Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma

Area of Science:

• Immunotherapy
• Oncology
• Molecular Biology

Background:

• Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) shows efficacy in multiple myeloma (MM).
• Relapses in MM patients treated with BCMA CAR T therapy are common due to low or absent BCMA expression.
• There is a critical need for alternative targets in MM CAR T cell therapy.

Purpose of the Study:

• To identify and validate novel targets for CAR T cell therapy in relapsed MM.
• To evaluate the efficacy of SEMA4A as a target for CAR T cell therapy in MM.
• To develop and test SEMA4A-directed CAR T cells for potential clinical application.

Main Methods:

• Quantitative profiling of antigen density in MM patient samples.
• Generation of monoclonal antibodies against SEMA4A.
• Construction and screening of SEMA4A-specific CAR T cells for expansion, cytokine release, and cytotoxicity.
• Assessment of CAR T cell reactivity against normal tissues.
• In vivo efficacy studies in mouse models and patient-derived xenografts.

Main Results:

• High SEMA4A expression was observed in MM cells with low BCMA expression.
• SEMA4A deletion inhibited MM cell growth, migration, tissue infiltration, and osteoclast formation, improving mouse survival.
• Developed SEMA4A CAR T cells demonstrated potent anti-MM activity and were superior to BCMA CAR T cells in preclinical models.
• Lead SEMA4A CAR T cell constructs showed no reactivity against normal non-hematopoietic tissues.

Conclusions:

• SEMA4A is a promising novel target for CAR T cell therapy in multiple myeloma, particularly for patients relapsing after BCMA-targeted therapy.
• SEMA4A CAR T cells exhibit significant preclinical efficacy and a favorable safety profile.
• These findings support the initiation of a Phase 1 clinical trial for SEMA4A-directed CAR T cell therapy in MM.