherapy agent to the tumor microenvironment, activate tumor killing macrophages and/or enable a tumor suppressive microenvironment.

Aldoxorubicin

Aldoxorubicin is an albumin-associated anthracycline chemo modulator designed to target immune evasion in cancer.

Aldoxorubicin has the same cytotoxic mechanism of action as doxorubicin, which is currently approved for use in 14 indications, including breast cancer, Hodgkin’s lymphoma and small cell lung cancer (SCLC), but also has unique pharmacological properties resulting in lower cardiotoxicity as shown in Phase 2 and Phase 3 clinical trials for soft tissue sarcoma previously conducted by CytRx Corporation (CytRx).

CytRx out-licensed global development, manufacturing, and commercialization rights for aldoxorubicin to us in 2017.

The investigative therapeutic is currently in a Phase 2 trial in pancreatic cancer in combination with Anktiva and PD-L1 t-haNK, and we plan to include it in a new randomized, multi-center, Phase 2 GBM trial (QUILT 3.078) currently being developed to evaluate the efficacy and safety of the combinations of Anktiva, aldoxorubicin, PD-L1 t-haNK, and bevacizumab.

Aldoxorubicin is an albumin-associated anthracycline designed to target immune evasion in cancer.

Aldoxorubicin has the same cytotoxic mechanism of action as doxorubicin, which is currently approved for use in 14 indications, including breast cancer, Hodgkin’s lymphoma and small-cell lung cancer (SCLC), but also has unique pharmacological properties resulting in lower cardiotoxicity as shown in Phase 2 and Phase 3 clinical trials for soft tissue sarcoma previously conducted by LadRx Corporation (LadRx, formerly CytRx Corporation).

LadRx out-licensed global development, manufacturing, and commercialization rights for aldoxorubicin to us in 2017.

The investigative therapeutic is currently in a Phase 2 trial in metastatic pancreatic cancer (QUILT 88) of DAMP inducers combined with N-803 and PD-L1 t-haNK to evaluate the safety and efficacy of the combination.

VRx-3996 (nanatinostat), an orally available histone deacetylase (HDAC) inhibitor, is being developed by Viracta.

Nanatinostat is selective for specific isoforms of Class I HDACs, which is key to inducing viral genes that are epigenetically silenced in EBV-associated malignancies.

Nanatinostat is selective for specific isoforms of Class I HDACs, which is key to inducing viral genes that are epigenetically silenced in Epstein-Barr virus-associated malignancies.

In preclinical studies, nanatinostat has been shown to reactivate silenced transgenes in tumor cells thereby turning them into preferential targets for NK cell killing, while also serving to broadly stimulate a patient’s immune system, offering the potential for improved clinical responses in cancer patients.

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We entered into an agreement with Viracta under which we were granted exclusive worldwide rights in patents and know-how related to nanatinostat for use in combination with our platform of NK cell therapies.

In infectious diseases, our pipeline currently targets such pathogens as SARS-CoV-2 and HIV.

Through the date of this Annual Report, our product candidates have been tested in various Phase 1, 2 and 3 clinical trials that have enrolled over 2,400 patients.

Non-Muscle Invasive Bladder Cancer (QUILT 3.032) (QUILT 2.005)

These are among the most frequent and lethal cancer types for which there are high failure rates for existing standards of care or, in some cases, no available effective treatment.

We are constantly monitoring and deciding which trials to initiate or continue based upon the availability of our resources and the efficacy and market developments of our, and our competitors’, products and product candidates, among other factors.

Non-Muscle Invasive Bladder Cancer

In the U.S., bladder cancer is the fourth most commonly-diagnosed solid malignancy in men and twelfth in women.

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There is an urgent, unmet need to treat NMIBC and avoid radical cystectomy of the bladder in an attempt to control the disease.

Although such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval, Anktiva has been awarded both Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC CIS as well as Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC CIS.

In our QUILT 3.032 trial, the company reported that the primary end points were met for both BCG-unresponsive NMIBC CIS and papillary in October 2021 with a complete remission rate of 72% and a 12-month disease-free rate of 57%, respectively.

Seminal patents covering intravesical administration of BCG and Anktiva were issued (US 11,173,191 B2 and US 9,925,247 B2) providing term coverage until 2035.

Although such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval, Anktiva has received Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC CIS (Cohort A) with or without Ta or T1 disease as well as Fast Track designation for BCG-unresponsive NMIBC papillary (Cohort B) and BCG-naïve NMIBC CIS.

In our QUILT 3.032 trial, the company reported in November 2022, as published in NEJM Evidence , that the primary end points were met for both BCG-unresponsive NMIBC CIS with a complete response rate of 71%, and BCG-unresponsive NMIBC papillary with a 12-month disease-free rate of 55%.

As presented at ASCO 2022, the combination of BCG plus Anktiva (as measured in BCG-unresponsive NMIBC patients, Cohorts A and B combined) was well-tolerated with 1% treatment-related serious adverse events, 0% immune-related serious adverse events, and 100% bladder cancer-specific overall survival at 24 months.

Low-grade treatment-related adverse events include dysuria (22%), pollakiuria (20%), hematuria (17%), fatigue (16%), and urgency (12%), and all other treatment-related adverse events were seen at 7% or less.

Seminal patents covering intravesical administration of BCG and Anktiva were issued providing term coverage until 2035.

BCG-Unresponsive CIS (QUILT 3.032)

In our Phase 2/3 open-label multi-center trial of BCG-unresponsive high grade NMIBC CIS patients, the patients are receiving BCG plus Anktiva weekly for six consecutive weeks during induction.

In our Phase 2/3 open-label multi-center trial of BCG-unresponsive high grade NMIBC patients, the patients are receiving BCG plus Anktiva weekly for six consecutive weeks during induction.

The patients also receive additional treatment including three weekly maintenance instillations every three months for up to 12 months and then at month 18.

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The primary endpoint of the BCG-unresponsive NMIBC CIS trial is a CR rate at any time equal to or greater than 30% and the lower bound of the 95% confidence interval must be greater than or equal to 20% for success.

Complete response, or the disappearance of measurable disease in response to treatment, is evaluated at three months or six months following initial administration of Anktiva plus BCG (and every three months thereafter until 24 months).

Complete response, or the disappearance of measurable disease in response to treatment, is evaluated at three months or six months following initial administration of BCG plus Anktiva (and every three months thereafter until 24 months).

This endpoint would be achieved once at least 24 of the 80 patients in the trial achieve complete response.

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There can be no assurance that the FDA will agree with this conclusion.

A data cutoff occurred in January 2022, which provided a median follow-up in Cohort A in excess of 24 months.

Data presented at the ASCO ® Genitourinary Cancers Symposium in February 2022 showed a complete response in 59 of 83 patients 71% CR rate (95% CI:

60.1, 80.5) and a median duration of CR of 24.1 months.

In those patients who responded to the investigational therapeutic, the probability of avoiding both progression of bladder cancer and cystectomy at 24 months exceeded 90%.

The combination of Anktiva and BCG had a well-tolerated profile with 0% treatment-related serious adverse events (SAEs), 0% immune-related AEs, and 100% bladder cancer-specific overall survival at 24 months.

Low-grade treatment related AEs include dysuria, hematuria, and pollakiuria (all 16%), urgency (14%), and bladder spasm (8%), all other AEs were seen at 6% or less.

No immune-related SAEs have been observed.

We continue to engage in discussions with the FDA, and we anticipate filing a BLA for BCG-unresponsive NMIBC CIS in the first quarter of 2022.

A data cutoff occurred in January 2022, which provided a median follow-up in Cohort A of approximately 24 months.

Data as published in NEJM Evidence in November 2022 showed a complete response in 58 of 82 patients with a 71% CR rate (95% CI:

59.6, 80.3) and a median duration of CR of 26.6 months (95% CI:

9.9, [upper bound not reached]).

At 24 months in patients with complete response, the probability of avoiding cystectomy and disease-specific survival was 91.4% and 100%, respectively.

Also at 24 months in all patients in Cohort A, the probability of avoiding cystectomy and of disease-specific survival was 84.1% and 100%, respectively.

In May 2022, we announced the submission of a BLA to the FDA for our product candidate, Anktiva in combination with BCG for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without Ta or T1 disease .

In July 2022, we announced that the FDA had accepted our BLA for review and set a target PDUFA action date of May 23, 2023.

It is unclear when the FDA will approve our BLA, if at all.

BCG-Unresponsive Papillary (QUILT 3.032)

In our Phase 2, open-label multi-center trial of BCG-unresponsive high grade NMIBC papillary patients (Cohort B), the patients are receiving BCG plus Anktiva weekly for six consecutive weeks during induction.

In our Phase 2, open-label multi-center trial of BCG-unresponsive high grade NMIBC papillary patients (Cohort B), the patients are receiving BCG plus N-803 weekly for six consecutive weeks during induction.

The patients also receive additional treatment including three weekly maintenance instillations every three months for up to 12 months and then every nine months for up to 24 months.

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To meet the primary endpoint, 24 out of 80 patients must be disease free at 12 months.

Data presented at the ASCO ® Genitourinary Cancers Symposium in February 2022 showed a 12-month disease-free rate of 57% (95% CI:

44, 68) in the papillary Cohort B, in which 73 of 77 patients (95%) have not progressed to radical cystectomy after a median duration of follow-up of 20.7 months, and a 99% bladder cancer-specific survival through the January 2022 data cutoff.

A data cutoff occurred in January 2022, which provided a median follow-up in Cohort B of approximately 21 months.

Data as published in NEJM Evidence in November 2022 showed a 12-month disease-free survival rate of 55% (95% CI:

42.0, 66.8), with median disease-free survival of 19.3 months (95% CI:

7.4, [upper bound not reached]).

At the cutoff date 67 of 72 patients, 93.1%, had not progressed to radical cystectomy and the 24 month disease-free survival rate was 97.7%.

We met with the FDA in December 2022, and the FDA advised us to conduct a randomized trial in localized BCG-unresponsive NMIBC papillary disease.

BCG-N aïve (QUILT 2.005)

As discussed above, Anktiva has been awarded Fast Track designation by the FDA for the treatment of BCG-naïve NMIBC CIS.

We are currently enrolling patients in our Phase 2b blinded, randomized, two-cohort, open-label, multi-center trial of intravesical Anktiva plus BCG versus BCG alone, in BCG naïve patients with high-grade NMIBC CIS (Cohort A) and NMIBC papillary (Cohort B ).

As discussed above, N-803 has been awarded Fast Track designation by the FDA for the treatment of BCG-naïve NMIBC CIS.

We are currently enrolling patients in our Phase 2b blinded, randomized, two-cohort, open-label, multi-center trial of intravesical BCG plus Anktiva versus BCG alone, in BCG naïve patients with high-grade NMIBC CIS (Cohort A) and NMIBC papillary (Cohort B ).

Planned enrollment for Cohort A (CIS) and Cohort B (papillary) is 366 patients and 230 patients, respectively.

Lung Cancer (Lung-MAP) (QUILT 2.023)

According to the American Cancer Society, lung cancer is the second most common cancer in the U.S.

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and 127,070 deaths will be attributed to the disease.

Non-small cell lung cancer accounts for about 80% to 85% of all lung cancers diagnoses and there are very few successful treatment options for these patients once the cancer spreads beyond the lungs.

The development of checkpoint inhibitors in non-small cell lung cancer (NSCLC) has been revolutionary, doubling the median overall survival in some settings;

Non-small cell lung cancer (NSCLC) accounts for about 80% to 85% of all lung cancers diagnoses and there are very few successful treatment options for these patients once the cancer spreads beyond the lungs.

The development of checkpoint inhibitors in NSCLC has been revolutionary, doubling the median overall survival in some settings;

however, patient response may be short lived, due to late response and/or progression after achieving an initial response.

As with bladder cancer, Anktiva enhances the proliferation and activation of NK and T cells critical for targeting and killing lung cancer cells.

There is therefore a strong rationale to evaluate Anktiva in addition to an anti-PD-1 or anti-PD-L1 checkpoint inhibitor for patients with NSCLC who have relapsed after achieving an initial response to PD-1 or PD-L1 checkpoint inhibitor therapy.

Analysis of the pooled data from a Phase 1/2 trial conducted from January 2016 to June 2017 in 23 patients, and a subsequent investigator-initiated Phase 2 trial conducted by the Medical University of South Carolina, yielded confirmation of activity of the combination of checkpoint inhibitors and Anktiva in relapsed NSCLC.

As with bladder cancer, N-803 enhances the proliferation and activation of NK and T cells critical for targeting and killing lung cancer cells.

There is therefore a strong rationale to evaluate N-803 in addition to an anti-PD-1 or anti-PD-L1 checkpoint inhibitor for patients with NSCLC who have relapsed after achieving an initial response to PD-1 or PD-L1 checkpoint inhibitor therapy.

Analysis of pooled data from a Phase 1/2 trial conducted from January 2016 to June 2017 in 23 patients, and a subsequent investigator-initiated Phase 2 trial conducted by the Medical University of South Carolina, yielded confirmation of activity of the combination of checkpoint inhibitors and N-803 in relapsed NSCLC.

In 15 patients with PD-L1 greater than 50%, the overall response rate was 38% and the median overall survival rate was 17.1 months.

These preliminary findings were favorable relative to the historical response rate seen in this patient population in the first-line setting with checkpoint inhibitor therapy.

On the basis of these findings, we initiated a single-arm Phase 2b multi-cohort basket trial (QUILT 3.055) of Anktiva and checkpoint inhibitor combinations in patients who have previously received treatment with PD-1/PD-L1 immune checkpoint inhibitors per an FDA-approved indication.

On the basis of these findings, we initiated a single-arm Phase 2b multi-cohort basket trial (QUILT 3.055) of N-803 and checkpoint inhibitor combinations in patients who have previously received treatment with PD-1/PD-L1 immune checkpoint inhibitors per an FDA-approved indication.

Patients enrolled in this trial were eligible if actively progressing on checkpoint inhibitor therapy.

Upon enrollment, patients continued on the same checkpoint inhibitor but with the addition of Anktiva.

Upon enrollment, patients continued on the same checkpoint inhibitor but with the addition of N-803.

Despite progressing on checkpoint inhibitor therapy upon entry into the trial, the majority of patients reverted to stable disease and demonstrated durability of stable disease, some extending as long as nine months.

Data presented at the ASCO Annual Meeting in 2021 showed that despite the patients’ prior progression on checkpoint inhibitor therapy alone, upon entry into the trial the majority of patients experienced clinical benefit either as stable disease (49%) or a partial response (9%).

Among 133 cancer patients enrolled in QUILT 3.055, the common Anktiva attributed grade 1 and 2 AEs included:

Among 140 patients enrolled in QUILT 3.055, the common N-803 attributed grade 1 and 2 adverse events included:

injection site reaction (71%), chills (34%), fatigue (27%), pyrexia (24%), flu-like illness (13%), and decreased appetite (10%).

A total of 18 grade 3 and 4 AEs attributed to Anktiva have been reported among 16 patients (12%) in the trial as of February 2021.

All reported grade 3 and 4 AEs occurred at a frequency of 5% or less;

A total of 18 grade 3 and 4 adverse events attributed to N-803 have been reported among 16 patients (12%) in the trial as of February 2021.

All reported grade 3 and 4 adverse events occurred at a frequency of 5% or less;

two patients reported increased alanine amino transferase, increased aspartate amino transferase or increased blood alkaline phosphatase, anemia, injection-site reaction or injection-site pain.

All other occurrences of grade 3 or 4 AEs that the clinical trial site investigators reported as suspected as being due to Anktiva include:

All other occurrences of grade 3 or 4 adverse events that the clinical trial site investigators reported as suspected as being due to N-803 include:

decreased lymphocyte count;

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and maculopapular rash.

In October 2021, we announced that Anktiva had been chosen by Lung Cancer Master Protocol (Lung-MAP), a public-private partnership—which includes the NCI, the National Clinical Trials Network (NCTN) Cooperative Groups (SWOG, ECOG-ACRIN, Alliance, and NRG), Friends of Cancer Research, and the Foundation for the National Institutes of Health (FNIH)—to study Anktiva in the Lung-MAP trial.

The trial with Anktiva in combination with Keytruda ® (pembrolizumab) will include up to 478 second-line patients with tumors that are not targetable with a drug, which accounts for the majority of NSCLC cases.

In the fourth quarter of 2021, approval was received from the Institutional Review Board (IRB) overseeing the Lung-MAP study to proceed with the trial—one of the NCI’s largest lung cancer clinical trials with more than 700 sites.

Enrollment has begun for this trial.

We are enrolling patients in a randomized Phase 3 trial (QUILT 2.023) to evaluate Anktiva plus checkpoint inhibitor combinations versus other checkpoint inhibitor combinations in the first line setting for NSCLC.

Patients will be treated as described below:

Although further studies are warranted, based on this relatively well-tolerated adverse event profile, coupled with NK and CD8+ T cell stimulatory effects, we believe that N-803 has the potential to become a standard in combination with other immunotherapies for multiple indications.

Non-small Cell Lung Cancer (Lung-Map)

In October 2021, we announced that N-803 had been chosen by Lung Cancer Master Protocol (Lung-MAP), a public-private partnership—which includes the NCI, the National Clinical Trials Network (NCTN) Cooperative Groups (SWOG, ECOG-ACRIN, Alliance, and NRG), Friends of Cancer Research, and the Foundation for the National Institutes of Health (FNIH)—to study N-803 in the Lung-MAP trial.

The trial design is a randomized comparison of N-803 in combination with Keytruda ® (pembrolizumab) compared to standard of care chemotherapy options in two separate cohorts:

• Primary Resistance (Cohort 1).

Disease progression during or after anti-PD-1 or anti-PD-L1 therapy that occurred less than or equal to (≤) 84 days following initiation (Cycle 1 Day 1) of anti-PD-1 or PD-L1 therapy (combination or monotherapy).

• Acquired Resistance (Cohort 2).

Disease progression during or after anti-PD-1 or anti-PD-L1 therapy that occurred more than (>) 84 days following initiation (Cycle 1 Day 1) of anti-PD-1 or PD-L1 therapy (combination or monotherapy).

The trial will include up to 478 second-line patients with tumors that are not targetable with a drug, which accounts for the majority of NSCLC cases.

In April 2022, we announced that the first participants had been enrolled in the trial.

Non-small Cell Lung Cancer (QUILT 2.023)

On the basis of earlier trials in NSCLC, and our belief that N-803 enhances the proliferation and activation of NK and T cells, we enrolled patients in a randomized Phase 3 trial to evaluate N-803 plus checkpoint inhibitor combinations versus other checkpoint inhibitor combinations in the first-line setting for NSCLC in the cohorts described below:

• Immunotherapy for either squamous or non-squamous NSCLC with PD-L1 TPS >1% (Cohort A).

Combination of Anktiva with Keytruda ® versus Keytruda as the standard of care control arm in this randomized trial.

Combination of N-803 with Keytruda versus Keytruda as the standard of care control arm in this randomized trial.

• Chemoimmunotherapy for squamous NSCLC (Cohort B).

Combination of Anktiva with Carboplatin, Abraxane ® and Keytruda versus Carboplatin, Abraxane / paclitaxel and Keytruda as the standard of care control arm in this randomized trial.

Combination of N-803 with Carboplatin, Abraxane ® and Keytruda versus Carboplatin, Abraxane / paclitaxel and Keytruda as the standard of care control arm in this randomized trial.

• Chemoimmunotherapy for non-squamous NSCLC (Cohort C).

Combination of Anktiva with Cisplatin / Carboplatin, Keytruda and Pemetrexed versus Cisplatin / Carboplatin, Keytruda and Pemetrexed as the standard of care control arm in this randomized trial.

Pancreatic Cancer (QUILT 88)

According to the American Society of Clinical Oncology, in the U.S.

Combination of N-803 with Cisplatin / Carboplatin, Keytruda and Pemetrexed versus Cisplatin / Carboplatin, Keytruda and Pemetrexed as the standard of care control arm in this randomized trial.

The trial is currently ongoing.

Pancreatic Cancer

According to ASCO, in the U.S.

pancreatic cancer is the fourth leading cause of cancer-related death in both men and women and has one of the highest mortality rates of all major cancers, taking nearly 50,000 lives every year, with a five-year survival rate for late-stage cases of only 3%.

Exploratory Phase 1b/2 trials in patients with second-line or greater metastatic pancreatic cancer in which Anktiva and aldoxorubicin were combined with off-the-shelf NK (haNK) cells, other agents, and stereotactic body radiotherapy (SBRT) showed encouraging results in patients with advanced disease.

The primary endpoints of the Phase 1b and 2 portions of the trial were safety and objective response rate, respectively.

In aggregate, 82% of patients (14/17) with advanced pancreatic cancer achieved disease control following combination therapy including Anktiva and aldoxorubicin.

There were no Anktiva-related grade 3 or 4 AEs reported.

On the basis of these exploratory trials, together with the preclinical findings that PD-L1 t-haNK is as active as haNK + anti-PD-L1 mAbs, we initiated a first- through third-line pancreatic cancer clinical trial (QUILT 88) that uses PD-L1 t-haNK as described below.

Advanced Pancreatic Cancer (QUILT 88)

Exploratory Phase 1b/2 trials in patients with second-line or greater metastatic pancreatic cancer in which N-803 and aldoxorubicin were combined with off-the-shelf NK (haNK) cells, other agents, and stereotactic body radiotherapy (SBRT) showed encouraging results in patients with advanced disease.

The primary endpoints of the Phase 1b and 2 portions of the trials were safety and objective response rate, respectively.

In aggregate, 82% of patients (14/17) with advanced pancreatic cancer achieved disease control following combination therapy including N-803 and aldoxorubicin.

There were no N-803-related grade 3 or 4 adverse events reported.

• First-line advanced pancreatic cancer (Cohort A) .

Combination of Anktiva with aldoxorubicin and low-dose chemotherapy plus SBRT with or without PD-L1 t-haNK versus gemcitabine/Abraxane ® as the standard of care control arm in this randomized trial.

Combination of N-803 with aldoxorubicin and low-dose chemotherapy plus SBRT with or without PD-L1 t-haNK versus gemcitabine/Abraxane ® as the standard of care control arm in this randomized trial.

• Second-line advanced pancreatic cancer (Cohort B) .

Combination of Anktiva with aldoxorubicin and low-dose chemotherapy plus SBRT + PD-L1 t-haNK versus 5FU/Onivyde ® as the standard of care control arm in this randomized trial.

Combination of N-803 with aldoxorubicin and low-dose chemotherapy plus SBRT + PD-L1 t-haNK versus 5FU/Onivyde ® as the standard of care control arm in this randomized trial.

• Third-line and beyond (Cohort C) .

Combination of Anktiva with aldoxorubicin and low-dose chemotherapy plus SBRT + PD-L1 t-haNK in a single arm cohort of this trial with a primary endpoint of overall survival.

Combination of N-803 with aldoxorubicin and low-dose chemotherapy plus SBRT + PD-L1 t-haNK in a single arm cohort of this trial with a primary endpoint of overall survival.

On October 13, 2021, we announced that the trial’s Cohort C was fully enrolled.

In January 2022 at the ASCO Gastrointestinal Cancer Symposium, we reported that 27% of third-line or greater patients (17/63) remain on study and that the median overall survival in this highly advanced group of patients (who failed two to six prior lines of treatment) is 5.8 months (95% CI:

3.9, 6.9 months) exceeding the approximately three-month historical median overall survival.

Based on the strength of earlier data and the significant unmet medical need, we submitted an amendment to the FDA to increase enrollment in Cohort C.

As of January 2023 as reported at ASCO GI, the median overall survival in this highly advanced group of patients (who failed two to six prior lines of treatment) is 5.8 months (95% CI:

4.9, 6.4 months) exceeding the approximately two- to three-month historical median overall survival.

Of the 83 patients, 41 (49.4%) had progressed after two prior lines of therapy.

Median overall survival in this group was 6.3 months (95% CI:

5.0, 9.8 months), more than doubling the historical overall survival.

(Survival of three months as reported by Manax et al ASCO GI 2019).

In Cohort C, four patients (7%) experienced treatment-related SAEs that included peripheral edema, pyrexia, anemia and atrial flutter.

No treatment-related deaths were reported.

Based on the strength of earlier data and the significant unmet medical need, we submitted an amendment to the FDA to increase enrollment in Cohort C and plan to meet with the FDA in 2022 to discuss a potential path for the approval of combination therapies for pancreatic cancer.

Triple-Negative Breast Cancer (QUILT 3.058)

According to the Breast Cancer Research Foundation, globally more than 2.3 million women were diagnosed with breast cancer in 2020 and 685,000 died from it.

Triple-negative breast cancer is especially aggressive and accounts for 10-15% of breast cancers according to the American Cancer Society.

In a prior exploratory Phase 1b/2 trial (QUILT 3.067), which included nine heavily pre-treated metastatic TNBC patients, we treated them with a combination immunotherapy that included Anktiva and aldoxorubicin, haNK cell therapy, along with several other immunotherapy agents.

The primary endpoints of the Phase 1b and 2 portions of the trial were safety and objective response rate, respectively.

The exploratory Phase 1b/2 trial in nine patients with advanced TNBC showed a disease control rate of 89% with a complete or partial response of 67% (6/9), including two patients (22%) with a complete response to the combination therapy.

The median progression-free survival was 14.3 months with median overall survival of 20.2 months as of December 2020.

Eight of the nine patients had primarily chemotherapy-related neutropenia or anemia, but all cases were low grade.

A total of 27 grade 3 AEs were reported by 9 patients (100%) and included disease progression, pyrexia, mastitis, pneumonia, nausea, cholecystitis, and pain in extremity.

However, none of these SEAs were attributed to Anktiva.

There were three grade 3 haNK-related AEs with fever and fatigue, but no patient withdrew due to an SAE or experienced cytokine release syndrome.

Based on this encouraging data, in June 2021 we announced we had received FDA authorization to conduct a Phase 1b/2 open-label study to evaluate the safety and preliminary efficacy of Anktiva and PD-L1 t-haNK cells in combination with standard chemotherapy and Trodelvy ® (sacituzumab govitecan-hziy) in patients with advanced TNBC.

The study consists of two phases and will enroll up to 79 patients.

The Phase 1b portion of the study has 2 parts:

Part 1 involves dose escalation using a 3+3 design, and Part 2 involves the expansion of the recommended Phase 2 dose (RP2D) to further evaluate the safety and efficacy of sacituzumab govitecan-hziy plus chemoimmunotherapy.

The Phase 2 portion of the study is based on a Simon’s two-stage optimal design.

In Phases 1b and 2, all patients receive sacituzumab govitecan-hziy plus chemotherapy combined with immunotherapy:

cyclophosphamide, Anktiva, and PD-L1 t-haNK on a 3-week schedule.

The dose of sacituzumab govitecan-hziy is dependent on dose level cohort for Phase 1b and will be set at the RP2D for Phase 2.

The doses of cyclophosphamide, Anktiva, and PD‑L1 t-haNK will remain the same in all dose level cohorts and phases.

This trial is open and currently enrolling patients.

Glioblastoma Mulitforme (QUILT 3.078)

According to the American Association of Neurological Surgeons, GBM is the most common malignant brain and other tumors accounting for approximately 48% of all primary brain tumors with a low survival rate of approximately 40% in the first year after diagnosis and only 17% in the second year.

A single arm Phase 2 trial was completed in 2016 that assessed the preliminary efficacy and safety of aldoxorubicin administered to recurrent GBM patients who progressed after first-line therapy.

The primary endpoint of the trial was objective response rate.

Out of 28 patients, investigator assessment of best overall tumor response reported three patients with a partial response, seven patients with progressive disease, and 11 patients with stable disease.

Treatment-related grade 3 or 4 AEs included:

neutropenia, thrombocytopenia, febrile neutropenia, and lymphopenia.

A new randomized, multi-center, Phase 2 trial is currently being developed to evaluate the efficacy and safety of the combinations of Anktiva, aldoxorubicin, PD-L1 t-haNK and bevacizumab in this indication.

A pilot phase will evaluate different combinations of triplets and the quadruplet, and a winner will be selected for the randomized portion versus bevacizumab monotherapy as the current standard of care for relapsed/refractory (r/r) GBM.

We plan to begin enrollment of this trial in 2022.

Human Papillomavirus-Associated Tumors (Cervical and Head & Neck)

5.0, 7.2 months), more than doubling the historical overall survival (survival of three months as reported by Manax et al ASCO GI 2019).

In Cohort C, grade 3 or greater treatment-related adverse events included anemia (32%), neutropenia (25%), thrombocytopenia (13%) and fatigue (7%) while all other grade 3 or greater treatment-related adverse events occurred at a frequency of less than 5%.

We met with the FDA in December 2022 to obtain guidance toward a registration pathway in metastatic pancreatic cancer with combination immunotherapy and NK cell therapy, and the FDA advised us to conduct a randomized trial in late-stage metastatic pancreatic cancer.

Glioblastoma Multiforme

According to the American Association of Neurological Surgeons, GBM is the most common malignant brain tumor accounting for approximately 48% of all primary brain tumors with a low survival rate of approximately 40% in the first year after diagnosis and only 17% in the second year.

In preclinical settings, we evaluated the preclinical activity of N-803 in a murine GL261-luc glioblastoma model.

We showed that N-803, as a single-agent treatment as well as in combination with an anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in prolonged survival including complete remission in tumor bearing mice.

N-803-treated mice had decreased tumor volume and increased median survival compared to control.

In addition, N-803 treatment resulted in long-term immune memory against glioblastoma tumor rechallenge.

A new randomized, multi-center, Phase 3 trial is currently being developed to evaluate the safety and efficacy of the combinations of N-803, PD-L1 t-haNK and bevacizumab in patients with recurrent or progressive GBM.

A pilot phase will evaluate the safety of this combination prior to the randomized Phase 3 portion versus bevacizumab monotherapy as the current standard of care.

• Pilot (Part A).

Enrollment will initiate with a single-arm study of 10 patients to receive N-803, PD-L1 t-haNK, and bevacizumab combination therapy.

Continued development of the experimental arm in Part B will be based on the overall risk/benefit of the combined treatment regimen observed in Part A.

• Randomized Comparison of Combination Therapy versus Bevacizumab Monotherapy (Part B).

Part B will enroll 336 patients to be randomly assigned (1:1) to the experimental arm or to the control arm.

Human Papillomavirus-Associated Tumors

According to the Centers for Disease Control and Prevention, every year about 19,400 women and 12,100 men experience cancers caused by the human papillomavirus (HPV), which is the most common sexually transmitted infection in the U.S.

According to the NCI, head and neck cancers account for nearly 4% of all cancers in the U.S.

It was estimated that more than 68,000 men and women in the U.S.

would be diagnosed with head and neck cancers in 2021.

IBRX-042 leverages our hAd5-based vaccine platform to target tumors caused by HPV infection, which includes most types of cervical cancer and some types of head/neck cancers.

According to ASCO, head and neck cancers account for nearly 4% of all cancers in the U.S.

It is estimated that more than 66,470 men and women in the U.S.

will be diagnosed with head and neck cancers in 2023, and 15,050 will die from the disease.

HPV Associated Cancer in Lower Genitourinary, Cervical, and Head & Neck

Backed by data from preclinical animal models, we are exploring IBRX-042 that leverages our hAd5-based vaccine platform to target tumors caused by HPV infection (which includes most types of lower genitourinary (GU), cervical, and some types of head/neck cancers).

Our second-generation hAd5 vector includes enhancements with the E1, E2b, E3 regions of the hAd5 deleted (E1-, E2b-, E3-), decreasing the risk for vector-directed immune responses that may reduce efficacy, while maintaining high target antigen production.

The platform has previously been used to generate vaccines against tumor-associated antigens such as MUC1 and Brachyury.

The platform has previously been used to generate vaccines against TAAs such as CEA, MUC1 and Brachyury.

In IBRX-042, hAd5 encodes HPV-16 E6 and E7 tumor-associated proteins (oncotarget antigens).

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To support clinical studies, we have successfully completed the GMP production of GMP IBRX-042.

We are planning a Phase 1/2 open-label trial to evaluate the safety and efficacy of subcutaneous (SC) IBRX-042 vaccination combined with Anktiva (to enhance immune responses) and PD-L1 t-haNK cells in patients with HPV-associated tumors.

We intend to add Anktiva to evaluate the safety and efficacy of the combination followed by PD-L1 t-haNK.

We plan to begin enrollment of this trial in 2022.

Solid Tumor (QUILT 3.076)

An initial clinical trial showed that healthy and patient-derived M-ceNK cells killed NK-resistant tumor cells.

We initiated a Phase 1 study of cryopreserved M-ceNK cells in combination with Anktiva to evaluate safety in subjects with locally advanced or metastatic solid tumors.

The study will compare the quantity and quality of the M-ceNK cells collected and manufactured from newly diagnosed patients who have not received prior treatment to the M-ceNK cells collected and manufactured from patients who have received at least two prior treatments for their cancer.

The study consists of two cohorts and there will be 10 participants in each cohort.

Cohort 1 includes participants with newly diagnosed high-risk solid tumors who have not received prior treatment;

and Cohort 2 includes participants with r/r solid tumors who have progressive disease after receiving at least two prior therapies.

Participants will be enrolled in the two cohorts simultaneously.

Participants in Cohort 1 will participate in apheresis collection of lymphocytes (part A) and will not receive any investigational therapy in this study.

Participants in Cohort 2 will undergo an apheresis collection of lymphocytes (part A) prior to receiving approximately four weeks of disease-specific therapy per their oncologists’ recommendations.

Non-Hodgkin’s Lymphoma

According to the American Cancer Society, in 2022 it is estimated that 80,470 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed in the U.S., and 20,250 deaths will be attributed to the disease.

A Phase 1 trial evaluating Anktiva in combination with rituximab, an anti-CD20 mAb therapy, in patients with indolent non-Hodgkin’s lymphoma (iNHL), who had relapsed or were refractory after two lines of therapy, was published in the American Association for Cancer Research journal, Clinical Cancer Research , in 2021.

The combination regimen of Anktiva and Rituxan ® was well tolerated with a single reported grade 4 AE and no reported grade 5 AEs.

For patients with anti-CD20 mAb sensitive disease, the ORR in the SQ cohort was 78% (7 of 9) with 7 of 7 (100%) responses in the SQ cohorts were complete remissions (CRs).

We are planning a Phase 1/2 open-label trial to evaluate the safety and efficacy of subcutaneous IBRX-042 vaccination combined with N-803 (to enhance immune responses) in combination with standard of care in patients with HPV-associated tumors.

Autologous M-ceNK in Locally Advanced or Metastatic Solid Tumors (QUILT 3.076)

An initial study conducted by the NCI showed that N-803-enhanced NK cell anti-tumor activity against all variants of small-cell lung cancer (Fousek 2022).

Based on this data and other preclinical analysis, we initiated a two-part, open-label Phase 1 trial to evaluate safety and preliminary efficacy of cryopreserved M-ceNK cells, in combination with N-803 for subcutaneous administration, in patients with locally advanced or metastatic solid tumors.

The trial will compare the quantity and quality of the M-ceNK cells collected and manufactured from newly diagnosed patients who have not received prior treatment or who have received prior first-line treatment (prior to the M-ceNK cells collected and manufactured) to the quantity and quality of the M-ceNK cells collected and manufactured from patients who have progressive disease and who have received at least two prior treatments for their cancer.

The trial consists of two cohorts and there will be up to 80 participants total with up to 30 enrolled in Cohort 1 and up to 50 enrolled in Cohort 2.

• Newly diagnosed or no more than one line of treatment (Cohort 1) .

Includes patients with newly diagnosed high-risk solid tumors who have not received prior treatment for high-risk tumors or who have received prior first-line treatment.

Patients in Cohort 1 will participate in apheresis collection of lymphocytes (Part A) and will not receive any investigational therapy unless they subsequently enroll in Cohort 2 (Part B) if they have progressive disease after ≥ 2 prior therapies or if they have progressive disease within 12 months of receiving neoadjuvant or adjuvant chemotherapy.

They must also meet the inclusion criteria to participate in the treatment phase (Part B).

• Progressive disease with at least two prior lines of treatment (Cohort 2) .

Includes patients with r/r solid tumors who have progressive disease after receiving at least two prior therapies.

◦ Apheresis collection (Part A) .

Patients in Cohort 2 will undergo an apheresis collection of lymphocytes prior to receiving four weeks of disease-specific therapy per their oncologists’ recommendations.

◦ Treatment with M-ceNK and N-803 (Part B) .

If an adequate number of M-ceNK cells can be manufactured from the autologous apheresis product and the patients are eligible to participate in the treatment phase (Part B), M-ceNK will be infused in combination with subcutaneous N-803 on monthly repeatable cycles, subject to adequate doses of M-ceNK being available.

Non-Hodgkin Lymphoma

According to the American Cancer Society, in 2023 it is estimated that 80,550 people will be diagnosed with non-Hodgkin lymphoma (NHL) in the U.S.

and 20,180 deaths will be attributed to the disease.

A Phase 1 trial evaluating N-803 in combination with rituximab, an anti-CD20 mAb therapy, in patients with indolent non-Hodgkin lymphoma (iNHL), who had relapsed or were refractory after two lines of therapy, was published in the American Association for Cancer Research journal, Clinical Cancer Research , in 2021.

The combination regimen of N-803 and Rituxan ® was well tolerated with a single reported grade 4 adverse event and no reported grade 5 adverse events.

For patients with anti-CD20 mAb sensitive disease, the overall response rate in the SQ cohort was 78% (7 of 9) with 7 of 7 (100%) responses in the SQ cohorts were complete remissions (CRs).

Most B-cell malignancies express high levels of CD19, including the majority of NHLs, such as diffuse large B Cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma.

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The CD19 t-haNK cell line combines the engineered enhancements of haNK cells with the expression of a CAR targeting CD19, and thus has potential to demonstrate robust ADCC antitumor activity against cancerous B cells and provide clinical benefit to patients with r/r NHL.

We are currently developing an open-label, Phase 1 trial of CD19 t-haNK as a single agent and in combination with Anktiva and rituximab in patients with r/r NHL.

In addition to the studies listed above, we are pursuing several other both company-sponsored and investigator-initiated studies of our product candidates including in colon cancer (hAd5 CEA), Kaposi’s sarcoma (aldoxorubicin), and head and neck cancer (Anktiva, hAd5 CEA, MUC1, and Brachyury) among others.

Infectious Diseases

COVID-19 Programs

In order to address the ever-evolving COVID-19 pandemic, several key findings have emerged through intense research activity since the virus was first identified.

We believe these findings include the need for second-generation COVID-19 vaccines with cross-reactive memory B and T cells in the face of antigenic drift and a heterologous prime/boost approach without cold chain limitations.

Vaccines against SARS-CoV-2 were developed with exceptional speed and initially showed a high degree of efficacy against the wild-type virus, with RNA vaccines showing the highest degree of efficacy and a sound safety profile.

However, in the time since their authorization, we believe that a number of important limitations have been recognized.

First, these vaccines have required boosting for increased efficacy.

Second, their availability in the low income global community has been limited.

Third, they have shown reduced efficacy against emergent variants of concern (VOC).

Fourth, they exhibit heat-sensitivity and require a cold chain that may be infeasible in many low-resource settings.

Researchers aim to address these limitations and have recently made several relevant advances.

For example, second-generation COVID-19 vaccines with DNA and RNA delivery platforms that are heat-stable, potent and broadly protective against multiple VOC have been developed and are in clinical trials .

Additionally, vaccines which stimulate the innate immune system through the TLR system invoke strong and broad humoral and cellular responses.

We believe that T cell immunity plays a central role in the control of SARS-CoV-2 and its importance may have been relatively underestimated thus far.

Our COVID-19 vaccine product candidates are designed to provide second-generation T cell as well as antibody-based protection .

Spike in Combination with Nucleocapsid

Since the inception of the pandemic, we have hypothesized that antibody-based vaccines, specifically those that target the S protein alone, would prove insufficient over an extended time period to prevent transmission and infectivity due to their inability to overcome viral evolution in the face of a rapidly mutating S protein on the SARS-CoV-2 virus.

In fact, what has been observed over the past year is that anti-S antibody levels and immune protection against COVID-19 subsides following vaccination with currently available S targeting vaccines, requiring booster shots at approximately six months.

Compounding the limitations of an S-only approach is the spike protein is under intense immune pressure from vaccine-induced antibodies, which drives the evolution of vaccine escape variants.

Internal proteins of the SARS-CoV-2 virus, such as the N protein, are more highly conserved and less subject to mutation and thus may be more appropriate targets to maintain vaccine efficacy in the face of this viral evolution.

From the onset, we believed strongly that an immune response generating a combination of antibodies, T cells, and memory B cells is critical to prevent infection, reduce viral load, prevent transmission, provide durable protection and ultimately overcome this pandemic.

Therefore, we focused our efforts on developing vaccine candidates with an S-Fusion + N-ETSD that express both an optimized viral spike (S) protein (S-Fusion) and a nucleocapsid protein with an Enhanced T-cell Stimulation Domain (N-ETSD) that directs N to the endo/lysosomal subcellular compartment to enhance MHC Class II responses.

In order to reduce viral load, T cells are necessary to kill virally-infected cells in the nasal and lung passages and thereby prevent transmission even from highly transmissible variants.

We performed a non-human primate COVID virus challenge study in September 2020 (supported by BARDA and published in September 2021 in Frontiers in Immunology entitled, “Dual-Antigen COVID-19 Vaccine Subcutaneous Prime Delivery with Oral Boosts Protects NHP Against SARS-CoV-2 Challenge”) confirming that our second-generation adenovirus hAd5 S+N vaccine accomplished the goal of reducing viral load to non-detectable levels following a COVID-19 virus challenge.

On the basis of these findings, a program was designed to pursue this strategy of driving T cell and antibody protection, and to develop a second-generation vaccine with broad depth of antigenic coverage.

The initial study, which began in March 2020, showed that hAd5 S+N vaccination as a single prime alone induced a 10-fold increase in mean T cell responses in Phase 1 participants that were sustained against spike variants.

Heterologous Prime Boost

Moreover, since initiating the initial homologous prime boost trial in the U.S., it has become apparent that a “mix-and-match” strategy (i.e., a heterologous approach combining different vaccine platforms) could potentially provide maximal immune protection against current and future variants such as Delta and Omicron.

For example a “Prime” with an RNA vaccine leads to strong antibody response while a “Boost” with a DNA or an EDV/adjuvant vaccine could convey strong cellular immune responses.

On this basis we have acquired the rights to multiple platforms and initiated a consortium that includes 3M, Amyris, BCM, EnGeneIC and IDRI to develop, manufacture and scale second-generation vaccines that combine different advanced DNA, RNA, protein constructs, and adjuvants.

We have adopted a long-term approach to addressing COVID-19 and future pandemics and believe these mix-and-match components are critical to providing accessible, broad, and durable protection.

Importantly we believe that the technologies behind these heterologous approaches are not burdened by the limitations of first-generation RNA cold-chain requirements.

hAd5 S+N Platform Prime & Boost—U.S.

(COVID 4.001 and 4.005) and South Africa COVID (4.007)

In October 2020, the FDA authorized a Phase 1 trial of our dual construct Spike+Nucleocapsid (hAd5 S+N) COVID-19 vaccine, designed to drive both T cell and antibody immunity.

We undertook a rigorous development strategy to explore multiple methods of administration (oral, intranasal, subcutaneous, and combinations of each) to determine the best site of delivery to achieve maximum antibody, T cell and mucosal immunity.

In February 2021, this trial was expanded to South Africa (the ProVIVA-SA1 Trial).

Through the date of this Annual Report, 114 participants have enrolled in the U.S.

and South African Phase 1 trials.

Data acquisition and analysis from both trials is ongoing.

Preliminary analysis has shown that subcutaneous dosing of hAd5 S+N provides strong T-cell responses to both Spike and Nucleocapsid antigens with no SAEs reported through the date of this Annual Report.

These trials formed the basis of the Universal T Cell Boost Trial (SISONKE Boost Trial) activated in South Africa in July 2021.

SISONKE Boost Trial—South Africa ( COVID 4.010)

In July 2021 we announced authorization from the South African Health Products Regulatory Authority (SAHPRA) to proceed with our SISONKE T-Cell Universal Boost trial in South Africa.

This Phase 1/2/3 trial was the first DNA/DNA heterologous mix-and-match trial of Ad26 and hAd5 and was designed to study the efficacy, safety, and immunogenicity of ImmunityBio’s T-Cell COVID-19 vaccine as a boost in participants who had already received a spike-only antibody-based vaccine.

The trial is designed to explore whether the T cell-based vaccine could prevent breakthrough infections from the Delta variant in health care workers who are already vaccinated.

The goal of the hAd5 S+N vaccine is to potentially provide increased protection and long-term immunity against the multiple variants and multiple waves affecting South Africa and other countries.

The SISONKE Universal Boost Phase 2 trial is fully enrolled wi th 60 partic ipants with no SAEs reported through the date of this report.

The Phase 3 trial is now open and enrollment began in January 2022.

THEMBA saRNA Vaccine Boost—South Africa (COVID 4.015) and U.S.

(COVID 4.016)

The THEMBA trials are the first studies of our saRNA with next-generation NLCs.

In South Africa, we initiated the filing of a Phase 1/2 trial assessing the safety, reactogenicity, and immunogenicity of saRNA-based vaccines against SARS-CoV-2 as boost vaccines in participants that have been previously vaccinated against or previously infected with COVID-19, which is under regulatory review at the SAHPRA awaiting authorization to begin .

In the U.S., we submitted a similar Phase 1/2 trial design for FDA review in the first quarter of 2022.

The Phase 1 trial, for up to 60 previously vaccinated/infected participants will be enrolled as 6 separate cohorts to receive a single vaccine boost consisting of different doses of either saRNA encoding the Spike protein (AAHI-SC2 vaccine) or saRNA encoding the Spike and nucleocapsid proteins (AAHI-SC3 vaccine) delivered by NLC.

The Phase 2 trial, of up to 120 previously vaccinated/infected additional participants, will be enrolled with a randomized 1:1:1:1 design to receive Janssen, Moderna or Pfizer-BioNTech vaccines (control arm), the AAHI-SC2 vaccine (experimental arm 1), or the AHHI-SC3 (experimental arms 2 and 3).

PULA Trial RBD Subunit Protein with TLR Adjuvant Boost—Botswana (COVID 4.014)

We plan on submitting a Phase 1/2/3 trial assessing the safety, reactogenicity, and immunogenicity of a yeast-based COVID-19 vaccine with a TLR activating adjuvant to the Botswana Medical Research Authority (BOMRA) to be called PULA.

In November 2021, we announced we had licensed a recombinant protein COVID-19 vaccine (RBD Subunit) candidate from BCM.

Protein-based vaccines have long been used to confer immunity against hepatitis B and HPV, as immune responses often target proteins that are part of viruses and bacteria.

This recombinant protein vaccine technology is proven and well-established.

Production of these vaccines can be easily scaled up in low-resource countries.

We are combining this subunit protein with a 3M-052/Alum adjuvant and related technology licensed from IDRI and 3M Company and its affiliates in this PULA trial.

In June 2021, we announced the opening of a Phase 1 “HIV Cure Study” in patients on therapy and a Phase 2 study in acutely infected patients.

Both studies have opened and are actively enrolling participants.

Relapsed/Refractory Non-Hodgkin Lymphoma (QUILT 3.092)

We are currently developing an open-label, Phase 1, first-in-human, open-label trial to study the safety of CD19 t-haNK as a single agent and the safety and preliminary efficacy of CD19 t-haNK in combination rituximab only (Cohort A) and in combination with N-803 and rituximab (Cohort B) in patients with r/r NHL.

Other Oncology Indications

In addition to the trials listed above, we are exploring or pursuing several other both company-sponsored and investigator-initiated studies of our product candidates including in colon cancer (N-803, hAd5 CEA), prostate cancer (N-803, hAd5 PSA), Lynch Syndrome (N-803, hAd5 CEA, hAd5 MUC1, hAd5 Brachyury), and head and neck cancer (N-803, hAd5 CEA, hAd5 MUC1, hAd5 Brachyury) among others.

Since the inception of the pandemic, we have believed that a highly mutable S-only focused, antibody-based vaccine approach that could require boosters approximately every six months, would prove insufficient to overcome viral evolution.

We have believed T cell response is critical to clearing the virus and long-term immunity and so our focus is on vaccine candidates that also target the more highly conserved N protein.

With mass adoption of first-generation S-only vaccines, our data from our prior NHP Challenge Study and early trials have formed the basis of our design of a universal T cell boost vaccine candidate and the associated set of trials currently underway in South Africa.

THEMBA saRNA Vaccine Boost—South Africa (COVID 4.015)

The THEMBA trials are the first studies of our joint venture saRNA technology with next-generation NLCs.

In South Africa in 2022, we initiated a Phase 1/2 trial assessing the safety, reactogenicity, and immunogenicity of saRNA-based vaccines against SARS-CoV-2 as boost vaccines in participants that have been previously vaccinated against or previously infected with COVID-19.

We are testing both an saRNA S and saRNA N construct .

The Phase 1 portion of the trial is ongoing in the first quarter of 2023.

The Phase 1 trial, for up to 60 previously vaccinated/infected participants, will be enrolled as 6 separate cohorts to receive a single vaccine boost consisting of different doses of either saRNA encoding the Spike protein (AAHI-SC2 vaccine) or saRNA encoding the nucleocapsid protein (AAHI-SC3 vaccine) delivered by NLC.

We expect the Phase 2 trial, of up to 120 previously vaccinated/infected additional participants, to be enrolled with a randomized 1:1:1:1 design to receive Janssen, Moderna or Pfizer-BioNTech vaccines (control arm), the AAHI-SC2 vaccine (experimental arm 1), or the AHHI-SC3 (experimental arms 2 and 3).

HIV affects tens of millions of people globally and currently has no known cure.

One current strategy for curing HIV is known as the “kick and kill” approach.

The “kick” is to induce HIV out of its latent resting state in T cells and the “kill” is to remove or kill the infected cells via an immune response or immunotherapy.

We believe N-803 is a molecule capable of both “kick and kill” in this strategy because of its ability to activate viral transcription in CD4+ T cells (“kick”) while strongly activating CD8+ effector memory cells and NK cells important for recognizing and killing HIV infected cells (“kill”), as well as directing these cells to sites of viral reservoirs.

HIV Cure Study

Sponsored by the NIAID and AIDS Clinical Trials Group, the “HIV Cure Study” will evaluate whether Anktiva alone or together with broadly neutralizing antibodies can control HIV following interruption of antiretroviral therapy (ART).

In June 2021, we announced the opening of a study sponsored by the AIDS Clinical Trials Group (ACTG) and the NIAID (the “HIV Cure Study”) that will evaluate whether N-803 alone or together with broadly neutralizing antibodies can control HIV following interruption of antiretroviral therapy (ART).

The Phase 1 open-label, randomized trial will enroll 46 people living with HIV whose virus has been suppressed by ART for approximately two years, including at least 30% cisgender women or transgender men.

Thai Red Cross and the US Military HIV Research Program

An additional Phase 2 trial, enrolling 15 patients, has been initiated with the Thai Red Cross and the U.S.

Thai Red Cross and the U.S.

Military HIV Research Program

The trial is designed to investigate the safety, tolerability and immunostimulatory effects of administering Anktiva during acute HIV infection.

Anktiva will be administered subcutaneously at weeks zero, three and six (for a total of three doses) and will be initiated together with antiretroviral therapy in order to determine if the immunostimulatory effects of Anktiva will reduce the amount of HIV present during acute infection.

In April 2021, we announced the launch of a Phase 2 trial sponsored by the Thai Red Cross and the U.S.

Military HIV Research Program.

The trial is enrolling 15 patients and is designed to investigate the safety, tolerability and immunostimulatory effects of administering N-803 during acute HIV infection.

N-803 will be administered subcutaneously at weeks zero, three and six (for a total of three doses) and will be initiated together with antiretroviral therapy in order to determine if the immunostimulatory effects of N-803 will reduce the amount of HIV present during acute infection.

The trial duration for individual participants will be approximately 12 weeks.

It is hypothesized that Anktiva initiated with anti-retroviral therapy during acute HIV infection will not result in complications or additional toxicities compared with anti-retroviral therapy alone, and may result in a reduced viral load in these patients by inhibiting early establishment of HIV reservoirs in infected individuals.

It is hypothesized that N-803 initiated with anti-retroviral therapy during acute HIV infection will not result in complications or additional toxicities compared with anti-retroviral therapy alone, and may result in a reduced viral load in these patients by inhibiting early establishment of HIV reservoirs in infected individuals.

NIAID University of Minnesota Trial

An ongoing Phase 1b, non-randomized, open label clinical trial sponsored by the University of Minnesota in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) is investigating the effect of Anktiva on B cell follicles in antiretroviral treated HIV disease.

This trial includes 10 HIV-infected adults on effective antiretroviral therapy who will receive Anktiva to intensively investigate the immunological effects of treatment.

The hypothesis is that in HIV infected humans treated with Anktiva , CD8 T cells will migrate to and increase in number in B cell follicles that will result in a reduction in the frequency of cells with an inducible HIV provirus.

The trial is fully enrolled, and there are currently 2 active patients on study as of this date of this report.

A Phase 1b, non-randomized, open-label clinical trial sponsored by the University of Minnesota in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) investigated the effect of N-803 on B cell follicles in antiretroviral treated HIV disease.

This trial included 10 HIV-infected adults on effective antiretroviral therapy who received N-803 to intensively investigate the immunological effects of treatment.

The hypothesis is that in HIV-infected subjects treated with N-803 , CD8+ T cells will migrate to and increase in number in B cell follicles that will result in a reduction in the frequency of cells with an inducible HIV provirus.

The trial is in data analysis mode with all subjects having completed the trial.

In addition to the studies and trials listed above, we are exploring an additional HIV trial with our Thai and U.S.

Military collaborators using N-803 plus broadly neutralizing antibodies (bNAbs) and HIV vaccines.

Our Large-Scale GMP Biologic Manufacturing Capabilities

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Our ability to create an efficient manufacturing process and supply chain will be important in enabling us to develop novel therapies.

Our strategy is to anticipate the needs of our early-stage research and development initiatives for preclinical and eventual clinical product candidates with a focus on rapid capability to produce at scale fusion proteins, hAd5, saRNA, subunit protein, EDV, and NK cell products.

In addition, our pipeline for development of synthetic small molecules and immunomodulatory peptides uses innovative technology to derive new therapies.

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Commercial cGMP Production

For our Anktiva product candidate, we have contracted with a multi-national biologics manufacturer with multiple cGMP-compliant facilities in the U.S., Europe and Asia for our current clinical trials and future commercial sales, if approved.

For our N-803 product candidate, we have contracted with a multi-national biologics manufacturer with multiple cGMP-compliant facilities in the U.S., Europe and Asia for our current clinical trials and future commercial sales, if approved.

The facilities have robust process development and validation and quality oversight with high-capacity production suites operating multiple 2,000-20,000L production bioreactors.

Clinical Trial GMP Antibody and Fusion Protein Production

We are establishing a cGMP-compliant multi-platform facility in California, which includes a large space for the production of antibodies and fusion proteins (including Anktiva) to treat cancers and infectious diseases.

We are establishing a cGMP-compliant multi-platform facility in California, which includes a large space for the production of antibodies and fusion proteins (including N-803) to treat cancers and infectious diseases.

This facility will include fully integrated biologic upstream and downstream production suites and a quality assurance/quality control release laboratory for high-capacity antibody and fusion protein production.

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We have established other cGMP-compliant facilities for saRNA, adenovirus, and yeast production in multiple sites in California and a site in Colorado for oncology and infectious diseases.

One of our sites in California is dedicated to adenovirus product candidates for the production of vaccine candidates to treat infectious diseases.

One of our sites in California is dedicated to adenovirus product candidates for the production of vaccine candidates to treat infectious diseases and oncology TAAs.

These facilities generally have fully-integrated biologic upstream and downstream production suites and quality assurance/quality control release laboratories for high capacity, continuous, or personalized just-in-time vaccine production.

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On February 14, 2022, we acquired a leasehold interest in approximately 409,000 rentable square feet of cGMP ISO Class 5 pharmaceutical manufacturing space in western New York (the Dunkirk Facility).

This facility provides us with a state-of-the-art biotech production center that substantially expands and diversifies our existing manufacturing capacity in the U.S.

and will be used across all of our key platforms.

See Note 13 , Subsequent Events , of the “Notes to Consolidated Financial Statements” that appears in Part II, Item 8.

“Financial Statements and Supplementary Data” of this Annual Report for additional information.

In September 2022, we initiated a workforce reduction at the Dunkirk Facility as a result of upcoming construction at the project, which we believe may take approximately 12 to 18 months.

We believe this facility will provide us with a state-of-the-art biotech production center that will substantially expand and diversify our existing manufacturing capacity in the U.S.

and the ability to scale production across all of our key platforms.

Manufacture of Platform Product Candidates

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Any product candidates that we successfully develop and commercialize will compete with current therapies and new therapies that may become available in the future.

We believe that the key competitive factors affecting the success of any of our product candidates will include efficacy, safety profile, convenience, cost, market access, level of promotional activity devoted to them, competitive intensity, and intellectual property protection.

We believe that the key competitive factors affecting the success of any of our product candidates will include safety profile, efficacy, convenience, cost, market access, level of promotional activity devoted to them, competitive intensity, and intellectual property protection.

We have focused our efforts on oncological and infectious disease indications that are difficult to treat and with large unmet needs, and we believe our platform will be broadly applicable across multiple tumor types and infections.

Based on the breadth and depth of our platforms, we believe our competitors will range from large pharmaceutical companies to emerging novel biotechnology companies.

• Antibody Cytokine Fusion Proteins.

• Antibody Cytokine Fusion and Recombinant Proteins.

This platform primarily competes with large pharmaceutical companies marketing checkpoint inhibitors.

However, the potential exists for some of these large pharmaceutical companies to seek collaboration for combination of Anktiva with their marketed checkpoint inhibitor.

However, the potential exists for some of these large pharmaceutical companies to seek collaboration for combination of N-803 with their marketed checkpoint inhibitor.

This platform will also compete with immunotherapy fusion protein companies developing similar approaches, including Nektar Therapeutics, Neoleukin Therapeutics, Inc., Novartis International AG (Novartis), F.

Hoffmann-La Roche AG (Roche), Sanofi, S.A.

(Sanofi), and in the context of NMIBC, FerGene, Inc., Merck & Co., Inc.

(Merck), and Sesen Bio, Inc.

• DNA, RNA, Recombinant Protein Vaccine Technologies .

Hoffmann-La Roche AG (Roche), Xencor, Inc., Sanofi, S.A.

(Sanofi), and in the context of NMIBC, Ferring Pharmaceuticals, Merck & Co., Inc.

(Merck), and CG Oncology Inc.

• DNA, RNA, and Recombinant Protein Vaccine Technologies .

This platform and the associated product candidates will likely compete with other cancer vaccines.

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There is currently one approved dendritic cell-based cancer vaccine, which is marketed by Dendron Pharmaceuticals, LLC for the treatment of metastatic castration-resistant prostate cancer.

Competitor companies focused on dendritic cell-based approaches include Argos Therapeutics, Inc., Merck, Immune Design, Inc., Inovio Pharmaceuticals, Inc., Precigen Corporation, Inc., Medigene AG, and Northwest Biotherapeutics, Inc.

• Toll-Like Receptor Activating Adjuvants .

This platform competes with companies offering other TLR agonist-based approaches, including Dynavax Technologies Corporation, Idera Pharmaceuticals, Inc., Panacela Labs LLC, Primmune Therapeutics, Inc., and Statera BioPharma, Inc.

Competitor companies focused on dendritic cell-based approaches include Argos Therapeutics, Inc., Merck, Inovio Pharmaceuticals, Inc., Precigen Corporation, Inc., Medigene AG, and Northwest Biotherapeutics, Inc.

• Toll-Like Receptor Activators .

This platform competes with companies offering other TLR agonist-based approaches, including Dynavax Technologies Corporation, Panacela Labs LLC, Primmune Therapeutics, Inc., and Statera BioPharma, Inc.

• NK Cell Therapy.

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In addition, our NK cell product candidates compete with other cell and molecule-based immunotherapy approaches using or targeting natural killer cells, NKT cells, T cells, macrophages, and dendritic cells.

There are currently four approved T cell-based treatments marketed by Novartis, Gilead Sciences, Inc.

(Gilead)/Kite Pharma (two marketed products), and Bristol-Myers Squibb Company (BMS).

There are currently six approved T cell-based treatments marketed by Novartis, Gilead Sciences, Inc.

(Gilead)/Kite Pharma (two marketed products), Bristol-Myers Squibb Company (BMS) (two marketed products), and Janssen Pharmaceuticals, Inc.

(Janssen)/Johnson & Johnson.

Additional companies focused on CAR‑T-related treatment approaches include Allogene Therapeutics, Inc., BMS, Novartis, Pfizer, Inc.

(Pfizer), Cellectis SA, Poseida Therapeutics, Inc., Celularity, Takeda, and Gilead.

(Pfizer), Cellectis SA, Poseida Therapeutics, Inc., Janssen, Celularity, Takeda, and Gilead.

Competitor companies focused on other T cell-based approaches include Adaptimmune Ltd., Adicet Bio, Inc., Autolus Therapeutics, plc, GlaxoSmithKline plc.

(GSK), Precision Biosciences, Inc., Janssen Pharmaceuticals, Inc.

(Janssen), Beam Therapeutics Inc., BioNTech, Sensei Biotherapeutics, Inc., Senti Biosciences, Inc., and TCR² Therapeutics Inc.

(GSK), Precision Biosciences, Inc., Beam Therapeutics Inc., BioNTech, Sensei Biotherapeutics, Inc., Senti Biosciences, Inc., and TCR² Therapeutics Inc.

• DAMP Inducers .

This platform competes with companies offering various chemotherapeutic agents, including Abraxane ® , doxorubicin and paclitaxel/Taxol, as well as an antibody drug conjugate produced by Immunomedics, Inc.

This platform competes with companies offering various chemotherapeutic agents, including Abraxane ® (BMS), doxorubicin and paclitaxel/Taxol, as well as an antibody drug conjugate produced by Immunomedics, Inc.

(acquired by Gilead).

Other potential immunotherapy competitors in oncology include Affimed GmbH, AgenTus Therapeutics, Inc., Appia Bio, Inc., Codiak Biosciences, Compass Therapeutics, Inc., Glycostem Therapeutics BV, Kuur Therapeutics Limited, GammaDelta Therapeutics Ltd., Lyell Immunopharma, Inc., and GT Biopharma, Inc.

(Takeda), Lyell Immunopharma, Inc., and GT Biopharma, Inc.

Infectious Diseases

Currently, our infectious disease product candidates are primarily focused on SARS-CoV-2 and HIV.

Competitor companies focused on COVID-19 vaccines (adenovirus, mRNA, and other approaches) include AstraZeneca, Johnson & Johnson/Janssen, Merck, Moderna Therapeutics, Inc., Novavax, Inc., Pfizer/BioNTech, and Pluristem Therapeutics, Inc.

In addition, a very large number of companies, government agencies and academic centers around the world are developing COVID-19 vaccines and therapeutics.

In the HIV space, we have product candidates that use Anktiva that will likely compete with companies who have approved therapeutics for HIV, including Abbott Laboratories Inc., BMS, Gilead, and GSK.

In addition, a very large number of companies, government agencies and academic centers around the world are developing or have developed COVID-19 vaccines and therapeutics.

In the HIV space, we have product candidates that use N-803 that will likely compete with companies who have approved therapeutics for HIV, including Abbott Laboratories Inc., BMS, Gilead, and GSK.

Intellectual Property

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and (3) activated tumoricidal macrophages.

With respect to activated NK and T cells, we have developed Anktiva, an N72D variant IL-15 complexed to a dimeric IL-15Ra/Fc fusion protein;

With respect to activated NK and T cells, we have developed N-803, an N72D variant IL-15 complexed to a dimeric IL-15Ra/Fc fusion protein;

with respect to memory T cell activation, we have developed adenoviral and yeast immunotherapies expressing tumor antigens such as CEA, MUC1, and Brachyury, and in-licensed saRNA technologies;

and with respect to activated tumoricidal macrophages, we have in-licensed intellectual property licensed to aldoxorubicin, a tumor-targeted doxorubicin conjugate, from CytRx.

We own patents and patent applications related to the development and commercialization of Anktiva.

As of December 31, 2021, our owned patent portfolio directed to Anktiva, methods of use of Anktiva, and combinations with additional therapeutics consists of approximately 13 issued U.S.

and with respect to activated tumoricidal macrophages, we have in-licensed intellectual property licensed to aldoxorubicin, a tumor-targeted doxorubicin conjugate, from LadRx.

We own patents and patent applications related to the development and commercialization of N-803.

As of December 31, 2022, our owned patent portfolio directed to N-803, methods of use of N-803, and combinations with additional therapeutics consists of approximately 19 issued U.S.

patents and 8 pending U.S.

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Excluding any patent term adjustment and patent term extension, the issued U.S.

patents directed to Anktiva, methods of use of Anktiva and combinations with additional therapeutics are expected to expire from 2028 to 2035.

patents directed to N-803, methods of use of N-803 and combinations with additional therapeutics are expected to expire from 2028 to 2039.

Excluding any applicable extensions, the issued foreign patents are expected to expire from 2028 to 2038.

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For example, these patents and patent applications include claims directed to:

• Anktiva compositions of matter;

• uses of Anktiva in methods of treating cancers;

• uses of Anktiva in treating HIV;

• combination treatments using Anktiva and additional therapeutics.

We own and in-license from Institute for Cancer Research patents and patent applications related to the development and commercialization of cell-based therapies.

As of December 31, 2021, our patent portfolio directed to NK, haNK, and t-haNK cell lines, methods of use of these cells, and combinations with additional therapeutics consists of approximately 15 issued U.S.

• N-803 compositions of matter;

• uses of N-803 in methods of treating cancers;

• uses of N-803 in treating HIV;

• combination treatments using N-803 and additional therapeutics.

We own and in-license patents and patent applications related to the development and commercialization of cell-based therapies.

As of December 31, 2022, our owned patent portfolio directed to NK, haNK, and t-haNK cell lines, methods of use of these cells, and combinations with additional therapeutics consists of approximately 15 issued U.S.

patents and 24 pending U.S.

patent applications, as well as approximately 32 patents issued in jurisdictions outside of the U.S., including Europe, China, Japan, Canada, and Australia.

patent applications, as well as approximately 32 patents issued in jurisdictions outside of the U.S., including Europe, China, Japan, and Australia.

As of December 31, 2022, our in-licensed patent portfolio directed to NK, haNK, and t-haNK lines, methods of use of these cells, and combinations with additional therapeutics consists of approximately 4 issued U.S.

patents, as well as approximately 41 patents issued in jurisdictions outside of the U.S., including Europe, Canada, and Australia.

Excluding any patent term adjustment and patent term extension, the issued U.S.

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• PD-L1 t-haNK cells.

We own and in-license patents and patent applications related to development and commercialization of our preclinical assets N-820 and N-809.

We own patents and patent applications related to development and commercialization of our preclinical assets N-820 and N-809.

As of December 31, 2022, our owned patent portfolio directed to N-820 and N-809 and methods of use of N-820 and N-809 consists of approximately 7 issued U.S.

patents and approximately 3 pending U.S.

patent applications, as well as approximately 46 patents issued in jurisdictions outside of the U.S.

patents and 1 pending U.S.

patent application, as well as approximately 48 patents issued in jurisdictions outside of the U.S.

Excluding any patent term adjustment and patent term extension, the issued U.S.

patents directed to N-820 and N-809 are expected to expire from 2028 to 2039.

If patents issue from our pending U.S.

patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2031 to 2037.

If a patent issues from our pending U.S.

patent application, excluding any patent term adjustment and patent term extension, this patent will be expected to expire in 2028.

For example, these patents and patent applications include claims directed to fusions of checkpoint inhibitor and TAA antibodies and binding molecules with IL-15/IL-15Ra/Fc fusion proteins complexes.

We exclusively in-license patents and patent applications from CytRx related to the development and commercialization of aldoxorubicin.

We exclusively in-license patents and patent applications from LadRx related to the development and commercialization of aldoxorubicin.

As of December 31, 2022, our licensed patent portfolio directed to aldoxorubicin and methods of use of aldoxorubicin consists of approximately 3 issued U.S.

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We exclusively own, and co-own with and in-license from the U.S.

Department of Health and Human Services (HHS), patents and patent applications related to the development and commercialization of adenovirus-based cancer immunotherapies.

As of December 31, 2021, our patent portfolio directed to adenovirus and methods of use of adenovirus in treating or preventing cancer consists of approximately 16 issued U.S.

Department of Health and Human Services (HHS), patents and patent applications related to the development and commercialization of adenovirus-based cancer and viral immunotherapies.

As of December 31, 2022, our patent portfolio directed to adenovirus and methods of use of adenovirus in treating or preventing cancer and viral diseases consists of approximately 27 issued U.S.

patents and approximately 6 pending U.S.

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Excluding any patent term adjustment and patent term extension, the issued U.S.

patents directed to adenovirus-based cancer immunotherapies are expected to expire from 2024 to 2038.

patents directed to adenovirus-based cancer and viral immunotherapies are expected to expire from 2024 to 2038.

If patents issue from our pending U.S.

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• uses of adenovirus vectors and virus particles in methods of treating cancers.

We own, co-own with HHS and in-license from the University of Colorado, patents and patent applications related to the development and commercialization of yeast-based cancer immunotherapies.

As of December 31, 2021, our patent portfolio directed to yeast-based cancer immunotherapies and methods of use of yeast-based cancer immunotherapies in treating or preventing cancer consists of approximately 20 issued U.S.

We own, co-own with HHS and in-license from HHS and the University of Colorado, patents and patent applications related to the development and commercialization of yeast-based cancer and viral immunotherapies.

As of December 31, 2022, our patent portfolio directed to yeast-based cancer and viral immunotherapies and methods of use of yeast-based cancer and viral immunotherapies in treating or preventing cancer and viral diseases consists of approximately 24 issued U.S.

patents and approximately 4 pending U.S.

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Excluding any patent term adjustment and patent term extension, the issued U.S.

patents directed to yeast-based cancer immunotherapies are expected to expire from 2023 to 2038.

patents directed to yeast-based cancer and viral immunotherapies are expected to expire from 2023 to 2036.

If any patents issue from our pending U.S.

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patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire in 2040 and 2042.

We in-license patents and patent applications from IDRI related to the development and commercialization of adjuvant formulations and saRNA based vaccines.

We in-license patents and patent applications from AAHI related to the development and commercialization of adjuvant formulations and saRNA based vaccines.

As of December 31, 2022, our licensed patent portfolio directed to adjuvant formulations and saRNA vaccine platforms consists of approximately 4 issued U.S.

patents and approximately 4 pending U.S.

patent applications, as well as approximately 28 patents issued in jurisdictions outside of the U.S.

patent applications, as well as 1 issued patent in jurisdictions outside of the U.S.

Excluding any patent term adjustment and patent term extension, the issued U.S.

patents directed adjuvant formulations and saRNA-based vaccines are expected to expire from 2027 to 2038.

patents directed to adjuvant formulations and saRNA-based vaccines are expected to expire from 2027 to 2038.

If any patents issue from our pending U.S.

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This patent is directed to vaccine compositions comprising certain lipid adjuvants.

We believe IDRI has meritorious defenses against the opposition.

We believe AAHI has meritorious defenses against the opposition.

We own patents and patent applications related to the development and commercialization of GMP-in-a-Box.

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Excluding any patent term adjustment and patent term extension, the issued U.S.

patents directed to GMP-in-a-Box are expected to expire between 2030 and 2037.

If patents issue from our pending patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2030 to 2039.

patents directed to GMP-in-a-Box are expected to expire in 2030 and 2037.

If patents issue from our pending patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire in 2035 and 2039.

For example, these patents and patent applications include claims directed to methods, bioreactors, and apparatuses for monitoring and culturing cells.

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Amyris Joint Venture

In December 2021, Immunity Bio and Amyris entered into a 50:50 joint venture arrangement and formed a new limited liability company to conduct the business of the joint venture, to accelerate the commercialization of a next-generation COVID-19 vaccine utilizing IDRI’s RNA vaccine platform to which Amyris holds a license.

As part of the limited liability agreement, Amyris contributed, in part, rights to its license agreement with IDRI for the IDRI RNA platform for the field of COVID-19, and ImmunityBio contributed, in part, priority access to its manufacturing capacity for the joint venture product.

In December 2021, Immunity Bio and Amyris entered into a 50:50 joint venture arrangement and formed a new limited liability company to conduct the business of the joint venture.

The purpose of the joint venture is to accelerate commercialization of a next-generation COVID-19 vaccine utilizing an RNA vaccine platform license.

As part of the limited liability agreement, Amyris agreed to contribute, in part, rights to its license agreement with AAHI for an RNA platform for the field of COVID-19, and ImmunityBio agreed to contribute, in part, priority access to its manufacturing capacity for the joint venture product.

National Cancer Institute

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Pursuant to the Cooperative Research and Development Agreement (CRADA), the NCI provides scientific staff and other support necessary to conduct research and related activities as described in the CRADA.

During the term of the initial and amended CRADAs, we collaborated with the NCI on the preclinical and clinical development of an adenovirus technology expressing tumor-associated antigens for cancer immunotherapy, the preclinical and clinical development of our proprietary yeast-based Tarmogens expressing tumor-associated antigens, and the proprietary adenovirus technology expressing tumor-associated antigens for cancer immunotherapy.

In 2021, the CRADA was amended and the research plan was modified to include the preclinical and clinical development of ImmunityBio’s proprietary adenovirus platform expressing tumor-associated antigens;

proprietary yeast platform expressing tumor-associated antigens;

proprietary agent Anktiva and derivatives, agent N-808 and derivatives, and/or TxM product candidates;

During the term of the initial and amended CRADAs, we collaborated with the NCI on the preclinical and clinical development of an adenovirus technology expressing TAAs for cancer immunotherapy, the preclinical and clinical development of our proprietary yeast-based Tarmogens expressing TAAs, and the proprietary adenovirus technology expressing TAAS for cancer immunotherapy.

In 2021, the CRADA was amended and the research plan was modified to include the preclinical and clinical development of ImmunityBio’s proprietary adenovirus platform expressing TAAs;

proprietary yeast platform expressing TAAs;

proprietary agent N-803 and derivatives, agent N-809 and derivatives, and/or TxM product candidates;

proprietary recombinant NK cells and mAbs;

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The term of the CRADA was extended through May 2026.

Under this agreement, we have agreed to pay NCI funding totaling $1.3 million per year, payable in semi-annual installments from 2022 through 2025.

Under this agreement, we agreed to pay NCI funding totaling $1.3 million per year, payable in semi-annual installments each year through 2025.

License Agreements

CytRx Corporation

In 2017, we entered into an exclusive license agreement with CytRx pursuant to which we obtained a royalty-bearing, exclusive, worldwide license, with the right to sublicense, CytRx’s applicable intellectual property to research, develop and commercialize aldoxorubicin for all indications.

Under the terms of the license agreement, CytRx is entitled to receive milestone payments of up to $345.7 million related to regulatory approvals and commercial milestones for aldoxorubicin.

In addition, CytRx will receive increasing low double-digit percentage royalties on net sales of aldoxorubicin for the treatment of soft tissue sarcomas and mid-to-high single-digit percentage royalties on net sales of aldoxorubicin for all other indications.

We may terminate the agreement in its entirety at any time upon twelve (12) months written notice to CytRx.

Upon termination of the agreement, any licenses granted to us under the agreement are terminated, and we must cease the development, manufacture, and commercialization of aldoxorubicin.

EnGeneIC Licensing Agreement

During the fourth quarter of 2021, we signed a binding term sheet with EnGeneIC for an exclusive, worldwide license to develop, manufacture and commercialize their patented EDV nanocell technology as a single agent in certain cancer fields and with respect to the treatment and prevention of COVID-19 and in combination with our COVID-19 vaccine and anti-cancer drugs in a more broadly defined field of use.

The companies have agreed to a 50:50 split of the net profit from worldwide sales of EDV-based products, and we have agreed to pay certain periodic license fees.

3M Innovative Properties Company (3M IPC) and AAHI License Agreement

We have licensed rights to 3M-052, a synthetic TLR7/8 agonist, 3M-052 formulations and related technology from 3M IPC and its affiliates and AAHI.

In November 2021 we obtained nonexclusive rights in the field of SARS-CoV-2 and in June 2022 we modified those rights and expanded the scope of the license to include (1) SARS-CoV-2 and other infectious diseases including malaria, HIV, tuberculosis, hookworm and varicella zoster on an exclusive basis in countries other than low- and middle-income countries (LMIC), and (2) oncology applications, when used in combination with our proprietary technology and/or IL-15 agonists.

In consideration for the license, we agreed to make certain periodic license payments, including $2.25 million each year through June 2025.

We have also agreed to make payments upon the achievement of certain regulatory milestone events and tiered royalties ranging from the low to high single-digits as a percentage of net sales.

Beginning in April 2026, the annual minimum licensing payment is $1.0 million, which can be credited against any royalty payments due under this agreement.

We may terminate this license for any reason after providing 3M and AAHI sixty (60) days written notice.

AAHI License Agreements

In May 2021, we entered into two license agreements with the AAHI pursuant to which we received a license to certain patents and know-how relating to AAHI’s (i) adjuvant formulations for the treatment, prevention and/or diagnosis of SARS-CoV-2 (the AAHI Adjuvant Formulation License Agreement) and (ii) RNA vaccine platform as further described below (the AAHI RNA License Agreement).

Under both agreements, we were obligated to pay one-time, non-creditable, non-refundable upfront cash payments totaling $2.0 million.

In addition, under the AAHI Adjuvant Formulation License Agreement we owe milestone payments to a total of up to $2.5 million based on the achievement of certain development and regulatory milestones for the first licensed product and royalties on annual net sales of licensed products on a country-by-country and product-by-product basis of a low-single digit percentage, subject to certain royalty-reduction provisions.

In September 2021, we amended and restated the AAHI RNA License Agreement, pursuant to which AAHI granted us an exclusive, worldwide, sublicensable license to AAHI’s rights to an RNA vaccine platform for the development and commercialization of certain therapeutic, diagnostic or prophylactic products for the prevention, treatment or diagnosis of any indication, other than those subject to pre-existing third-party license grants, including, without limitation, SARS-CoV-2.

Pursuant to the terms of the amended and restated AAHI RNA License Agreement, we made an additional one-time, non-creditable, non-refundable, upfront payment to AAHI of $1.5 million.

We are also required to pay license maintenance fees to AAHI as follows:

$3.0 million paid in 2022 and $5.5 million annually from 2023 through 2030.

The company may terminate the restated agreement without cause by paying AAHI a $10.0 million one-time early termination fee.

In addition, the milestone payments to AAHI based on the achievement of certain development and regulatory milestones for the first licensed product were amended to a total of up to $4.0 million.

We are required to pay royalties on annual net sales of licensed products on a country-by-country and product-by-product basis of a low- to mid-single digit percentage.

In connection with the license agreements, in May 2021 we also entered into a sponsored research agreement (SRA) with AAHI pursuant to which we will fund continued research of at least $2.0 million per year, payable in four equal quarterly installments each year until May 2024, or such year of earlier termination.

GlobeImmune, Inc.

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We may terminate this agreement, in whole or on a licensed-product-by-licensed-product and/or country-by-country basis, at any time upon sixty (60) days written notice to GlobeImmune.

Infectious Disease Research Institute

In May 2021, we entered into two license agreements with the IDRI pursuant to which we received a license to certain patents and know-how relating to IDRI’s (i) adjuvant formulations for the treatment, prevention and/or diagnosis of SARS-CoV-2 (the IDRI Adjuvant Formulation License Agreement) and (ii) RNA vaccine platform as further described below (the IDRI RNA License Agreement).

Under both agreements, we were obligated to pay one-time, non-creditable, non-refundable upfront cash payments totaling $2.0 million.

In addition, under the IDRI Adjuvant Formulation License Agreement we owe IDRI milestone payments to a total of up to $2.5 million based on the achievement of certain development and regulatory milestones for the first licensed product and royalties on annual net sales of licensed products on a country-by-country and product-by-product basis of a low-single digit percentage, subject to certain royalty-reduction provisions.

In September 2021, we amended and restated the IDRI RNA License Agreement, pursuant to which IDRI granted us an exclusive, worldwide, sublicensable license to IDRI’s rights to an RNA vaccine platform for the development and commercialization of certain therapeutic, diagnostic or prophylactic products for the prevention, treatment or diagnosis of any indication, other than those subject to pre-existing third-party license grants, including, without limitation, SARS-CoV-2.

Pursuant to the terms of the amended and restated IDRI RNA License Agreement, we were required to make an additional one-time, non-creditable, non-refundable, upfront payment to IDRI of $1.5 million.

The company is also required to pay license maintenance fees to IDRI as follows:

$3.0 million in 2022 and $5.5 million annually from 2023 through 2030.

The company may terminate the restated agreement without cause by paying IDRI a $10.0 million one-time early termination fee.

In addition, the milestone payments to IDRI based on the achievement of certain development and regulatory milestones for the first licensed product were amended to a total of up to $4.0 million.

We are required to pay royalties on annual net sales of licensed products on a country-by-country and product-by-product basis of a low- to mid-single digit percentage.

In connection with the license agreements, in May 2021 we also entered into a sponsored research agreement (SRA) with IDRI pursuant to which we will fund continued research of at least $2.0 million per year, payable in four equal quarterly installments each year until May 2024, or such year of earlier termination.

LadRx Corporation

In 2017, we entered into an exclusive license agreement with LadRx pursuant to which we obtained a royalty-bearing, exclusive, worldwide license, with the right to sublicense, LadRx’s applicable intellectual property to research, develop and commercialize aldoxorubicin for all indications.

Under the terms of the license agreement, LadRx is entitled to receive milestone payments of up to $345.7 million related to regulatory approvals and commercial milestones for aldoxorubicin.

In addition, LadRx will receive increasing low double-digit percentage royalties on net sales of aldoxorubicin for the treatment of soft tissue sarcomas and mid-to-high single-digit percentage royalties on net sales of aldoxorubicin for all other indications.

We may terminate the agreement in its entirety at any time upon twelve (12) months written notice to LadRx.

Upon termination of the agreement, any licenses granted to us under the agreement are terminated, and we must cease the development, manufacture, and commercialization of aldoxorubicin.

Sanford Health

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Shenzhen Beike Biotechnology Co.

In 2014, Altor entered into a license, development and commercialization agreement with Beike, which agreement was amended and restated in 2017, pursuant to which Altor granted to Beike an exclusive license under certain of its intellectual property rights in order to use, research, develop and commercialize products based on Anktiva in China for human therapeutic uses, in exchange for consideration that includes up to $195.5 million in total milestone payments based on the successful completion of regulatory and sales milestones for each resulting product, and a royalty on net sales of licensed products, on a product-by-product basis ranging in percentage from the mid-single digits to the mid-teens.

In 2014, Altor entered into a license, development and commercialization agreement with Beike, which agreement was amended and restated in 2017, pursuant to which Altor granted to Beike an exclusive license under certain of its intellectual property rights in order to use, research, develop and commercialize products based on N-803 in China for human therapeutic uses, in exchange for consideration that includes up to $195.5 million in total milestone payments based on the successful completion of regulatory and sales milestones for each resulting product, and a royalty on net sales of licensed products, on a product-by-product basis ranging in percentage from the mid-single digits to the mid-teens.

Beike’s obligation to pay royalties continues, on a licensed product-by-licensed product basis, until the later of (i) the date on which such licensed product is no longer covered by a valid claim of a patent licensed pursuant to the agreement in China and (ii) ten years after the first commercial sale of such licensed product in China.

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Sorrento Therapeutics, Inc.

In 2015, we and Sorrento established NANTibody as a stand-alone biotechnology company with $100.0 million in initial joint funding.

In 2015, our subsidiary NantCell, Inc.

and Sorrento established NANTibody as a stand-alone biotechnology company with $100.0 million in initial joint funding.

We own 60% of the equity interests and Sorrento owns 40% of the equity interests in NANTibody, which focuses on accelerating the development of multiple therapeutic product candidates that are being developed as standalone treatments as well as in combination with other therapies as part of an immune-oncology treatment regimen.

In 2015, we entered into an exclusive license agreement with Sorrento pursuant to which we obtained an exclusive license under certain patent rights and antibody materials, including antibody sequences and complementary DNA (cDNA) and clones and a non-exclusive license under certain know-how, in each case to use, research and develop certain antibodies and anti-body drug conjugates (ADCs) including for neoepitopes, which are epitopes resulting from mutations specific to an individual’s cancer cells, and to commercialize the resulting licensed products, in exchange for consideration that included an upfront cash payment of $10 million, equity consideration with a valuation of $100 million, and mid-single digit percentage royalties on net sales of the resulting licensed products.

Our obligation to pay royalties continues, on a licensed product-by-licensed product and country-by-country basis, until the later of (i) the date on which such licensed product is no longer covered by a valid claim of a patent licensed pursuant to the agreement in such country and (ii) ten years after the first commercial sale of such licensed product in such country.

In addition, the agreement provides us with the right to negotiate an exclusive license from Sorrento for two CAR-T/NK cell products to be mutually determined on terms substantially similar to the terms of the license agreement.

We must use commercially reasonable efforts to develop and commercialize the licensed products.

Subject, as applicable, to the licenses granted by Sorrento to us, each party shall own all inventions and other developments it creates or develops in the course of activities conducted pursuant to the agreement.

Sorrento has the first right to prosecute, maintain, defend and enforce the patents licensed pursuant to the agreement, subject to our ability to exercise such rights if Sorrento fails to do so.

We may terminate the agreement, in our sole discretion, in whole or on a product-by-product and country-by-country basis, at any time upon 60 days’ prior written notice to Sorrento.

In addition, either party may terminate the agreement in the event of a material breach by the other party.

In 2015, NantCell entered into an exclusive license agreement with Sorrento pursuant to which we obtained an exclusive license under certain patent rights and antibody materials, including antibody sequences and complementary DNA (cDNA) and clones and a non-exclusive license under certain know-how, in each case to use, research and develop certain antibodies and anti-body drug conjugates (ADCs) including for neoepitopes, which are epitopes resulting from mutations specific to an individual’s cancer cells, and to commercialize the resulting licensed products, in exchange for consideration that included an upfront cash payment of $10 million, equity consideration with a valuation of $100 million, and mid-single digit percentage royalties on net sales of the resulting licensed products.

Our obligation to pay royalties was, on a licensed product-by-licensed product and country-by-country basis, until the later of (i) the date on which such licensed product is no longer covered by a valid claim of a patent licensed pursuant to the agreement in such country and (ii) ten years after the first commercial sale of such licensed product in such country.

In addition, the agreement provided us with the right to negotiate an exclusive license from Sorrento for two CAR-T/NK cell products to be mutually determined on terms substantially similar to the terms of the license agreement.

NantCell was to use commercially reasonable efforts to develop and commercialize the licensed products.

Subject, as applicable, to the licenses granted by Sorrento to us, each party was to own all inventions and other developments it creates or develops in the course of activities conducted pursuant to the agreement.

In 2015, NANTibody entered into an exclusive license agreement with Sorrento pursuant to which NANTibody obtained a royalty-free exclusive license under certain patent rights and materials, including antibody sequences and cDNA, and clones and a non-exclusive license under certain know-how, in each case related to up to 75 immuno-oncology antibodies, immune-check point antibodies, bi-specific antibodies and/or ADCs from Sorrento’s G-MAB library to be mutually identified by the parties (21 of which were already identified at the time of signing the agreement), to use, research, develop and commercialize the resulting licensed products.

NANTibody must use commercially reasonable efforts to develop and commercialize the licensed products.

Subject, as applicable, to the licenses granted by Sorrento to NANTibody, each party shall own all inventions and other developments it creates or develops in the course of activities conducted pursuant to the agreement.

Sorrento has the first right to prosecute, maintain and defend the patents licensed pursuant to the agreement, subject to NANTibody’s ability to exercise such rights if Sorrento fails to do so.

NANTibody has the first right to enforce antibody-specific patents and Sorrento has the first right to enforce the other patents licensed pursuant to the agreement.

NANTibody may terminate the agreement, in its sole discretion, in whole or on a product-by-product and country-by-country basis, at any time upon 90 days’ prior written notice to Sorrento.

In addition, either party may terminate the agreement in the event of a material breach by the other party.

In 2019, we filed cross-claims against Sorrento in the Superior Court of California, Los Angeles County, alleging that Sorrento breached the exclusive license agreement with us;

these claims are now being pursued in arbitration.

In January 2020 and April 2020, Sorrento sent letters purporting to terminate the exclusive license agreement with us and the exclusive license agreement with NANTibody.

We believe we have cured any perceived breaches during the 90-day contractual cure period provided under the agreements.

Sorrento filed counterclaims against the company and NANTibody in the arbitration and requested leave to file a dispositive motion.

The hearings in the NANTibody arbitration commenced in April 2021 and concluded in early August 2021.

After post-hearing briefing was concluded, the parties were notified on November 30, 2021 that the arbitrator in the NANTibody arbitration had passed away.

A substitute arbitrator was appointed on February 25, 2022, and the parties will work with the substitute arbitrator to conclude the proceedings.

In 2019, we filed cross-claims against Sorrento in the Superior Court of California, Los Angeles County, alleging that Sorrento had breached the exclusive license agreement with us;

these claims were pursued in arbitration.

Sorrento filed counterclaims against the company and NANTibody in the arbitration.

On December 2, 2022, the arbitrator issued a final award finding that Sorrento had breached the two exclusive license agreements with NantCell and NANTibody.

In addition, the arbitrator determined that our license agreement remains in full force and effect with respect to ImmunityBio’s PD-L1 NK-cell.

The arbitrator ruled that Sorrento, NantCell, and NANTibody have no further rights or obligations under either license agreement with respect to other targets.

Sorrento has no further obligation to contribute materials or know how with respect to the PD-LI antibody, and NantCell and NANTibody are not required to return any materials or know-how received from Sorrento.

For more information, see Note 7 , Commitments and Contingencies—Sorrento Therapeutics, Inc.

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These clinical trials are intended to establish the overall risk to benefit ratio of the product and provide an adequate basis for product labeling.

In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.

These so-called Phase 4 trials may be made a condition to approval of the BLA or NDA.

Companies may voluntarily pursue additional clinical trials after a product is approved to gain more information about the product for that approved indication.

In some cases, the FDA may require an additional trial after a product is approved, and these so-called Phase 4 trials may be a condition to approval of the BLA or NDA.

Phase 1, Phase 2 and Phase 3 testing may not be completed successfully within a specified period, if at all, and there can be no assurance that the data collected will support FDA approval or licensure of the product.

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We may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from the COVID-19 virus.

For example, in March 2020, the FDA issued a guidance, which FDA subsequently updated, on conducting clinical trials during the pandemic, which describes a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical trial report contingency measures implemented to manage the trial, and any disruption of the trial as a result of the COVID-19 pandemic;

a list of all subjects affected by the COVID-19-pandemic related study disruption by unique subject identifier and by investigational site and a description of how the individual’s participation was altered;

and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the trial.

In June 2020, FDA also published a guidance on Good Manufacturing Practice considerations for responding to COVID-19 infection in employees in drug and biological products manufacturing.

Since March 2020, the FDA has issued various COVID-19 related guidance for sponsors and manufacturers, including guidance on, on conducting clinical trials during the pandemic, and Good Manufacturing Practice considerations for responding to COVID-19 infection in employees in drug and biological products manufacturing, among others.

The extent to which the COVID-19 pandemic impacts our business, preclinical studies and clinical trials will depend on future developments, which are highly uncertain and cannot be predicted with confidence.

Recently, President Biden announced that the administration intends to end the COVID-19 national and public health emergencies on May 11, 2023.

The full impact of the termination of the public health emergencies on FDA and other regulatory policies and operations are unclear.

BLA/NDA Submission and Review by the FDA

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 for a biologic product candidate or an NDA for a small molecule product candidate requesting approval to market the product for one or more indications.

The BLA/NDA must include all relevant data available from pertinent 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.

Unless agreed to in advance with the FDA, the BLA/NDA must include all data available from pertinent 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.

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 studies initiated by investigators.

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Post-marketing studies or completion of ongoing studies after marketing approval are generally required to verify the product’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.

In December 2022, the Consolidated Appropriations Act, 2023, including the Food and Drug Omnibus Reform Act (FDORA), was signed into law.

FDORA made several changes to the FDA’s authorities and its regulatory framework, including, among other changes, reforms to the accelerated approval pathway, such as requiring the FDA to specify conditions for post-approval study requirements and setting forth procedures for the FDA to withdraw a product on an expedited basis for non-compliance with post-approval requirements.

In addition, the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) established Breakthrough Therapy designation.

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If our present or future suppliers are not able to comply with these requirements, the FDA may, among other things, halt our clinical trials, require us to recall a product from distribution, or withdraw approval of the BLA or NDA.

In the U.S., once a drug is approved, its manufacture is subject to comprehensive and continuing regulation by the FDA.

FDA regulations require that drugs be manufactured in specific facilities per the BLA or NDA approval and in accordance with cGMP.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

These regulations also impose certain organizational, procedural, and documentation requirements with respect to manufacturing and quality assurance activities.

BLA or NDA holders using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms.

These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such facilities or the ability to distribute drugs manufactured, processed, or tested by them.

Future FDA and state inspections may identify compliance issues at our facilities or at the facilities of contract manufacturers that may disrupt production or distribution, or require substantial resources to correct.

In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved BLA or NDA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing.

The FDA may also require post-approval testing, sometimes referred to as Phase 4 testing, risk minimization action plans, and post-marketing surveillance to monitor the effects of an approved drug or place conditions on an approval that could restrict the distribution or use of the drug.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product, including AEs of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

imposition of post-market studies or clinical trials to assess new safety risks;

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The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

Prescription drug advertising is subject to federal, state, and foreign regulations.

In the U.S., the FDA regulates prescription drug promotion, including direct-to-consumer advertising.

Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use.

Any distribution of prescription drugs and pharmaceutical samples must comply with the U.S.

Prescription Drug Marketing Act (PDMA), a part of the FDCA.

The Drug Supply Chain Security Act (DSCSA), enacted in 2013, aims to build an electronic system to identify and trace certain prescription drugs distributed in the U.S.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers.

The law’s requirements include the quarantine and prompt investigation of a suspect product to determine if it is illegitimate and notifying trading partners and the FDA of any illegitimate product.

Drug manufacturers and their collaborators are also required to place a unique product identifier on prescription drug packages.

Premarket Clearance and Approval Requirements for Medical Devices

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The investigators must obtain patient informed consent, rigorously follow the investigational plan and trial protocol, control the disposition of investigational devices and comply with all reporting and recordkeeping requirements.

Clinical trials for significant risk devices may not begin until the IDE application is approved by the FDA and the appropriate IRBs at the clinical trial sites.

Clinical trials for significant risk devices may not begin until the

IDE application is approved by the FDA and the appropriate IRBs at the clinical trial sites.

An IRB is an appropriately constituted group that has been formally designated to review and monitor medical research involving subjects and which has the authority to approve, require modifications in, or disapprove research to protect the rights, safety and welfare of human research subjects.

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Other Healthcare Laws and Compliance Requirements

We are subject to numerous foreign, federal, state, and local environmental, health, and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment, and disposal of hazardous materials and wastes.

In addition, our leasing and operation of real property may subject us to liability pursuant to certain U.S.

environmental laws and regulations, under which current or previous owners or operators of real property and entities that disposed or arranged for the disposal of hazardous substances may be held strictly, jointly, and severally liable for the cost of investigating or remediating contamination caused by hazardous substance releases, even if they did not know of and were not responsible for the releases.

The distribution of pharmaceutical drugs is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage, and security requirements intended to prevent the unauthorized sale of pharmaceutical drugs.

The failure to comply with regulatory requirements subjects firms to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines, or other penalties, injunctions, voluntary recall or seizure of drugs, total or partial suspension of production, denial or withdrawal of product approvals, or refusal to allow a firm to enter into supply contracts, including government contracts.

In addition, even if a firm complies with FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval.

Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

Our sales, promotion, medical education, clinical research and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the U.S.

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Our promotional and scientific/educational programs must comply with the AKS, the FCA, physician payment transparency laws, privacy laws, security laws, and additional federal and state laws similar to the foregoing.

If drugs are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.

Drugs must meet applicable child-resistant packaging requirements under the U.S.

Poison Prevention Packaging Act.

Manufacturing, sales, promotion, and other activities are also potentially subject to federal and state consumer protection and unfair competition laws.

Changes in regulations, statutes, or the interpretation of existing regulations could impact our business in the future by requiring, for example:

(i) changes to our manufacturing arrangements;

(ii) additions or modifications to product labeling;

(iii) the recall or discontinuation of our products;

or (iv) additional record-keeping requirements.

If any such changes were to be imposed, they could adversely affect the operation of our business.

The AKS prohibits, among other things, the knowing and willing, direct or indirect offer, receipt, solicitation or payment of remuneration in exchange for or to induce the referral of patients, including the purchase, order or lease of any good, facility, item or service that would be paid for in whole or part by Medicare, Medicaid or other federal health care programs.

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In addition, certain companies that were found to be in violation of the FCA have been forced to implement extensive corrective action plans and have often become subject to consent decrees or corporate integrity agreements, restricting the manner in which they conduct their business.

HIPAA created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors;

The Health Insurance Portability and Accountability Act (HIPAA) created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors;

knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services;

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The ACA, among other things, under the federal Physician Payment Sunshine Act, imposed reporting requirements on certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, for payments or other transfers of value made by them to certain covered recipients, including physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Effective January 1, 2022, for data reported to the Centers for Medicare & Medicaid Services (CMS) in 2022, these reporting obligations with respect to covered recipients have been extended to include payments and transfers of value made to non-physician providers such as physician assistants and nurse practitioners.

Effective January 1, 2022, these reporting obligations with respect to covered recipients have been extended to include payments and transfers of value made to non-physician providers such as physician assistants and nurse practitioners.

Covered manufacturers are required to collect and report detailed payment data and submit legal attestation to the accuracy of such data to the government each year.

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Third-party payors are increasingly challenging the price, examining the cost-effectiveness, and reducing reimbursement for medical products and services.

In addition, significant uncertainty exists as to the reimbursement status of newly approved healthcare products.

In the U.S., no uniform policy of coverage and reimbursement for drugs or biological products exists, and one payor’s determination to provide coverage and adequate reimbursement for a product does not assure that other payors will make a similar determination.

In the U.S., the principal decisions about reimbursement for new medicines are typically made by the CMS, an agency within the HHS, as the CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare.

Private third-party payors tend to follow Medicare coverage and reimbursement limitations to a substantial degree, but also have their own methods and approval process apart from Medicare determinations.

Significant uncertainty exists as to the reimbursement status of newly approved healthcare products.

government, state legislatures and foreign governments have continued implementing cost containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products.

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In addition, other legislative changes have been proposed and adopted since the ACA was enacted.

These changes include, among others, the Budget Control Act of 2011, which mandates aggregate reductions to Medicare payments to providers of up to 2% per fiscal year effective April 1, 2013, and, due to subsequent legislative amendments, will remain in effect through 2030, with the exception of a temporary suspension implemented under various COVID-19 relief legislation from May 1, 2020 through March 31, 2022, followed by a 1% payment adjustment from April 1 to June 30, 2022 and a 2% payment adjustment beginning July 1, 2022, unless additional Congressional action is taken.

These changes include, among others, the Budget Control Act of 2011, which mandates aggregate reductions to Medicare payments to providers of up to 2% per fiscal year effective April 1, 2013, and, due to subsequent legislative amendments, will remain in effect through 2031, with the exception of a temporary suspension implemented under various COVID-19 relief legislation from May 1, 2020 through March 31, 2022.

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, President Obama signed into law the ARTA, which, among other things, further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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Further, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at increasing competition for prescription drugs.

Congress is considering legislation that, if passed, could have significant impact on prices of prescription drugs covered by Medicare, including limitations on drug price increases.

In August 2022, Congress passed the Inflation Reduction Act of 2022, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum fair price for certain high-priced single source Medicare drugs, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes.

The impact of these legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by the Biden administration on us and the pharmaceutical industry as a whole is unclear.

The impact of these regulations and any future healthcare measures and agency rules implemented by the Biden administration on us and the pharmaceutical industry as a whole is currently unknown.

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Accordingly, the ACA remains in effect in its current form.

It is unclear how this Supreme Court decision, future litigation, or healthcare measures promulgated by the Biden administration will impact our business, financial condition and results of operations.

It is possible that the ACA will be subject to judicial or Congressional challenges in the future.

It is unclear how additional challenges and healthcare reform measures of the Biden administration will impact the ACA.

Complying with any new legislation or changes in healthcare regulation could be time-intensive and expensive, resulting in material adverse effect on our business.

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Human Capital

Our Human Capital Talent Strategy relies on attracting, retaining and developing top talent that align with our culture and mission to “outsmart your disease”.

We promote a culture that is focused on delivering treatments utilizing natural immunities, and we seek to harness our science first focus to deliver solutions to patients and families.

As of December 31, 2021, we had 587 employees located in our offices in Southern California, Washington, Colorado, Florida, North Carolina, Massachusetts, and Italy.

Our Human Capital talent strategy relies on attracting, retaining and developing top talent that align with our culture and mission to “outsmart your disease.” We promote a culture that is focused on delivering treatments utilizing natural immunities, and we seek to harness our science first focus to deliver solutions to patients and families.

As of December 31, 2022, we had 725 employees located across the U.S.

Among our employees, 23% are focused on research and development, 14% on clinical development and regulatory, 40% on manufacturing and quality, and 23% on general and administrative functions.

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Our ongoing response to the COVID-19 pandemic, which complies with government orders in all the states and counties where we operate, focuses on employee health and wellness.

We implemented a number of health-related measures over the past two years.

We continue to support a general work from home policy and restrict on-site access to essential employees such as laboratory personnel, increasing hygiene, cleaning and sanitizing procedures at our office and laboratory facilities, requiring face masks be worn while on company premises, and implementing temperature checks and COVID-19 testing requirements in order to enter company facilities.

We implemented a number of health-related measures over the past three years that included work from home policies, on-site access restrictions, and increased cleaning and sanitizing procedures.

Organization and Development of ImmunityBio, Inc.

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In April 2015, it was converted to a Delaware corporation, NantCell, Inc., and in May 2019 changed its name to ImmunityBio, Inc.

(a private company).

On December 21, 2020 , NantKwest, Inc.

and ImmunityBio, Inc.

entered into a merger agreement (the Merger Agreement) providing for the combination of the two companies (the Merger), with NantKwest, Inc.

being the surviving company which then changed its name to ImmunityBio, Inc.

(and ImmunityBio, Inc., a private company, changed its name back to NantCell, Inc.

and is now our wholly owned subsidiary).

At the time, NantKwest, Inc.

was an innovative, clinical-stage immunotherapy company focused on harnessing the power of the innate immune system to treat cancer and infectious diseases, and ImmunityBio, Inc.

was a clinical-stage immunotherapy company developing next-generation therapies that drive immunogenic mechanisms for defeating cancer and infectious diseases, with an immunotherapy platform designed to activate both the innate and adaptive immune systems to create long-term “immunological memory.” We believe that the Merger, which closed on March 9, 2021 as described below, combined two companies to create a clinical-stage biotechnology company developing next-generation therapies and vaccines that complement, harness, and amplify the immune system to defeat cancers and infectious diseases.

(a private company) (NantCell).

On December 21, 2020 , NantKwest and NantCell entered into an Agreement and Plan of Merger (the Merger Agreement), pursuant to which NantKwest and NantCell agreed to combine their businesses.

The Merger Agreement provided that a wholly-owned subsidiary of the company would merge with and into NantCell (the Merger), with NantCell surviving the Merger as a wholly-owned subsidiary of the company.

We believe that the Merger, which closed on March 9, 2021, combined two companies to create a clinical-stage biotechnology company developing next-generation therapies and vaccines that complement, harness, and amplify the immune system to defeat cancers and infectious diseases.

ImmunityBio is incorporated in Delaware and its principal executive offices are located in San Diego, California.

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Financial and other information about our company is available on our website at https://www.immunitybio.com .

We make available on our website, free of charge, copies of our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (the Exchange Act), as soon as reasonably practicable after we electronically file such material with, or furnish it, to the U.S.

We make available on our website, free of charge, copies of our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material with, or furnish it, to the U.S.

Securities and Exchange Commission (the SEC).

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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.

What changed 10-K

Item 1. Business