Natural killer cell-based immunotherapies, antibody cytokine fusion proteins and adenovirus mediated vaccines are key to future cancer treatments. Our investigational NK-92®-engineered cells, superagonist Anktiva, and human adenovirus platform have demonstrated wide therapeutic potential across multiple tumor types, and, in clinical studies, have proven to be well-tolerated, making them ideal for clinical trial investigations.
A Smarter Treatment
Accessibility Facilitated by Outpatient DeliveryPatients receive our NK cells in the outpatient setting—hospitalization is not required. Because community-based healthcare delivery facilities are available to the vast majority of patients throughout the country, this treatment is more accessible to patients than those based on autologous CAR-T technology, which can only be administered at designated medical centers that are certified to competently manage potentially life-threatening side effects. Use of our NK cells is further streamlined by the universality of our NK-92 cell platform that eliminates the need for harvesting patient T-cell for the individualized therapy required by other platforms.
Engineered to Boost Innate NK PotencyOur NK cell-based platform is suitable for incorporation of chimeric antigen receptors (CARs) and antibody receptors to create higher-potency therapies and allow precise targeting. Addition of these receptors augments NK cell killing capabilities against cancers and virus-infected cells. Our ability to bioengineer and tailor NK cells significantly enhances the potential of our NK cells to successfully treat disease.
Predicted to be safeThe ImmunityBio cell therapy platforms have been well tolerated, with a favorable preliminary safety profile. Our engineered natural killer cells are administered in the outpatient setting and have shown no dose-limiting toxicities in patients who have received therapy. While clinical trials with CAR-T cell therapy require hospitalization and some severe adverse events have been reported, including cytokine release syndrome, no such severe toxicities have been noted to date with ImmunityBio’s natural killer cells.
Designed to Augment the Immune SystemUnlike most standard cancer and infectious disease therapies that severely weaken or deplete the immune system, ImmunityBio’s approach is designed to bolster and invigorate it. Our targeted NK cell immunotherapies act as an extension to the body’s innate, fast-response immune system to outsmart disease and potentially eliminate cancerous or infected cells.
Readily AvailableOur NK cells are available ‘off-the-shelf’, ready for delivery as a result of our cost-efficient and scalable manufacturing processes. We have manufactured more than three trillion cells and have multiple FDA-authorized IND applications. Our NK cells can be cryopreserved in long-term storage facilities for on-demand access from what we believe is the world’s only Good Manufacturing Practices (GMP)-compliant NK cell-line bank, a proprietary asset of our company.
We knew there was something unusual and rare about these cells when we first encountered them back in 1992. On a hunch we decided to set it up in culture, little did we know it would quickly become the surrogate cell line for studying natural killer cells by researchers around the world, let alone the basis for a pioneering cell therapy platform.
Advance Your Medical Research
NK cell-based immunotherapies are key to next-generation cancer treatments. Our NK-92®-engineered cells have demonstrated wide therapeutic potential across multiple tumor types and have preliminary safety indicating they may be well-tolerated, making them ideal for clinical trial investigations.
ImmunityBio is actively pursuing clinical studies of our NK cell therapeutics, Anktiva IL-15 superagonist, and hAd5 adenovirus platform across a range of oncology and infectious disease indications. Our comprehensive approach engages both innate and adaptive immunity through cellular and cellular-activating agents, thus bringing together a whole immune system response to patients’ therapeutic needs. In contrast to other immune therapeutic approaches, our therapeutic agents work together to generate long-term immune memory—with a goal of a durable response to therapy. The frozen, off-the-shelf, blood bag format of our cellular therapies is designed to make therapy simpler, more accessible, and ready to use. These cellular therapies are being manufactured at scale for clinical studies and await investigators ready to take the next step in their patients’ immunotherapy journey.
Our Off-the-Shelf, Genetically Engineered Natural Killer Cells
haNK cells are natural killer cells engineered to incorporate a high-binding affinity receptor (CD16) that binds to an administered antibody, potentially enhancing its cancer cell-killing effect.
These antibody-targeted haNK cells directly bind to IgG1-type antibodies, such as avelumab, trastuzumab, cetuximab, and rituximab, to enhance 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.1. 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, exhibit a poorer response to antibody therapies).
1. 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
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.
Our novel, GMP-grade, cryopreserved, “off-the-shelf,” bi-specific, PD-L1 t-haNK natural killer cell therapy candidate targets PD-L1 via a chimeric antigen receptor (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 is not intended for use as a monotherapy; it will be the backbone of a combination regimen that includes a therapeutic monoclonal antibody, in addition to the IL-15 superagonist Anktiva (N-803), through our exclusive co-development agreement with ImmunityBio, Inc. We believe that the addition of this selective IL-15 cytokine therapy 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.
Cytokine-Enriched Natural Killer Cell Platform
Cytokine-induced memory-like natural killer cells (ceNK) are a unique set of immune cells that differentiate after a brief pre-activation with activating cytokines, and exhibit enhanced responses to cytokine re-stimulation. These cells have been isolated, and are characterized by their unique cell-surface marker profile and their highly desirable immune-memory feature. ceNK cells have pronounced immunomodulatory activity with potential applications for cancer and infectious diseases, making these cells a research focus for more than a decade. Our cytokine-enriched natural killer cell program is based on the ability to enrich and expand donor-sourced natural killer (NK) cells in a GMP facility to a clinically relevant scale. This allows for the production of a pure cytokine- activated and expanded NK cell population that possesses the unique phenotype we call ceNK cells. ImmunityBio has developed a unique portfolio of distinct ceNK cell products through the application of ImmunityBio’s proprietary bioreactors (GMP-in-a-box), cytokines, and our proprietary methods.
Investigational Therapies for Difficult Diseases
We are conducting a Phase II, open-label, randomized, three-cohort comparative study of our PD-L1 t-haNK natural killer cell product with ImmunityBio’s proprietary IL-15 superagonist Anktiva (N-803) and aldoxorubicin in combination with standard-of-care therapy, versus standard-of-care therapy alone for front-line maintenance, and second-line or greater treatment for locally-advanced or metastatic pancreatic cancer. All three study cohorts of the trial are open and actively enrolling patients at multiple centers across the U.S. (Trial name: QUILT 88)
Merkel Cell Carcinoma
We are conducting a Phase II, open-label, single-arm trial to evaluate the novel triple combination of our “off-the-shelf” investigational CD16-targeted natural killer cell therapy (haNK) with ImmunityBio’s proprietary IL-15 superagonist Anktiva (N-803) and avelumab (without chemotherapy) in subjects that have progressed after treatment with a checkpoint inhibitor for Merkel cell carcinoma. This trial is actively recruiting patients at multiple centers across the U.S. (Trial Name: QUILT 3.063)
Non-Small Cell Lung Cancer
We are conducting a Phase IIb, open-label, multi-cohort study of combination immunotherapy in patients with non-small cell lung cancer, or NSCLC, who have previously received treatment with immune checkpoint inhibitors. The study will evaluate our investigational PD-L1 t-haNK natural killer cell therapy with ImmunityBio’s proprietary IL-15 superagonist Anktiva (N-803). This trial is actively recruiting patients at multiple centers across the U.S. (Trial name: QUILT 3.055)
Triple-Negative Breast Cancer
We recently concluded a Phase II, open-label, single-arm trial to evaluate the novel triple combination of our “off-the-shelf” CD16-targeted investigational natural killer cell therapy (haNK) with ImmunityBio’s proprietary IL-15 superagonist Anktiva (N-803) and avelumab following a tumor- conditioning regimen in subjects that have progressed on or after standard-of-care therapy for triple-negative breast cancer. Based on results from this trial, we plan to conduct an open label, randomized controlled phase II trial of PD-L1 t-haNK and N-803 in combination with standard-of-care therapy versus standard-of-care therapy alone in patients with third-line TNBC. This trial will begin enrolling patients in 2021.
We are conducting a Phase II/III, multicenter trial to evaluate the novel combination of our proprietary IL-15 superagonist Anktiva plus Bacillus Calmette-Guerin (BCG), a vaccine used against tuberculosis and for treating bladder tumors or bladder cancer, in patients with BCG unresponsive high-grade non-muscle invasive bladder cancer. The FDA had granted Fast Track Designation to the pivotal trial based on Phase I data. In December 2019, the FDA granted ImmunityBio Breakthrough Therapy Designation based on interim Phase 2 data indicating the primary endpoint of the trial was already met. (Trial name: QUILT-3.032)
We are developing a protocol to treat recurrent glioblastoma using aldoxorubicin and our proprietary IL-15 superagonist Anktiva. Unlike doxorubicin, aldoxorubicin appears to penetrate the blood-brain barrier in humans and is associated with objective tumor responses, stable disease and prolonged survival.
We are involved with two trials that are designed to study our IL-15 superagonist Anktiva in combination with other HIV therapeutics for treating, and potentially curing, patients infected with HIV.
The first trial (NCT04340596) is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and will be conducted by the AIDS Clinical Trials Group (ACTG). The Phase I trial will study Anktiva plus two bNAbs, which are broadly neutralizing HIV-1 antibodies, and enrollment is anticipated to begin in Q2 2021.
The second trial (NCT04505501) is sponsored by the Thai Red Cross AIDS Research Centre, The Henry M. Jackson Foundation for the Advancement of Military Medicine, and Walter Reed Army Institute of Research and will investigate the safety, tolerability, and immunostimulatory effects of administering Anktiva during acute HIV infection. This Phase II, 15-patient trial is expected to begin in 2021.
One Vaccine, Three Trials, Three Routes of Immune Protection
We are conducting three trials to evaluate the safety, reactogenicity, and immunogenicity of the combination of our T-cell hAd5 vaccine administered orally, sublingually (under the tongue) and subcutaneously (injection) to select an optimal combination dose for future studies. A Phase I trial has also been initiated in Cape Town, South Africa to assess the safety, reactogenicity, and immunogenicity of the T-cell hAd5 vaccine and select a dose for future studies. Trials using sublingual delivery and room temperature-stable oral capsules are anticipated to follow. (Trial numbers: NCT04591717, NCT04732468, NCT04710303)
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