Contributions
Abstract: S177
Type: Oral Presentation
Session title: Basic and translational myeloma research
Background
B cell maturation antigen (BCMA) is a promising immunotherapy target for patients with multiple myeloma (MM). Although BCMA CAR-T therapies have delivered high overall and complete response rates in heavily pretreated patients, a majority of patients continue to relapse and MM remains incurable, supporting the need for more potent and durable therapies.
Aims
To develop a more potent and persistent BCMA therapy, we engineered BCMA CAR-Ts with membrane bound IL-15 (mbIL15) to determine whether IL15 could improve BCMA CAR-T performance, enabling greater in vivo expansion potential and antigen-independent CAR-T persistence following tumor clearance. To engender this potent product with titratable, drug-like properties, we also coupled mbIL15 to Obsidian’s regulated cytoDRiVE™ technology, providing superior efficacy and safety for patients with MM.
Methods
Obsidian’s cytoDRiVE™ platform consists of small, fully human protein sequences called drug responsive domains (DRD)s that enable regulated expression of a fused target protein under control of FDA-approved, orally bioavailable small molecule ligands. BCMA CAR-T cells were engineered with mbIL15 fused to a carbonic anhydrase 2 (CA2) DRD that facilitates regulation of mbIL15 expression via acetazolamide (ACZ) administration. In vitro mbIL15 activity was assessed in an assay of CAR-T expansion and survival in the absence of antigen or exogenous cytokines and by immunophenotyping. CAR-T function was assessed in vitro using cytotoxicity and cytokine production assays. We also evaluated IL15-driven antigen-independent BCMA CAR-T cell expansion in non-tumor-bearing NSG mice, as well as anti-tumor efficacy in a BCMA⁺ MM xenograft tumor model.
Results
mbIL15-BCMA CAR-T cells retained equivalent CAR activity compared with standard BCMA CAR-Ts not expressing mbIL15, as evidenced by cytotoxicity against, and IFNγ and IL2 cytokine production in response to, BCMA+ RPMI8226 MM cells in vitro. In the presence of ACZ, functional levels of mbIL15 were expressed on the cell surface of the mbIL15-BCMA CAR-Ts, which supported in vitro antigen independent survival, expansion, and development of a CD45RO-, CCR7+, CD95+, CD27+ memory stem cell phenotype. Two weeks after adoptive cell transfer into non-tumor-bearing mice, animals receiving daily ACZ displayed elevated numbers of CAR-Ts in the peripheral blood, and mbIL15 was specifically expressed on CAR-Ts from ACZ- but not vehicle-dosed animals. In RPMI8226 tumor-bearing mice, regulated mbIL15 increased expansion of BCMA CAR-T cells, promoting anti-tumor activity at lower cell doses than BCMA CAR-Ts without mbIL15. Upon tumor rechallenge, regulated mbIL15 prevented tumor growth, demonstrating CAR-T persistence for up to 72 days post initial cell transfer. Regulation of mbIL15 expression on BCMA CAR-Ts also resulted in modulation of inflammatory cytokines detected in the plasma of MM tumor-bearing mice.
Conclusion
Regulated mbIL15 resulted in BCMA CAR-Ts marked by a memory stem cell phenotype with increased anti-tumor activity and enhanced response duration, even at suboptimal CAR-T cell doses. Regulating mbIL15 levels with our novel DRD control system supports improved antigen-independent T cell expansion and survival, translating to more potent and persistent BCMA CAR-Ts. Thus, Obsidian’s cytoDRiVE™ technology confers drug-like properties to CAR-Ts, providing physicians with potentially greater control of CAR-T expansion and survival to optimize durable CAR-T efficacy and safety for patients with MM.
Keyword(s): CAR-T, IL-15, Myeloma
Abstract: S177
Type: Oral Presentation
Session title: Basic and translational myeloma research
Background
B cell maturation antigen (BCMA) is a promising immunotherapy target for patients with multiple myeloma (MM). Although BCMA CAR-T therapies have delivered high overall and complete response rates in heavily pretreated patients, a majority of patients continue to relapse and MM remains incurable, supporting the need for more potent and durable therapies.
Aims
To develop a more potent and persistent BCMA therapy, we engineered BCMA CAR-Ts with membrane bound IL-15 (mbIL15) to determine whether IL15 could improve BCMA CAR-T performance, enabling greater in vivo expansion potential and antigen-independent CAR-T persistence following tumor clearance. To engender this potent product with titratable, drug-like properties, we also coupled mbIL15 to Obsidian’s regulated cytoDRiVE™ technology, providing superior efficacy and safety for patients with MM.
Methods
Obsidian’s cytoDRiVE™ platform consists of small, fully human protein sequences called drug responsive domains (DRD)s that enable regulated expression of a fused target protein under control of FDA-approved, orally bioavailable small molecule ligands. BCMA CAR-T cells were engineered with mbIL15 fused to a carbonic anhydrase 2 (CA2) DRD that facilitates regulation of mbIL15 expression via acetazolamide (ACZ) administration. In vitro mbIL15 activity was assessed in an assay of CAR-T expansion and survival in the absence of antigen or exogenous cytokines and by immunophenotyping. CAR-T function was assessed in vitro using cytotoxicity and cytokine production assays. We also evaluated IL15-driven antigen-independent BCMA CAR-T cell expansion in non-tumor-bearing NSG mice, as well as anti-tumor efficacy in a BCMA⁺ MM xenograft tumor model.
Results
mbIL15-BCMA CAR-T cells retained equivalent CAR activity compared with standard BCMA CAR-Ts not expressing mbIL15, as evidenced by cytotoxicity against, and IFNγ and IL2 cytokine production in response to, BCMA+ RPMI8226 MM cells in vitro. In the presence of ACZ, functional levels of mbIL15 were expressed on the cell surface of the mbIL15-BCMA CAR-Ts, which supported in vitro antigen independent survival, expansion, and development of a CD45RO-, CCR7+, CD95+, CD27+ memory stem cell phenotype. Two weeks after adoptive cell transfer into non-tumor-bearing mice, animals receiving daily ACZ displayed elevated numbers of CAR-Ts in the peripheral blood, and mbIL15 was specifically expressed on CAR-Ts from ACZ- but not vehicle-dosed animals. In RPMI8226 tumor-bearing mice, regulated mbIL15 increased expansion of BCMA CAR-T cells, promoting anti-tumor activity at lower cell doses than BCMA CAR-Ts without mbIL15. Upon tumor rechallenge, regulated mbIL15 prevented tumor growth, demonstrating CAR-T persistence for up to 72 days post initial cell transfer. Regulation of mbIL15 expression on BCMA CAR-Ts also resulted in modulation of inflammatory cytokines detected in the plasma of MM tumor-bearing mice.
Conclusion
Regulated mbIL15 resulted in BCMA CAR-Ts marked by a memory stem cell phenotype with increased anti-tumor activity and enhanced response duration, even at suboptimal CAR-T cell doses. Regulating mbIL15 levels with our novel DRD control system supports improved antigen-independent T cell expansion and survival, translating to more potent and persistent BCMA CAR-Ts. Thus, Obsidian’s cytoDRiVE™ technology confers drug-like properties to CAR-Ts, providing physicians with potentially greater control of CAR-T expansion and survival to optimize durable CAR-T efficacy and safety for patients with MM.
Keyword(s): CAR-T, IL-15, Myeloma