A Next-Generation Immunotherapy Platform

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Broad, Unparalleled Immunotherapy and Cell Therapy Platforms

The immune system is a collection of diverse immune cell families, each with a distinct role in protecting us from infections and diseases. Among these are the natural killer (NK) cells, the body’s first line of defense. As part of the ‘innate’ immune response, NK cells have the ability to recognize and destroy abnormal (such as cancerous or virally-infected) cells and are uniquely powerful: they are always activated and ready to eliminate diseased cells without delay. We harness this power with our activated natural killer (aNK) platform based upon NK cells from a distinct cell line.

To further leverage the power of innate immune responses, we have developed a proprietary interleukin-15 (IL-15) superagonist, Anktiva® (N-803), which selectively activates NK cells and T effector cells, without activating regulatory T cells that may dampen responses. The aNK and Anktiva platforms can be combined for clinical synergy in patients and such combination has produced complete responses and/or prolonged survival in difficult-to-treat cancers, such as Merkel Cell Carcinoma (MCC)1, advanced pancreatic cancer2, and advanced triple negative breast cancer (TNBC)3.

In addition to natural innate immunity, the second arm of the immune system, ‘adaptive’ immunity, can be targeted with vaccines. The majority of vaccines targeted to either cancer or infectious disease focus on the generation of antibody (humoral) responses mediated by B cells. ImmunityBio’s next-generation vaccine platform, the human adenovirus 5 (hAd5) vector with advanced modifications, offers an opportunity for a broader immune response that includes vigorous T-cell mediated responses. Combination of the humoral and cell-mediated aspects of immune response result in immunological memory and a longer duration of protection than vaccines targeted at antibody production alone. Additional features of our hAd5 platform are its large payload capacity, that is, its ability to deliver multiple antigens to elicit an immune response and efficacy even in the presence of pre-existing hAd5 immunity. The advantage of the latter is that the vaccine platform can be used safely and effectively for multiple doses or different vaccine targets, if needed. The safety and efficacy of hAd5-based vaccines has been established in several previous clinical studies, and clinical trials of ImmunityBio’s hAd5 cancer vaccine are underway, including a trial of ‘Tri-Ad5’ – a combination of three hAd5 cancer-targeted vaccines 4 – that is being studied for its ability to reduce incidence of colorectal cancer (CRC) in persons with Lynch Syndrome 5, a genetic risk factor for CRC.

1. Drusbosky, L.; Nangia, C.; Nguyen, A.; Szeto, C.; Newton, Y.; Spilman, P.; Reddy, S. B., Complete response to avelumab and IL-15 superagonist N-803 with Abraxane in Merkel cell carcinoma: a case study. J. Immunother. Cancer 2020, 8 (2). Link: https://jitc.bmj.com/content/8/2/e001098.long

2. Seery, T. E.; Nangia, C. S.; McKean, H. A.; Bhar, P.; Sender, L. S.; Reddy, S. K.; Soon-Shiong, P., Phase 2 Quilt 88 trial of DAMP inducers combined with IL15 superagonist, N-803, and anti–PD-L1 NK cell therapy more than doubles historical overall survival in patients with third- to sixth-line advanced pancreatic cancer. Journal of Clinical Oncology 2022, 40 (16_suppl), 4147-4147. Link: https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.4147

3. Kistler, M.; Nangia, C.; To, C.; Sender, L.; Lee, J.; Jones, F.; Jafari, O.; Seery, T.; Rabizadeh, S.; Niazi, K.; Rock, A.; Soon-Shiong, P., Safety and efficacy from first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK) in patients with 2nd line or greater metastatic triple-negative breast cancer (TNBC). Cancer Res. 2020, 80 (PS-04-02). Link: https://aacrjournals.org/cancerres/article/80/4_Supplement/P5-04-02/647290/Abstract-P5-04-02-Safety-and-efficacy-from-first

4. Gatti-Mays, M. E.; Redman, J. M.; Donahue, R. N.; Palena, C.; Madan, R. A.; Karzai, F.; Bilusic, M.; Sater, H. A.; Marte, J. L.; Cordes, L. M.; McMahon, S.; Steinberg, S. M.; Orpia, A.; Burmeister, A.; Schlom, J.; Gulley, J. L.; Strauss, J., A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)-Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer. Oncologist 2019, 25, 479.

5. Link: https://clinicaltrials.gov/study/NCT05419011?cond=Lynch%20Syndrome&term=N-803&rank=1

Antibody Cytokine Fusion Proteins

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Vaccine Technologies

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Natural Killer Cells

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Antibody Cytokine Fusion Proteins—Activated NK & T Cells

Anktiva® (also known as N-803 and nogapendekin alfa inbakicept or NAI) is our lead antibody cytokine fusion protein, a novel class of biopharmaceuticals created to amplify the therapeutic capability of cytokines and promote lymphocyte infiltration of the disease. Anktiva selectively activates NK and T cells through its proprietary IL-15 superagonist and is in late-stage clinical development. It is a soluble complex consisting of nogapendekin alfa (a human IL-15N72D variant) bound to inbakicept (a dimeric human IL-15Rα sushi domain/human IgG1 Fc fusion protein) 6.

To date, Phase I thru III trials have been completed or are in progress for liquid and solid tumors in over 700 patients, including an ongoing registrational Phase II / III trial of Anktiva in combination with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Anktiva previously achieved both FDA Breakthrough Therapy and Fast Track designations for treatment of BCG-unresponsive patients with NMIBC CIS, and Fast Track designations for BCG-unresponsive papillary NMIBC and BCG-naïve CIS NMIBC (these designations do not necessarily lead to faster development or regulatory review processes, or increase the likelihood of FDA approval). In the Phase II/III trial for BCG-unresponsive NMIBC, interim data showed that >70% of patients achieved a complete response, and the responses were durable, lasting a median of > 2 years 7. The patients in that study also reported good quality-of-life 8, indicating a favorable risk: benefit ratio for the combination Anktiva plus BCG therapy.

Anktiva is also in late-stage clinical trials for multiple solid tumor types, including lung cancer and glioblastoma, in combination with checkpoint inhibitors, chemotherapy, cell therapy, and other immune-stimulating agents. In addition to Anktiva, our prioritized novel antibody cytokine fusion constructs include N-820 (targeting CD20), N-809 (targeting PD-L1), N-812 (delivering IL-12 to necrotic tumor cells), and N-830 (delivering TGF-ß Trap to necrotic tumor cells).

6. Liu,B; Kong, L; Han, K; Hong, H; Marcus, WD; Chen, X; Jeng, EK; Alter, S; Zhu, X; Rubinstein, MP; Shi, S; Rhode, PR; Cai, W; Wong, HC. A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses. J Biol Chem. 2016 Nov 11;291(46):23869-23881. doi: 10.1074/jbc.M116.733600. Epub 2016 Sep 20. PMID: 27650494 PMCID: PMC5104912 DOI: 10.1074/jbc.M116.733600. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104912/

7. Chamie, K.; Chang Sam, S.; Kramolowsky, E.; Gonzalgo Mark, L.; Agarwal Piyush, K.; Bassett Jeffrey, C.; Bjurlin, M.; Cher Michael, L.; Clark, W.; Cowan Barrett, E.; David, R.; Goldfischer, E.; Guru, K.; Jalkut Mark, W.; Kaffenberger Samuel, D.; Kaminetsky, J.; Katz Aaron, E.; Koo Alec, S.; Sexton Wade, J.; Tikhonenkov Sergei, N.; Trabulsi Edouard, J.; Trainer Andrew, F.; Spilman, P.; Huang, M.; Bhar, P.; Taha Sharif, A.; Sender, L.; Reddy, S.; Soon-Shiong, P., IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. NEJM Evidence 2022, 2 (2200167), 1-11. Link: https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200167

8. Chamie, K.; Chang, S. S.; Kramolowsky, E. V.; Gonzalgo, M. L.; Huang, M.; Bhar, P.; Spilman, P.; Sender, L.; Reddy, S. K.; Soon-Shiong, P., Quality of Life in the Phase 2/3 Trial of N-803 Plus BCG in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer. Urol Pract 2024, 101097upj0000000000000517. Link: https://www.auajournals.org/doi/full/10.1097/UPJ.0000000000000517

Vaccine Technologies—Generating Memory T Cells

Our vaccine platforms, such as our second generation hAd5 platform, have been developed to deliver tumor-associated antigens (TAAs) and neoepitopes (expressed only by cancer cells). These vaccines are designed to induce T-cell memory through the activation of CD4+ and CD8+ T cells, along with B-cell based antibody (humoral) responses. Our hAd5 technology has produced several product candidates that have been studied in Phase I and II clinical trials as potential vaccines for certain cancers; these candidates have shown an ability to overcome previous adenovirus immunity in cancer patients and preclinical models. The hAd5 technology has also been used with common TAAs to establish memory T cells in multiple clinical trials.

A Powerful Investigational NK Cell Therapy Advancing to Multiple Phase II Trials

Combining our haNK platform with a Chimeric Antigen Receptor (CAR) to drive further tumor-targeted specificity

Off-the-Shelf, Genetically Engineered Natural Killer Cell Platform

Our NK platforms have demonstrated the ability to induce cell death in cancerous and virally-infected cells through a variety of concurrent killing mechanisms, including innate, antibody-mediated, CAR-directed, and a combination of both antibody-mediated and CAR-directed.


Antibody-mediated killing

High-affinity NK (haNK) cells are engineered to express a high-affinity CD-16 Fc receptor that facilitates binding to IgG1-type antibodies such as avelumab, trastuzumab, cetuximab, and rituximab, and enhances the cancer-killing efficacy of these antibodies. They boost the available number of natural killer cells that can kill cancer cells through Antibody-Dependent Cellular Cytotoxicity (ADCC).

Antibody products are abundantly utilized to treat cancer and are estimated to generate over $100 billion in reported annual sales. A growing number of studies suggest that clinically meaningful responses to these antibody therapies correlate directly with the overall health of a patient’s natural killer cell population, and whether they express the high-affinity variant of the CD16 receptor. Current literature estimates that only 10 to 15 percent of the eligible patient population carry high-affinity CD16 receptors 9. This suggests that our haNK product candidate may have significant market potential as a combination therapy for patients who do not carry high-affinity CD16 receptors and, as a result, are likely exhibit a poorer response to antibody therapies.

9. Jochems, C., Hodge, J. W., Fantini, M., Fujii, R., Morillon, Y. M., 2nd, Greiner, J. W., . . . Schlom, J. (2016). An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele. Oncotarget, 7(52), 86359-86373. doi:10.18632/oncotarget.13411. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341330/


CAR-Directed and Antibody-Mediated Killing

Our newest and most promising platform for the development of therapeutic product candidates is an innovative, bioengineered combination of our haNK platform together with a chimeric antigen receptor (CAR). The resulting product line candidates under this platform have the potential to kill in three ways: innate, antibody-mediated, and CAR-directed killing. These candidates also include one or more additional expression elements, such as functional cytokines, chemokines, and trafficking factors, making them some of the most versatile in our portfolio. These products 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 different cancer-specific proteins.

PD-L1 t-haNK

Our novel investigational bi-specific programmed death receptor ligand 1-targeted high-affinity NK (PD-L1 t-haNK) cell candidate targets PD-L1 via a CAR, and incorporates a high-binding affinity receptor (CD16) that binds to an administered antibody, potentially enhancing its cancer cell-killing effect. PD-L1 t-haNK cells are GMP-grade and cryopreserved, making them an “off-the-shelf” NK cell-based therapy.

PD-L1 t-haNK cells are not intended for use as a monotherapy; rather, they have the potential to be the backbone of a combination regimen that includes a therapeutic monoclonal antibody, in addition to the IL-15 superagonist Anktiva (N-803)10. We believe that the addition of Anktiva will complement the activity of our bispecific natural killer cell therapy through its stimulation of the patient’s own resident population of natural killer and cytotoxic CD8 T-cells.

10. Fabian, K. P.; Padget, M. R.; Donahue, R. N.; Solocinski, K.; Robbins, Y.; Allen, C. T.; Lee, J. H.; Rabizadeh, S.; Soon-Shiong, P.; Schlom, J.; Hodge, J. W., PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations. J. Immunother. Cancer 2020, 8 (1). Link: https://jitc.bmj.com/content/8/1/e000450.long


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

M-ceNK are created from the patient’s own cells called lymphocytes. These lymphocytes are collected from an individual and induced to differentiate to become m-ceNK cells by brief pre-activation with interleukin-12 (IL-12), IL-15, and IL-18, and are then re-injected into the patient to enhance immune responses. M-ceNK cells exhibit enhanced responses to cytokine re-stimulation that include enhanced IFN-γ production and cytotoxicity against leukemic and lung cancer cell lines. These cells are 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.

Lisa Ray

In her 30s, and at the peak of her career, actress and model Lisa Ray was diagnosed with multiple myeloma, an ‘incurable’ and often fatal form of cancer. Following a stem cell transplant, she opted for a clinical trial to receive Natural Killer cells. She has been in durable complete remission ever since.

Nunzio Varrichio

As a weight-lifter and active farmer, the diagnosis of Merkel Cell Carcinoma, a rare and difficult-to-treat form of skin cancer, came as an extreme blow to Nunzio Varrichio. He fought it with traditional therapies for over a decade until he finally found the opportunity to receive Natural Killer cells through a clinical trial. Following a single treatment, he remained in complete remission for over 15 years with no further medication.

How Can ImmunityBio Help You?

Solutions for Patients

Many cancer therapies, including radiation therapy, chemotherapy, CAR-T therapy, and B-cell immunotherapy, severely weaken the immune system—the human body’s most important natural disease-fighting weapon. But ImmunityBio creates targeted, personalized immunotherapies that are designed to strengthen the immune system and enable it to outsmart your disease.

Opportunities for Trial Investigators

The broad therapeutic potential and demonstrated safety of ImmunityBio’s immune-enhancing IL-15 superagonist Anktiva (N-803), engineered NK-92® cell-based therapies, and our next-generation adenovirus-vectored anti-cancer vaccines make them appealing therapeutics for testing by trial investigators who want to make a contribution to clinical cancer research. Interested clinicians and other are encouraged to contact ImmunityBio to find out how they may support discovery of future cancer treatments.

Tools for Research Scientists

Our NK-92® easy-to-maintain and highly cytotoxic natural killer cell line provides a versatile bioanalytical testing tool that can help researchers develop functional killing assays that are more consistent and reliable than donor blood and reporter gene assays.

ImmunityBio is continuously pursuing new immunotherapies designed to attack disease by enhancing the patient’s immune system, not weakening it.