ImmunityBio, Inc. (ImmunityBio) operates as a vertically-integrated commercial stage biotechnology company. The company is developing next-generation therapies that bolster the natural immune system to defeat cancers and infectious diseases.
The company’s range of immunotherapy platforms, alone and together, act to drive an immune response with the goal of creating durable immune memory generating safe protection against disease. The company is applying its science and platforms to treating can...
ImmunityBio, Inc. (ImmunityBio) operates as a vertically-integrated commercial stage biotechnology company. The company is developing next-generation therapies that bolster the natural immune system to defeat cancers and infectious diseases.
The company’s range of immunotherapy platforms, alone and together, act to drive an immune response with the goal of creating durable immune memory generating safe protection against disease. The company is applying its science and platforms to treating cancers, including the development of potential cancer vaccines, as well as developing immunotherapies and cell therapies. These platforms and their associated product candidates are designed to be more effective, accessible, and easily administered than current standards of care in oncology and infectious diseases.
Strategy
The key elements of the company’s strategy include advancing the commercialization of ANKTIVA as an integral component of immunotherapy combinations, including those with CPIs and cell therapy; accelerating product candidates generated from the company’s immunotherapy platforms with registrational intent to address difficult-to-treat oncological and infectious disease indications in large market segments; continuously refining its pipeline and investing in high-value discovery, development, and manufacturing capabilities for the company’s next generation product candidates; continuing to prospect, license, and acquire technologies to complement and strengthen its platforms and product candidates, both as single agent and combination therapies, in order to optimize responses of the innate and adaptive immune systems to generate cellular memory against multiple tumor types and infectious diseases; and cultivating new and expanding existing collaborations for its multi-stage pipeline to reach global scale efficiently.
ANKTIVA
The company's lead biologic product, ANKTIVA, is a novel first-in-class IL-15 receptor superagonist antibody-cytokine fusion protein. On April 22, 2024, the FDA approved the company's product, ANKTIVA, with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors (the approved product). ANKTIVA was approved with a label indicating an immunological mechanism of action, which proliferates and activates NK, CD8+, and memory T cells without the proliferation of immunosuppressive T-reg cells, leading to the establishment of memory T cells. The company began commercial distribution of its approved product in May 2024.
The company is also exploring or pursuing several other studies of ANKTIVA in combination with its other product candidates, including in prostate cancer (ANKTIVA in combination with hAd5 PSA), colon cancer (ANKTIVA in combination with hAd5 TriAd), and NHL (ANKTIVA in combination with rituximab). Additionally, the company is exploring ANKTIVA in infectious diseases, including HIV and long COVID.
Next-Generation Platforms
Cytokine Fusion Proteins
Cytokine fusion proteins, such as ANKTIVA, represent a novel class of biologics that improve immune responses by enhancing the therapeutic potential of cytokines and promoting lymphocyte infiltration at a site of disease. The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of key immune cells—NK and CD8+ killer T cells—that are involved in killing cancer cells. ANKTIVA is a first-in-class IL-15 receptor superagonist IgG1 fusion complex, consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15Ra, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. This fusion complex of ANKTIVA, which confers stability and longer half-life than recombinant or native IL-15, mimics the natural biological properties of the membrane-bound IL-15Ra, delivering IL-15 by dendritic cells and drives the activation and proliferation of NK cells with the generation of memory killer T cells that have retained immune memory against these tumor clones. By activating NK cells, ANKTIVA overcomes the tumor escape phase of clones resistant to T cells without stimulating immunosuppressive T-reg cells and restores memory T cell activity with resultant prolonged duration of CR. Further, by stimulating the release of interferon-gamma, ANKTIVA restores MHC-I expression, making more tumor cells targets for T-cell killing. As evidenced by its ability to increase lymphocyte counts in healthy adults in Phase 1 testing, ANKTIVA also has the potential to rescue lymphopenia, which is associated with poor prognosis in cancer before treatment or as a consequence of chemo- or radiation therapy.
ANKTIVA’s mechanisms-of-action make it an ideal ‘backbone’ for combination therapy with the company’s platforms, such as second-generation hAd5 vaccines, off-the-shelf CAR-engineered NK cells, and M-ceNK cells, as well as other therapeutics including BCG, targeted antibodies, and CPIs.
The company is developing multi-functional cytokine fusion proteins targeting TGF-ß, PD-L1, CD16, CD20, and comprising IL-12, IL-15, and IL-21, amongst others, to further enhance NK and T cell activation directed to the TME or virally infected cells and to modulate the systemic and local immune response to accelerate immunogenic cell death.
DNA and Vaccine Vectors
The company has developed and/or acquired rights to multiple vaccine delivery technologies for oncology to deliver common TAAs, and neoepitopes (expressed only by cancer cells) and for infectious diseases to target key viruses. These technologies can deliver DNA and protein subunits to induce B and T cell memory through activation of both CD4+ and CD8+ T cells along with antibody (humoral) responses.
The company's second-generation hAd5 vector 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. The company has developed several hAd5 product candidates that have been evaluated in multiple clinical trials as potential vaccines for and treatments of certain cancers and infectious diseases. Importantly, these product candidates have shown an ability to overcome previous adenovirus immunity in preclinical models and in cancer patients. In oncology, the company is clinically evaluating hAd5 product candidates in combination with ANKTIVA to yield immunological immunity in colon cancer (hAd5 TAAs CEA, MUC1, Brachyury; collectively the TriAd) and prostate cancer (hAd5 PSA), and as a single agent in HPV-associated cancers (hAd5 TAA [E6/E7]).
Cell Therapies
The company’s engineered NK cells have demonstrated the ability to induce cell death in cancers and virally-infected cells through a variety of concurrent mechanisms, including innate killing, antibody-mediated killing, and CAR-directed killing.
Off-The-Shelf Targeted High-Affinity NK Cells
The company's proprietary NK-92 cytotoxic cell line (also referred to as aNK) was established from a patient with clonal NK-cell lymphoma. aNK cells can be expanded in culture in the presence of cytokines (IL-2, IL-15). The company's ‘off-the-shelf’ aNK cell platform has been molecularly engineered in a variety of ways to boost its killing capabilities against cancers and virally-infected cells. Unlike normal NK cells, the company's aNK cells do not express the key inhibitory receptors that diseased cells often exploit to turn off the killing function of NK cells, thereby escaping elimination. Furthermore, the company has genetically engineered its aNK cell platform to generate haNK cells engineered to express the high-affinity variant of the Fcgamma receptor (FcgammaRIIIA/CD16a 158V) as well as endoplasmic reticulum-retained IL-2 that bind to antibodies with demonstrated enhanced ADCC-mediated antitumor activity (Jochems 2016).
The company’s advanced off-the-shelf NK cell platform, CAR-targeted t-haNK cells, enables innovative, bioengineered cell lines that incorporate all the features of the company’s haNK platform together with a CAR, such as PD-L1. Product candidates under this platform have three modes of killing: innate, antibody-mediated, and CAR-directed killing. These product candidates also include one or more additional expression elements, such as functional cytokines, chemokines, and trafficking factors. 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. A number of t-haNK cell lines that express CARs have been developed.
Clinical trials to assess the company’s t-haNK product candidates have been initiated: PD-L1 t-haNK in a Phase 1 trial in TNBC and a Phase 2 trial in pancreatic cancer; and CD19 t-haNK in a Phase 1 trial in R/R B-Cell NHL.
Autologous and Allogeneic M-ceNK
The company’s M-ceNK cells are generated from lymphocytes collected from donors that are then pre-activated ex-vivo by exposure to interleukins -12 (IL-12), -15 (N-803) and -18 (IL-18), which results in differentiation and acquisition of enhanced responses to cytokine re-stimulation. M-ceNK have increased antitumor characteristics, including enhanced IFN-gamma production and cytotoxicity against leukemic cell lines. M-ceNK cells are further distinguished 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. The company has developed a unique ability to generate a portfolio of distinct M-ceNK cell products through the application of its proprietary technology and cytokines. Also, the company can manufacture these cell products for clinical delivery using its proprietary methods and overall expertise in the scale manufacturing of NK cell-based products. A Phase 1 first-in-human trial is open and actively enrolling patients to study the M-ceNK platform in solid tumors (QUILT 3076). In addition, M-ceNK is being evaluated in combination with ANKTIVA and gemcitabine in patients with recurrent platinum-resistant high-grade ovarian cancer (ResQ209) and in combination with ANKTIVA and hAd5-PSA in high-risk prostate cancer (ResQ110A-B).
Indications (Current Prioritized Studies)
Bladder Cancer
In the company’s QUILT 3032 trial, as it reported in November 2022 in NEJM Evidence, the primary end points were met for both BCG-unresponsive NMIBC with CIS with a CR 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 NMIBC with CIS (Cohort A) – QUILT 3032
In the company’s Phase 2/3 open-label multi-center trial of BCG-unresponsive high-grade NMIBC patients with CIS, the patients receive 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. Patients with no disease or low-grade Ta disease at months 24, 30, and 36 are eligible for continued BCG plus ANKTIVA (Cohort A) or ANKTIVA alone (Cohort C) treatment (3 weekly instillations), at the principal investigators’ discretion.
The primary endpoint of the BCG-unresponsive NMIBC with CIS trial is a CR rate at any time equal to or greater than 30% and the lower bound of the 95% CI must be greater than or equal to 20% for success. CR, 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 a CR.
In May 2022, the company submitted a BLA to the U.S. Food and Drug Administration (FDA) for its product candidate, ANKTIVA in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. In May 2023, it received a CRL from the FDA, indicating that the FDA had determined it could not approve the original BLA submission in its initial form, citing deficiencies related to the FDA’s pre-license inspection of the company’s third-party CMOs, among other items and made recommendations to address the issues raised. On April 22, 2024, the FDA approved the company's product, ANKTIVA, with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS), with or without papillary tumors. The company is required to comply with certain post-marketing commitments, including the completion of its QUILT 3032 clinical trial and annual reporting for up to four years, with a final report submission to the FDA by the end of 2029. The company began commercial distribution of its approved product in May 2024.
BCG-Unresponsive NMIBC Papillary (Cohort B) – QUILT 3032
In its 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. 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. The primary endpoint of the trial is a 12-month disease-free rate greater than or equal to 30%, and the lower bound of the 95% CI must be greater than or equal to 20% for success. To meet the primary endpoint, 24 out of 80 patients must be disease-free at 12 months.
The company is preparing to submit an sBLA in 2025 for its innovative treatment targeting BCG-unresponsive NMIBC in the papillary indication. This immunotherapy of rescuing BCG with ANKTIVA represents a step towards providing therapeutic options for patients with BCG-unresponsive NMIBC in papillary disease, who currently have limited treatment choices and face radical total cystectomy (removal of the bladder).
BCG-Naïve NMIBC with CIS – QUILT 2005
ANKTIVA received Fast Track designation from the FDA for the treatment of BCG-naïve NMIBC with CIS. The company is enrolling patients in its 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 with 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. As part of its BLA resubmission for ANKTIVA in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors, the company provided an update on the long-term follow-up of BCG-naïve patients in QUILT 2005 receiving ANKTIVA plus BCG for CIS± Ta/T1 in the Phase 1b trial, examining the survival of the 9 subjects who entered the trial since 2014. As initially reported in 2021, all 9 patients (100%) achieved a CR, and in an 8-year follow-up, the 6 evaluable patients remain disease-free (two were deceased from causes other than bladder cancer and one was lost to follow-up) with bladder preservation over a median survival period of 8.8 years.
NMIBC – Recombinant BCG as Alternative Source of BCG
In May 2024, the company announced an exclusive global arrangement with Serum Institute, the world’s largest manufacturer of vaccines by number of doses produced, to supply ImmunityBio with rBCG for use exclusively in combination with ANKTIVA, subject to regulatory approvals. The company is responsible, in part, for regulatory submissions, clinical trials, and commercialization efforts, and its exclusive rights under the arrangement extend to the scope of the FDA’s approval obtained for Serum Institute’s rBCG product in the U.S. Serum Institute’s GMP capacity to manufacture large-scale volumes of rBCG, already tested for safety and efficacy in clinical trials in Europe in subjects with NMIBC, aims to address the shortage of TICE BCG. In February 2025, the FDA authorized an EAP allowing the company to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where the TICE BCG label is approved, and shipments of rBCG pursuant to the EAP are expected to begin during the first quarter of 2025. In addition, the company is testing rBCG in an FDA-approved clinical trial (ResQ133A) of intravesical rBCG in participants with NMIBC eligible to receive TICE BCG.
Lung Cancer
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 a PD-1 or PD-L1 CPI for patients with NSCLC who have relapsed after achieving an initial response to PD-1 or PD-L1 CPI 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 CPIs and ANKTIVA in relapsed NSCLC relative to historical response rates. 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 rates seen in this patient population in the first-line setting with CPI therapy.
Non-Small Cell Lung Cancer – QUILT 3055
On the basis of these findings discussed above, the company initiated a single-arm Phase 2b multi-cohort basket trial of ANKTIVA and CPI combinations in patients who have previously received treatment with PD-1/PD-L1 immune CPIs per an FDA-approved indication. Patients enrolled in this trial were eligible if actively progressing on CPI therapy. Upon enrollment, patients continued on the same CPI but with the addition of ANKTIVA.
Among 140 patients enrolled in QUILT 3055, the common ANKTIVA 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 adverse events attributed to ANKTIVA 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 adverse events that the clinical trial site investigators reported as suspected as being due to ANKTIVA include: decreased lymphocyte count; weight loss; influenza-like illness; injection-site pruritus; cellulitis; injection-site cellulitis; sepsis; deep vein thrombosis; hypovolemic shock; colitis; diarrhea; delirium; respiratory failure; and maculopapular rash.
In September 2024, Dr. John Wrangle gave an oral presentation of the updated QUILT 3055 NSCLC pooled data at the World Conference on Lung Cancer, with data through February 2024 from several cohorts of NSCLC patients who have progressed after CPI therapy. These cohorts are:
Cohort 1a – NSCLC patients with initial response on single-agent CPI therapy and subsequently progressed on or after that therapy.
Cohort 2 – NSCLC patients having high PD-L1 expression (tumor proportion score =50%) and disease progression on a PD-1/PD-L1 CPI after experiencing an initial response when received CPI as a single-agent for first-line treatment.
Cohort 3 – NSCLC patients with initial response but subsequently relapsed on maintenance PD-1/PD-L1 CPI therapy when initially received CPI therapy in combination with chemotherapy as first-line treatment.
Cohort 4 – NSCLC patients receiving PD-1/PD-L1 CPI therapy that progressed after experiencing stable disease for at least 6 months during previous treatment with PD-1/PD-L1 CPI therapy.
These results showed a median overall survival of 14.1 months in the 86 patients in the pooled analysis. This is in contrast to the overall survival of 6.1 months (Freeman et al. 2020) for patients who received any therapy post-CPI therapy progression or an overall survival of 7.5 months (Brueckl et al. 2021) for patients who received docetaxel plus ramucirumab after initial failure of first-line chemotherapy plus a CPI.
The Phase 2b study demonstrated prolonged overall survival when ANKTIVA was combined with the same CPIs on which patients were progressing, validating the rescue potential of ANKTIVA for T cells and CPIs. The combination of ANKTIVA plus a CPI represents an immunotherapeutic advance for this disease, when compared to the most frequently used chemotherapy docetaxel in this setting, which has an overall survival ranging from 7 to 10 months and which is associated with high toxicities as a chemotherapeutic agent.
Non-Small Cell Lung Cancer – ResQ201A
Following a meeting with the FDA, the company launched a pivotal, randomized, open-label Phase 3 clinical trial of ANKTIVA plus tislelizumab (anti-PD-1) and docetaxel vs. docetaxel monotherapy in participants with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy. A total of 462 patients will be enrolled 1:2 either in a control arm or an experimental arm.
Control arm: Docetaxel (standard of care) N=154. Repeated 3-week cycles with docetaxel.
Experimental arm: ANKTIVA, tislelizumab, N=308. Two 3-week cycles of ANKTIVA, tislelizumab plus docetaxel followed by repeated 3-week cycles of ANKTIVA and tislelizumab (no docetaxel).
Participant randomization to either the control or experimental arm will be stratified by geographical region (North America vs. Europe vs. Asia), NSCLC histology (squamous vs. nonsquamous), and actionable genomic alterations.
The primary outcome is the comparison of overall survival between the experimental and the control arms. The company expects full enrollment in early 2026 and a data readout in the second half of 2027.
Colorectal Cancer
Lynch Syndrome – QUILT 5015 (NCI)
Lynch Syndrome is the most common cause of hereditary colorectal cancer. People with this syndrome harbor mutations in mismatch repair genes that put them at high risk of developing colorectal cancer. Lynch Syndrome causes about 4,300 colorectal cancers per year. These cancers are more likely to develop at earlier ages, often before the age of 50. If someone has Lynch Syndrome, it means that their close relatives (parents, siblings, and children) have a 50% chance of having the mutation that causes it too.
A Phase 2 trial sponsored by the NCI evaluates the ability of ANKTIVA in combination with the company TriAd5–a combination of three vaccines targeting TAAs CEA, MUC1, and Brachyury– to reduce the incidence of cancer onset in people with Lynch Syndrome. The trial recently reached full accrual of participants in the first two open-label phases. The randomized controlled portion of the trial is now recruiting with plans to enroll up to 138 participants.
Pancreatic Cancer
Advanced Pancreatic Cancer – QUILT 88
Exploratory Phase 1b/2 trials in patients with second-line or greater metastatic pancreatic cancer in which ANKTIVA was combined with off-the-shelf haNK cells, other agents, and 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 ANKTIVA.
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, the company initiated a first-line through third-line pancreatic cancer clinical trial that uses PD-L1 t-haNK as described below:
First-line advanced pancreatic cancer (Cohort A). Combination of ANKTIVA with low-dose chemotherapy plus SBRT with or without PD-L1 t-haNK vs. gemcitabine/Abraxane as the standard-of-care control arm in this randomized trial.
First-line advanced pancreatic cancer (Cohort A). Combination of ANKTIVA with low-dose chemotherapy plus SBRT with or without PD-L1 t-haNK vs. gemcitabine/Abraxane as the standard-of-care control arm in this randomized trial.
Third-line and beyond (Cohort C). Combination of ANKTIVA with low-dose chemotherapy plus SBRT + PD-L1 t-haNK in a single arm cohort of this trial with a primary endpoint of overall survival.
In October 2021, the company announced that the trial’s Cohort C was fully enrolled. Based on the strength of earlier data and the significant unmet medical need, the company 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) was 5.8 months (95% CI: 4.9, 6.4 months), exceeding the approximately two- to three-month historical median overall survival.
Prostate Cancer
High-Risk Prostate Cancer – ResQ110A
The company has initiated a clinical trial to evaluate a new immunotherapy combination of ANKTIVA, hAd5 PSA, and M-ceNK in men with high-risk prostate cancer who have not had prostatectomy. Participants will receive immunotherapy pre- and post-surgery. This open-label study will enroll 20 patients and assess primary endpoints of event-free survival and biochemical recurrence-free survival post-surgery immunotherapy.
High-Risk Prostate Cancer – ResQ110B
The company has also initiated a clinical trial to evaluate the immunotherapy combination of ANKTIVA, hAd5 PSA, and M-ceNK in men with high-risk prostate cancer who are ineligible for prostate surgery and receiving external beam radiation therapy. This open-label study will enroll 20 patients and deliver the combination regimen prior to and after radiation therapy. Primary outcomes are complete pathologic response after pre-radiation immunotherapy and prostate-specific antigen levels following post-radiation immunotherapy.
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. GBM has a low survival rate of approximately 40% in the first year after diagnosis and only 17% in the second year. In a preclinical study, the company evaluated the activity of ANKTIVA alone and in combination with an anti-PD-1 antibody or stereotactic radiosurgery in a murine GL261-luc GBM model and demonstrated that ANKTIVA as a monotherapy or combination therapy with an anti-PD-1 antibody exhibits a robust antitumor immune response resulting in prolonged survival including complete remission in tumor bearing mice. In addition, treatment with ANKTIVA resulted in long-term immune memory against GBM tumor rechallenge.
Recurrent or Progressive GBM – QUILT 3078
A multi-center, open-label Phase 2/3 trial has been initiated to evaluate the safety and efficacy of combination therapy with ANKTIVA, PD-L1 t-haNK, and bevacizumab in patients with recurrent or progressive GBM. In Phase 2, safety of the combination will be assessed prior to Phase 3 wherein participants will be randomized to either combination therapy or bevacizumab monotherapy as the current standard of care.
Pilot (Part A). Enrollment will be initiated with a single-arm study of 10 patients to receive ANKTIVA, 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 vs. Bevacizumab Monotherapy (Part B). Part B will enroll patients to be randomly assigned (1:1) to the experimental arm or to the control arm.
Non-Hodgkin Lymphoma
A Phase 1 trial evaluating ANKTIVA in combination with rituximab, an anti-CD20 mAb therapy, in patients with iNHL, who had relapsed or were refractory after two lines of therapy, was published in Clinical Cancer Research in 2021. The combination regimen of ANKTIVA with rituximab was well tolerated with a single reported grade 4 adverse event and no reported grade 5 adverse events.
Relapsed/Refractory Non-Hodgkin Lymphoma – QUILT 3092
The company has initiated an open-label, Phase 1, first-in-human trial to evaluate the safety of CD19 t-haNK as a single agent and the safety and preliminary efficacy of CD19 t-haNK in combination with rituximab only and in combination with rituximab and ANKTIVA in subjects with relapsed/refractory NHL.
Ovarian Cancer
The American Cancer Society estimates that 20,890 women will be diagnosed with ovarian cancer and 12,730 deaths will be attributed to the disease in 2025. A woman’s risk of getting ovarian cancer in her lifetime is about 1 in 91 and her chance of dying from ovarian cancer is about 1 in 143.
Platinum-Resistant Ovarian Cancer – ResQ209
Platinum-based chemotherapy is the standard-of-care for ovarian cancer; however, 20-30% of patients have cancer recurrence following treatment and are considered platinum-resistant. An open-label Phase 2 trial of ANKTIVA plus M-ceNK in patients with platinum-resistant ovarian cancer has been initiated. In this trial, patients with platinum-resistant high-grade ovarian cancer will receive M-ceNK adoptive cell therapy in combination with ANKTIVA and gemcitabine. Participants will undergo mononuclear cell collection for M-ceNK generation, day 8 induction and every 28-day (if M-ceNK are available) maintenance dosing, along with ANKTIVA. Estimated enrollment is 20 participants. Primary endpoints are progression-free survival using RECIST 1.1 criteria, overall survival, overall response rate, duration of response, disease control rate, and CA-125 levels. Safety endpoints are adverse events, treatment-emergent adverse events and significant adverse events, graded using NCI Common Terminology Criteria for Adverse Events Version 5.0.
Other Oncology Indications
In addition to the indications above, findings from completed QUILT studies, including the achievement of complete remissions in late-stage and advanced tumors of many types, such as MCC, TNBC, pancreatic cancer and head & neck cancer, validate the concept of eliciting immunogenic cell death rather than the tolerogenic cell death induced by current standards of care.
In addition to the trials listed above, the company is exploring or pursuing several other company-sponsored and investigator-initiated studies of its product candidates, including in colon cancer (hAd5 CEA, ANKTIVA), prostate cancer (ANKTIVA, hAd5 PSA), head and neck cancer (ANKTIVA, hAd5 CEA, hAd5 MUC1, hAd5 Brachyury), among others.
Infectious Disease Indications
In addition to the trials listed above in oncology, the company approved product and other product candidates are being evaluated in several other company-sponsored and investigator-initiated studies in infectious diseases.
HIV
One strategy for curing HIV is known as the kick and kill approach. The kick involves inducing HIV out of its latent resting state in T cells, revealing infected cells to the immune system, and the kill refers to eliminating the infected cells via an immune response or immunotherapy. ANKTIVA is a promising molecule to elicit “kick and kill” because of its ability to activate viral transcription in CD4+ T cells (kick) while strongly activating CD8+ effector memory cells and NK cells that are important for recognizing and killing HIV-infected cells (kill), as well as directing these cells to sites of viral reservoirs. ANKTIVA is being evaluated in investigator-initiated trials as a single agent and in combination with broadly neutralizing antibodies to control HIV in persons living with HIV and those with acute HIV infection.
Active HIV Infection – University of Minnesota, National Institute of Allergy and Infectious Diseases
Based on the hypothesis that CD8+ T cells will migrate to B cell follicles and reduce the frequency of cells with an inducible HIV provirus in HIV-infected individuals treated with ANKTIVA, a Phase 1 proof-of-concept non-randomized, open-label dose-escalation clinical trial sponsored by the University of Minnesota in collaboration with the NIAID was conducted. The primary assessment is the safety of ANKTIVA in ART-suppressed people living with HIV, along with exploratory analysis of effects on the HIV reservoir. In a 2022 report, no significant laboratory adverse events attributable to ANKTIVA were recorded, and ANKTIVA was associated with proliferation and/or activation of CD4+ and CD8+ T cells and NK cells, with a small but significant decrease in the frequency of peripheral blood mononuclear cells with an inducible HIV provirus.
A separate small HIV Cure Phase 1 trial evaluating ANKTIVA in combination with haploidentical NK cells in HIV-infected patients was completed in 2023. Reported data from the study validate the hypothesis that ANKTIVA combined with NK cells has the potential to reduce viral load in people living with HIV, showing a marked decrease in HIV-producing cells in lymph nodes. The trial is complete, and results were published in May 2024.
Active HIV Infection – National Institute of Allergy and Infectious Diseases, Rockefeller University
In June 2021, the company announced the opening of a Phase 1 clinical trial sponsored by the AIDS Clinical Trials Group and the NIAID (the HIV Cure Study) that will evaluate whether ANKTIVA alone or together with bNAbs can control HIV following interruption of 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. This trial is actively enrolling as of January 2025.
An additional and companion Phase 1 trial utilizing ANKTIVA and 2 different bNAbs sponsored by The Rockefeller University opened in December 2022. This trial completed enrollment as of January 2025.
Acute HIV Infection – Thai Red Cross and the U.S. Military HIV Research Program
In April 2021, the company announced the launch of a Phase 2 trial sponsored by the Thai Red Cross and the U.S. Military HIV Research Program. The trial enrolled 14 patients and was designed to investigate the safety, tolerability and immunostimulatory effects of administering ANKTIVA during acute HIV infection. ANKTIVA was administered subcutaneously at weeks zero, three and six (for a total of three doses) and was 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. The trial duration for individual participants was 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. The trial was recently completed, and data analyses are ongoing.
Other Infectious Diseases
The company previously developed COVID-19 vaccine candidates based on its hAd5 platform that delivered DNA for SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, which underwent early clinical testing in the U.S. and South Africa. These trials demonstrated the tolerability of the platforms, which elicited no severe adverse events, and provided evidence of effective antigen delivery. The company remains interested in advancing the idea of a universal nucleocapsid vaccine. Studies on long-term immune responses to SARS-CoV-1, a virus very similar to SARS-CoV-2, have shown that T cell responses to the N protein can provide long-term immunity for at least 11 years after infection. An N-based vaccine would also overcome the problem of the rapid mutation of S, which renders vaccines less effective over time and necessitates continuous redesign.
Commercial cGMP Production
On April 22, 2024, the FDA approved the company's product, ANKTIVA, with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors. The company has contracted with multiple multi-national biologics manufacturers with several current Good Manufacturing Practice (cGMP)-compliant facilities in the U.S., Europe, and Asia for the production of ANKTIVA for commercial sale and for use in its clinical trials.
Clinical Trial GMP Antibody and Fusion Protein Production
The company is committed to the goal of 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. The company plans for this facility to include fully integrated biologic upstream and downstream production suites, as well as a quality assurance/quality control release laboratory for high-capacity antibody and fusion protein production.
Clinical Trial GMP Adenovirus
The company has established other facilities for adenovirus production at multiple sites in California and a site in Colorado for oncology and infectious diseases. The company is committed to the goal of complying with cGMP at these facilities. 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.
Clinical Trial GMP NK Cell Therapy Production
The company has established other facilities for NK cell therapy product production at multiple sites in California for oncology. The company is committed to the goal of complying with cGMP at these facilities. One of its sites in California is dedicated to its off-the-shelf product candidates (including PD-L1 t-haNK and CD19), while another is primarily focused on its M-ceNK product candidates, including a training lab for its second-generation offerings.
cGMP ISO Class 5 Manufacturing Facility
On February 14, 2022, the company acquired a leasehold interest in the Dunkirk Facility. This facility has construction needs that may require an additional 12 to 18 months to complete in order for it to be used as intended. These construction needs remain due to an ongoing dispute with the Dunkirk Facility’s general contractor and a stay in resolving the dispute related to Athenex’s ongoing bankruptcy proceedings.
Manufacture of Platform Product Candidates
ImmunityBio’s diverse product candidate portfolio and pipeline require a broad knowledge of various manufacturing and quality assurance methods. The company has invested heavily in the processes, systems, and technology to build an extensive range of manufacturing programs spanning various levels of development from IND-enablement through BLA preparation for its other product candidates.
Distribution
In connection with the approval of the company's product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors, by the FDA on April 22, 2024, the company engaged a leading third-party logistic provider in a title model to enable commercial distribution. The company began commercial distribution of its approved product in May 2024. It has contracted with large specialty distributors and a large specialty pharmacy provider to make its commercial product available across relevant clinics, hospitals, infusion centers, and government entities.
Competition
Oncology
Cytokine Fusion Proteins: In the context of NMIBC, the company competes with Ferring Pharmaceuticals and Merck & Co., Inc. (Merck).
Cell Therapies. This platform’s product candidates (t-haNK and M-ceNK) face competition from several companies focused on NK cell-based approaches, including Artiva Biotherapeutics Inc., Catamaran Bio Inc., Century Therapeutics, Inc., Fate Therapeutics, Inc., Gamida Cell, Ltd., INmune Bio Inc., Nkarta Therapeutics, Inc., NKGen Biotech, Inc., and Shoreline Biosciences, Inc.
In addition, the company’s NK cell product candidates compete with other cell and molecule-based immunotherapy approaches using or targeting NK cells, NKT cells, T cells, macrophages, and dendritic cells. There are seven approved CAR-T cell-based treatments marketed by Autolus Therapeutics, plc (Autolus), Bristol-Myers Squibb Company (BMS) (two marketed products), Gilead Sciences, Inc. (Gilead)/Kite Pharma (two marketed products), Janssen/Johnson & Johnson, and Novartis. Additional companies focused on CAR T-related treatment approaches include Allogene Therapeutics, Inc., BMS, Cellectis SA, Celularity, Inc., Gilead, Janssen, Novartis, Pfizer, Inc. (Pfizer), and Poseida Therapeutics, Inc./Roche. There is also one approved TIL therapy from Iovance Biotherapeutics, Inc. Competitor companies focused on other T cell-based approaches include Adaptimmune Ltd. (with an approved TCR-T cell therapy), Adicet Bio, Inc., Autolus, Beam Therapeutics Inc., BioNTech, GlaxoSmithKline plc. (GSK), Sensei Biotherapeutics, Inc., and Senti Biosciences, Inc.
Intellectual Property
The company has developed, acquired, and in-licensed patents and patent applications across platforms, as previously described, for activated NK and T cells, as well as memory T cell activation. With respect to activated NK and T cells, the company has developed N-803, an N72D variant IL-15 complexed to a dimeric IL-15Ra/Fc fusion protein. Regarding memory T cell activation, the company has developed adenoviral immunotherapies expressing TAAs such as CEA, MUC1, and Brachyury.
As of December 31, 2024, the company owned patents and patent applications related to the development and commercialization of N-803 in the U.S. and jurisdictions outside of the U.S. The company's owned patent portfolio is directed to compositions of matter of N-803, methods of use of N-803, and combinations with additional therapeutics. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to N-803 are expected to expire from 2028 to 2040. If patents issue from the company's pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2031 to 2045 For example, these compositions of matter of N-803; uses of N-803 in methods of treating cancers; uses of N-803 in treating HIV; and combination treatments using N-803 and additional therapeutics.
In June 2024, the company submitted applications to the USPTO for the extension of the patent term of several U.S. patents directed to compositions of matter of N-803, methods of use of N-803, and methods of manufacture of N-803. These applications are under review by the USPTO and FDA.
As of December 31, 2024, the company owned, co-owned, and in-licensed patents and patent applications related to the development and commercialization of cell-based therapies in the U.S. and jurisdictions outside of the U.S. The company's owned, co-owned, and in-licensed patent portfolio is directed to compositions of matter of NK, haNK, and t-haNK cell lines, methods of use of these cells, and combinations with additional therapeutics. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to these cell therapies, methods of use, and combinations with additional therapeutics are expected to expire from 2025 to 2040. If patents issue from the company's pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2034 to 2042. For example, these patents and patent applications include claims directed to: NK cells; haNK cells; EGFR t-haNK cells; CD19 t-haNK cells; HER2 t-haNK cells; and PD-L1 t-haNK cells.
As of December 31, 2024, the company owned patents and patent applications related to the development and commercialization of multi-functional antibody-based cytokine fusion proteins targeting the IL-12 pathway, the IL-15 pathway, TGF-ß, PD-L1, and CD20 in the U.S. and jurisdictions outside of the U.S. The company's owned patent portfolio is directed to compositions of matter and methods of use of these fusion proteins. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to these fusion proteins are expected to expire from 2028 to 2039. If patents issue from the company's pending U.S. patent applications, excluding any patent term adjustment and patent term extension, these patents will be expected to expire from 2028 to 2044. For example, these patents and patent applications include claims directed to fusions of CPI and TAA binding antibodies and binding molecules with IL-15/IL-15Ra/Fc fusion protein complexes.
As of December 31, 2024, the company owned patents and patent applications related to the development and commercialization of multi-functional cytokine fusion proteins targeting TGF-ß, the IL-15 pathway, the IL-21 pathway, and CD16 in the U.S. and jurisdictions outside of the U.S. The company's owned patent portfolio is directed to compositions of matter and methods of use of these fusion proteins. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to these fusion proteins are expected to expire from 2039 to 2041. If patents issue from the company's pending U.S. patent applications, excluding any patent term adjustment and patent term extension, these patents will be expected to expire from 2039 to 2044. For example, these patents and patent applications include claims directed to fusions of human transforming growth factor receptor and/or IL-15 with tissue factor.
As of December 31, 2024, the company exclusively owned, and co-owned with and in-licenses from the HHS, patents and patent applications related to the development and commercialization of adenovirus-based cancer and viral immunotherapies in the U.S. and jurisdictions outside of the U.S. The company's patent portfolio is directed to compositions of matter of adenovirus and methods of use of adenovirus in treating or preventing cancer and viral diseases. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to adenovirus-based cancer and viral immunotherapies are expected to expire from 2028 to 2039. If patents issue from the company's pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2028 to 2044. For example, these patents and patent applications include claims directed to: adenovirus vectors and virus particles comprising TAAs; and uses of adenovirus vectors and virus particles in methods of treating cancers.
As of December 31, 2024, the company owned U.S. patents and pending U.S. patent applications directed to therapeutics for COVID-19. Some of these patent applications are directed to the use of the company's adenovirus technologies for a COVID-19 vaccine. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to therapeutics for COVID-19 are expected to expire in 2040 and 2042. If any patents issue from the company's pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire in 2040 and 2042.
As of December 31, 2024, the company owned patents and patent applications related to the development and commercialization of GMP-in-a-Box in the U.S. and jurisdictions outside of the U.S. The company's patent portfolio is directed to GMP-in-a-Box. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to GMP-in-a-Box are expected to expire from 2030 to 2037. For example, these patents and patent applications include claims directed to methods, bioreactors, and apparatuses for monitoring and culturing cells.
Collaboration and License Agreements
Collaboration Agreements
National Cancer Institute
The company and its subsidiaries began their relationship with HHS, as represented by the NCI of the NIH in 2015. Pursuant to the CRADAs, the NCI provides scientific staff and other support necessary to conduct research and related activities as described in the CRADAs. During the term of the initial and amended CRADAs, the company collaborated with the NCI on the preclinical and clinical development of its 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 agent ANKTIVA and derivatives, an antibody-based cytokine fusion protein and derivatives and/or TxM product candidates, proprietary recombinant NK cells and mAbs, proprietary adjuvants, and other proprietary agents owned or controlled by ImmunityBio for cancer immunotherapy.
Serum Institute of India Private Limited
In May 2024, the company announced an exclusive global arrangement with Serum Institute, the world’s largest manufacturer of vaccines by number of doses produced, to supply ImmunityBio with rBCG for use exclusively in combination with its ANKTIVA product, subject to regulatory approvals.
BeiGene, Ltd.
In January 2025, the company announced a collaboration and supply agreement with BeiGene, Ltd. (to be renamed to BeOne Medicines, Ltd.), a global oncology company, to conduct a confirmatory randomized Phase 3 clinical trial (ResQ201A-NSCLC), combining BeOne’s tislelizumab, a PD-1 CPI, and its ANKTIVA (nogapendekin alfa inbakicept-pmln) product. The Phase 3 ResQ201A-NSCLC study aims to confirm the efficacy and safety of combination ANKTIVA plus CPI therapy previously demonstrated in the QUILT 3055 trial and provide evidence of the potential for these two immunotherapeutic agents to improve overall survival in patients with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy.
License Agreements
3M IPC License Agreement
The company has licensed rights to 3M-052, a synthetic TLR7/8 agonist, along with 3M-052 formulations and related technology from 3M IPC and its affiliates and AAHI. In November 2021, the company obtained nonexclusive rights in the field of SARS-CoV-2, and in June 2022, it 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 LMIC, and (2) oncology applications, when used in combination with its proprietary technology and/or IL-15 receptor superagonists. Adjuvants are either synthetic or naturally occurring molecules that activate TLRs, thereby enhancing the humoral and cell-mediated immune response of vaccines. There are 10 human TLRs expressed either on the inside or outside of the immune cell, and their function is to recognize foreign substances expressed by pathogens. Once activated, these TLRs stimulate danger signals to the immune cells, initiating an immune response. 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 immunogenic.
GlobeImmune, Inc.
In 2020, the company entered into an exclusive licensing agreement with GlobeImmune, a consolidated entity of the company, pursuant to which it obtained worldwide, exclusive licenses under certain patents, know-how, and other intellectual property to use, research, develop, and commercialize products with GlobeImmune’s Tarmogen-based programs and neoepitopes programs in exchange for a license fee for the first two years of the agreement.
Sanford Health
In 2017, and as amended in November 2021, the company entered into a license agreement with Sanford pursuant to which the company obtained a worldwide, exclusive license under Sanford's applicable patent and know-how rights to use, make, have made, sell, offer to sell, export and import products for all uses and applications of polynucleotides encoding mutant E16 antigen (mutant HPV16 E6 antigen + mutant HPV16 E7 antigen) and the encoded mutant E16 antigen.
Shenzhen Beike Biotechnology Co. Ltd.
In 2014, the company, Altor, entered into a license, development, and commercialization agreement with Beike, which was amended and restated in 2017. Pursuant to this agreement, Altor granted Beike an exclusive license under certain of its intellectual property rights to use, research, develop, and commercialize products based on ANKTIVA in China for human therapeutic uses.
Government Regulation
Biopharmaceutical manufacturers and their subcontractors 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, which impose certain procedural and documentation requirements upon the company and any third-party manufacturers that the company may decide to use.
The company relies on third parties for the production of clinical and commercial quantities of its drugs in accordance with cGMP regulations. When a 510(k) clearance is required, the company must submit a premarket notification to the FDA demonstrating that the company's proposed device is substantially equivalent to a predicate device, which is a previously cleared and legally marketed 510(k) device or a device that was in commercial distribution before May 28, 1976.
FDA regulations require the company to register as a medical device manufacturer with the FDA.
The company's 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.
In addition to the foregoing health care laws, the company is subject to the FCPA and similar worldwide anti-bribery laws, which generally prohibit companies and their intermediaries from making improper payments to government officials or private-sector recipients for the purpose of obtaining or retaining business. The anti-corruption policy mandates compliance with the FCPA and similar anti-bribery laws applicable to the company's business throughout the world.
