On February 27, 2025 ImmunityBio, Inc. (NASDAQ: IBRX), a leading immunotherapy company, reported the U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation for ANKTIVA and CAR-NK (PD-L1 t-haNK) for the reversal of Lymphopenia in Patients Receiving Standard-of-Care Chemotherapy/Radiotherapy and in Multiply Relapsed Locally Advanced or Metastatic Pancreatic Cancer (Press release, ImmunityBio, FEB 27, 2025, View Source [SID1234650704]).
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The complete blood count (CBC) is a standard assay widely used by oncologist to assess the status of the immune system following chemotherapy and radiation. To date, information of the cellular elements in the CBC assay provide information to the physician for the treatment of anemia, neutropenia and reduced platelet counts associated with the adverse events of chemotherapy and radiotherapy. Anemia, neutropenia and reduced platelet counts can be treated with currently approved therapies including EPOGEN, NEUPOGEN and platelet transfusion, respectively.
However, chemotherapy and radiation has also caused a reduction in the very cells necessary to kill cancer cells. This reduction in the lymphocytes by our standard of care also inhibits the induction of T cell memory in the absence of CD4+, CD8+ T cells. A treatment for the reversal of these adverse events of lymphopenia, induced by current standard-of-care, has eluded the industry for the past 50 years. ImmunityBio and its Founder Dr. Patrick Soon-Shiong developed a vision over the past decades that activation and proliferation of these key lymphocytes was necessary if we were to win the war against cancer and indeed even prevent cancer in subjects at high-risk such as with lynch syndrome with a cancer vaccine. The founder’s vision reflecting the pursuit of addressing lymphopenia over the past decades will be updated in March.
"RMAT designation for ANKTIVA combined with NK cells was applied for by the Founder in the initial 2017 IND. With the clinical results of the QUILT trials across multiple tumor types from 2017 to 2024, validating the hypothesis that high-dose chemotherapy and radiation induces lymphopenia and can be reversed by ANKTIVA together with off-the-shelf CAR-NK cells (PD-L1 t-haNK) resulting in prolongation of overall survival (OS), and enabling ImmunityBio to reapply for RMAT in 2025,"1 said Dr. Patrick Soon-Shiong, Founder, Executive Chairman and Global Chief Scientific & Medical Officer of ImmunityBio. "I am so grateful for the FDA to have recognized the evolution of science and the need for adoption of 21st century medicine and cell therapy, particularly the role of NK cell therapy in our war against cancer as a universal therapy in cancer, and in the potential treatment of infectious diseases such as HIV, HPV and COVID. Today’s designation of ANKTIVA and the first CAR-NK (PD-L1 T-haNK), both first-in-class molecules to activate lymphocytes within the body (via subcutaneous injection of ANKTIVA) and via ex-vivo infusion of off-the-shelf PD-L1 NK cells, is an inflection point and a paradigm change of how we could treat patients with cancer and viral infections. The absolute lymphocyte count (ALC) which has been largely ignored by physicians, since no therapy existed to address lymphopenia, could now be both a prognostic biomarker but more importantly, the potential as a therapeutic biomarker."
"Multiple publications in the last five years have shown that patients with low lymphocyte counts especially those with severe lymphopenia have a statistically lower survival rate regardless of the tumor types.2-5 With this RMAT designation and the attributes of a RMAT designation including all Breakthrough Therapy Designation features and statutory ways to support Accelerated Approval, we will move rapidly to file the BLA for these authorized indications provided by the RMAT designation," said Soon-Shiong. "In addition, per the requirement under section 561A(f)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), ImmunityBio will make publicly available the Expanded Access Policy of ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy within 15 days."
In the authorization letter, the FDA has committed to work closely with ImmunityBio to provide guidance and advice on generating the evidence needed to "support approval" of the indication above "in an efficient manner."
About ANKTIVA
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. By activating NK cells, ANKTIVA overcomes the tumor escape phase of clones resistant to T cells and restores memory T cell activity with resultant prolonged duration of complete response.
ANKTIVA is a first-in-class IL-15 agonist IgG1 fusion complex, consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15 receptor alpha, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. This fusion complex of ANKTIVA mimics the natural biological properties of the membrane-bound IL-15 receptor alpha, 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. The proliferation of the trifecta of these immune killing cells and the activation of trained immune memory results in immunogenic cell death, inducing a state of equilibrium with durable complete responses. ANKTIVA has improved pharmacokinetic properties, longer persistence in lymphoid tissues, and enhanced anti-tumor activity compared to native, non-complexed IL-15 in-vivo.
ANKTIVA was approved by the FDA in 2024 for BCG-unresponsive non-muscle invasive bladder cancer CIS with or without papillary tumors. For more information, visit ImmunityBio.com (Founder’s Vision) and Anktiva.com.
About CAR-NK (PD-L1 t-haNK)
PD-L1 t-haNK is a human, allogeneic, stable clonal NK cell line generated from the parental aNK cell line (NK-92), manufactured by the Sponsor under cGMP conditions.
Based on the demonstrated therapeutic efficacy of CAR targeting and on the important role of FcgR-mediated ADCC in the effectiveness of therapeutic IgG1 monoclonal antibodies, we hypothesized that modification of the parental aNK cell line to stably express both a PD-L1–targeted CAR and the high-affinity variant of CD16 would result in potent and selective antitumor activity. Myeloid-derived suppressor cells (MDSCs) express PD-L1 in concert with MHC-I loss to induce immune escape of tumors resistant or relapsed from chemo-immunotherapy including checkpoint inhibitors. Thus, there is a rationale for the combination of Anktiva (converting a cold tumor to hot tumor and rescuing T cells by re-expressing MHC-I) and PD-L1 t-haNK to overcome the immunosuppressive effect of TGFb secreted by MDSCs. The ability to target both the tumor and MDSCs with off-the-shelf, outpatient based safe infusion of allogeneic CAR-NKs targeting PD-L1, was the basis for the development of this CAR-NK. Preclinical studies published in the J Immunotherapy Cancer 2020 "PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations" (Fabian et al. 2020) demonstrate that PD-L1 targeting of high affinity NK cells (PD-L1 t-haNK) induced direct anti-tumor effects in TNBC tumor cell lines and target suppressive MDSCs populations.