On December 13, 2022 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported preclinical data of several novel strategies designed to enable administration of off-the-shelf cell-based cancer immunotherapies without conditioning chemotherapy at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. Conditioning chemotherapy, commonly used throughout the field of cell therapy, often results in hematologic toxicities, can limit the potential for administration of multiple doses, and can prohibit adoption as part of early-line treatment (Press release, Fate Therapeutics, DEC 13, 2022, View Source [SID1234625206]). Novel strategies to reduce or eliminate the need for conditioning chemotherapy presented by the Company at ASH (Free ASH Whitepaper) include arming iPSC-derived effector cells with an alloimmune defense receptor, which selectively targets and eliminates 41BB-expressing alloreactive host immune cells to promote expansion, persistence, and anti-tumor activity; the genetic ablation of CD38 in combination with CD38-targeted monoclonal antibody therapy, which uniquely targets and depletes CD38-expressing activated host immune cells; and the combined genetic ablation of the adhesion molecules CD54 and CD58, which reduces immune synapse formation resulting in host immune cell evasion.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"Eliminating the need for conditioning chemotherapy has the potential to significantly improve the safety and clinical benefit of cell therapies, and enable their use in a significantly broader population of patients with hematologic malignancies and solid tumors. Our next-generation iPSC product platform seeks to create the ideal off-the-shelf cell therapy, which would enhance functional persistence and anti-tumor activity while reducing or eliminating the need for conditioning chemotherapy to deplete host lymphocytes," said Bob Valamehr, Ph.D., Chief Research and Development Officer of Fate Therapeutics. "We are developing multiple promising strategies that can only be realized through precise multiplexed-engineering of cells, and we believe our leading iPSC product platform is uniquely positioned to generate clonal NK and T-cell product candidates that can thrive and resist rejection."
Alloimmune Defense Receptor Targeting 4-1BB
The cell surface receptor 4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is upregulated on activated CD4+, CD8+, and regulatory T cells as well as activated NK cells of the host immune system. Scientists from the Company and the laboratory of Maksim Mamonkin, Ph.D., Assistant Professor, Cell and Gene Therapy, Baylor College of Medicine, integrated a novel alloimmune defense receptor (ADR) that selectively targets 4-1BB into a master induced pluripotent stem cell (iPSC) line incorporating a CD19-targeted chimeric antigen receptor (CAR), that was subsequently differentiated into NK cells (ADR-armed, CD19-targeted CAR iNK cells). In the ASH (Free ASH Whitepaper) presentation (Abstract #1986), the scientists showed that in an in vitro co-culture assay with allogeneic peripheral blood mononuclear cells (allo PBMCs), ADR-armed, CD19-targeted CAR iNK cells expanded, persisted, and selectively eliminated 4-1BB+ allo PBMCs in contrast to ADR-null CD19-targeted CAR iNK cells, which were depleted. Further, a disseminated Nalm6 leukemia model comprised of allo-reactive T cells and tumor cells resistant to T-cell killing (MHC class 1-null), demonstrated that ADR-armed, CD19-targeted CAR iNK cells exhibited uncompromised effector function in vivo compared to ADR-null CD19-targeted CAR iNK cells, suggesting that ADR-armed NK cells functionally persist, proliferate, and durably kill tumor cells while resisting rejection by allo-reactive T cells.
CD38 Genetic Ablation in Combination with CD38-targeted Monoclonal Antibody Therapy
CD38-targeted monoclonal antibody therapies, such as daratumumab, are approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma. CD38 has also been shown to be highly expressed on activated immune cells, including CD8+ T cells, CD4+ T cells, and NK cells. The Company has incorporated the knock-out of CD38 into its proprietary iPSC product platform, which uniquely allows for CD38-null, iPSC-derived NK cells (CD38-null iNK cells) to be combined with CD38-targeted monoclonal antibody therapies and avoid fratricide. In the ASH (Free ASH Whitepaper) presentation (Abstract #3288), scientists from the Company showed that, in a humanized mouse model containing allogeneic CD38+ activated NK and T cells, administration of daratumumab selectively depleted allogeneic CD38+ NK and T cells and uniquely enabled CD38-null iNK cells to functionally persist through Day 28 compared to wild-type iNK cells. These preclinical data were supported by translational findings from the Company’s Phase 1 study of FT576 (NCT05182073), its multiplexed-engineered, BCMA-targeted CAR NK cell product candidate that incorporates the knock-out of CD38, where combination with daratumumab rapidly and selectively eliminated CD38+ patient immune cells through the first month of therapy. The translational findings suggest that following administration of daratumumab, CD38-null iNK cells may avoid rejection by activated host immune cells without requiring conditioning chemotherapy.
Combined CD54 and CD58 Genetic Ablation
Avoiding NK cell-mediated rejection has been an area of significant research in the field of allogeneic cell therapy. While it has been shown that the knock-out of MHC class-I and MHC class-II molecules can avoid T cell-mediated rejection, engineered cells integrating MHC class-I knock-out are aggressively targeted and eliminated by NK cells. In the ASH (Free ASH Whitepaper) presentation (Abstract #481), scientists from the Company, the laboratory of Karl-Johan Malmberg, M.D., Ph.D., Professor of Immunology, University of Oslo, Norway, and the laboratory of Michel S. Sadelain, M.D., Ph.D., Stephen and Barbara Friedman Chair; Director, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center presented a novel engineering strategy comprised of the knock-out of four genes: MHC class-I and MHC class-II as well as the adhesion molecules, CD54 and CD58. The scientists showed that the knock-out of CD54 and CD58 confers resistance to NK cell-mediated rejection across the spectrum of NK cell subpopulations compared to other engineering approaches such as HLA-E over-expression, which avoids recognition by NKG2A+ NK cells but induces killing by the most potent sub-set, NKG2C+ NK cells. Using multiplexed-engineered, iPSC-derived NK cells incorporating MHC class-I and MHC class-II knockouts, the scientists showed that the addition of CD54 and CD58 knockouts extended persistence in vivo in a humanized mouse model comprised of allogeneic NK cells.
About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that are designed to be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely designed to overcome numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.