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Background <p>CAR T cell therapy targeting BCMA has shown remarkable efficacy in multiple myeloma (MM), but relapses occur due to T cell exhaustion and the emergence of BCMA-negative subpopulations. Novel targets are needed to overcome antigen escape.</p> Methods <p>B7-H3 (CD276) expression was assessed on primary MM patient samples. We engineered nanobody-based CAR T cells (nanoCARs) targeting B7-H3 and evaluated their cytotoxicity and cytokine production in vitro, including against patient-derived myeloma cells. Anti-tumor activity was tested in two different MM xenograft models. Dual CAR T cells (BCMA/B7-H3) and CARpooling (mix of BCMA and B7-H3 CAR T cells) were also tested for efficacy in antigen escape models.</p> Results <p>B7-H3 expression was detected on plasma cells in 60% of MM patients. B7-H3 nanoCAR T cells exhibited strong antigen-specific cytotoxicity and effector cytokine secretion, including against primary MM cells. In vivo, they reduced tumor burden and improved survival. Dual (BCMA/B7-H3) CAR T cells and CARpooling effectively eliminated heterogeneous tumor populations with mutually exclusive BCMA or B7-H3 expression. These findings show that BCMA/B7-H3 targeting may be a strategy to overcome antigen escape mechanisms.</p> Conclusion <p>B7-H3 is a promising immunotherapy target in MM. B7-H3-specific and dual-targeting nanoCAR T cells could offer a strategy to prevent antigen escape and improve treatment durability.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Arne Van der Vreken,
  • Fien Meeus,
  • Chenggong Tu,
  • Lauren van den Broecke,
  • Vincenzo Raimondi,
  • Rosanna Vescovini,
  • Heleen Hanssens,
  • Fenja Watté,
  • Dorien Autaers,
  • Marta Marco Aragon,
  • Janne Billiau,
  • Kim De Veirman,
  • Karin Vanderkerken,
  • Yannick De Vlaeminck,
  • Lorenzo Franceschini,
  • Holly Lee,
  • Paola Neri,
  • Elke De Bruyne,
  • Paola Storti,
  • Nicola Giuliani,
  • Karine Breckpot,
  • Eline Menu

摘要

Background

CAR T cell therapy targeting BCMA has shown remarkable efficacy in multiple myeloma (MM), but relapses occur due to T cell exhaustion and the emergence of BCMA-negative subpopulations. Novel targets are needed to overcome antigen escape.

Methods

B7-H3 (CD276) expression was assessed on primary MM patient samples. We engineered nanobody-based CAR T cells (nanoCARs) targeting B7-H3 and evaluated their cytotoxicity and cytokine production in vitro, including against patient-derived myeloma cells. Anti-tumor activity was tested in two different MM xenograft models. Dual CAR T cells (BCMA/B7-H3) and CARpooling (mix of BCMA and B7-H3 CAR T cells) were also tested for efficacy in antigen escape models.

Results

B7-H3 expression was detected on plasma cells in 60% of MM patients. B7-H3 nanoCAR T cells exhibited strong antigen-specific cytotoxicity and effector cytokine secretion, including against primary MM cells. In vivo, they reduced tumor burden and improved survival. Dual (BCMA/B7-H3) CAR T cells and CARpooling effectively eliminated heterogeneous tumor populations with mutually exclusive BCMA or B7-H3 expression. These findings show that BCMA/B7-H3 targeting may be a strategy to overcome antigen escape mechanisms.

Conclusion

B7-H3 is a promising immunotherapy target in MM. B7-H3-specific and dual-targeting nanoCAR T cells could offer a strategy to prevent antigen escape and improve treatment durability.