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CAR-modified marrow infiltrating lymphocytes efficiently target malignant plasma cells with very low antigen density

Nicolas Camviel1, Davide Gambarotto2, Violaine Andre1

  • 1Department of Oncology UNIL-CHUV, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research Lausanne, 1011 Lausanne, Switzerland; Swiss Cancer Center Léman, 1011 Lausanne, Switzerland; AGORA Cancer Research Center, 1011 Lausanne, Switzerland.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|February 8, 2026
PubMed

Insights

Chimeric antigen receptor (CAR) T cells targeting BCMA and TACI show promise for multiple myeloma (MM). Dual-targeting CAR T cells effectively kill cancer cells, even with low antigen levels, suggesting TACI as a viable target.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • B cell maturation antigen (BCMA) is a key target for multiple myeloma (MM) immunotherapies.
  • Frequent relapses necessitate alternative therapeutic targets beyond BCMA.

Purpose of the Study:

  • To investigate the efficacy of a dual-specific chimeric antigen receptor (CAR) T cell therapy targeting both BCMA and Transmembrane activator and CAML interactor (TACI) in MM.
  • To evaluate the killing of MM cells by CAR T cells derived from patient marrow infiltrating lymphocytes (MILs).

Main Methods:

  • Development of a dual-specific CAR recognizing BCMA and TACI.
  • Expression of the CAR in patient-derived MILs.
  • Assessment of MM cell killing using flow cytometry and direct stochastic optical reconstruction microscopy (dSTORM).

Main Results:

  • CAR T cells efficiently killed malignant plasma cells (PCs) despite low or undetectable antigen levels by flow cytometry.
  • dSTORM revealed significantly underestimated BCMA and TACI expression levels compared to flow cytometry.
  • CAR T cells demonstrated polyfunctional killing capabilities at very low antigen densities.

Conclusions:

  • Transmembrane activator and CAML interactor (TACI) is a promising target for MM treatment.
  • Super-resolution microscopy (dSTORM) is valuable for assessing antigen density thresholds for CAR T cell therapies.
  • Dual-targeting CAR T cells offer a potent strategy against multiple myeloma.
Keywords:
APRIL-CARCARCAR-Tantigen densityantigen sensitivitychimeric antigen receptormarrow infiltrating lymphocytesmultiple myelomasuper-resolution microscopy

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