B7-H3 nanobody-based CAR T cells control multiple myeloma growth, while dual BCMA/B7-H3 CAR T cells overcome antigen...

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Chimeric antigen receptor (CAR) T cell therapy targeting B-cell maturation antigen (BCMA) is effective for multiple myeloma (MM).
• Relapse in MM after BCMA-targeted therapy is common due to T cell exhaustion and BCMA-negative tumor escape.
• Novel therapeutic targets are crucial to overcome antigen escape and enhance treatment durability in MM.

Purpose of the Study:

• To investigate B7-H3 as a novel immunotherapy target in multiple myeloma.
• To engineer and evaluate nanobody-based CAR T cells (nanoCARs) targeting B7-H3.
• To assess the efficacy of dual BCMA/B7-H3 targeting strategies against antigen escape.

Main Methods:

• Assessed B7-H3 expression on MM patient samples.
• Developed B7-H3-targeting nanoCAR T cells and evaluated their in vitro cytotoxicity and cytokine production.
• Tested anti-tumor activity of B7-H3 nanoCARs and dual-targeting strategies (BCMA/B7-H3 CAR T cells and CARpooling) in MM xenograft models.

Main Results:

• B7-H3 was expressed on plasma cells in 60% of MM patients.
• B7-H3 nanoCAR T cells demonstrated potent antigen-specific cytotoxicity and cytokine secretion against primary MM cells.
• In vivo studies showed reduced tumor burden and improved survival with B7-H3 nanoCAR T cells.
• Dual BCMA/B7-H3 targeting effectively eliminated heterogeneous MM populations, including antigen-escape variants.

Conclusions:

• B7-H3 represents a promising target for immunotherapy in multiple myeloma.
• B7-H3-specific and dual-targeting nanoCAR T cells offer a potential strategy to prevent antigen escape.
• These approaches may lead to more durable and effective treatment outcomes for MM patients.