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Manufacturing Chimeric Antigen Receptor CAR T Cells for Adoptive Immunotherapy
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CAR-mediated target recognition limits TCR-mediated target recognition of TCR- and CAR-dual-receptor-edited T cells

Tassilo L A Wachsmann1, Teuntje Poortvliet1, Miranda H Meeuwsen1

  • 1Department of Hematology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|March 1, 2025
PubMed

Insights

Dual-engineered T cells (TRaCR) targeting multiple myeloma antigens show dual specificity but preferential CAR engagement. This CAR preference can lead to tumor cell survival in heterogeneous multiple myeloma, necessitating caution for this approach.

Area of Science:

  • Immunotherapy
  • Cancer Biology
  • Cellular Engineering

Background:

  • Antigen escape limits the efficacy of engineered T cell therapies like chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells.
  • Targeting multiple antigens is a strategy to overcome antigen escape and broaden therapeutic targets.
  • Combining CAR and TCR targeting offers potential for broader antigen recognition.

Purpose of the Study:

  • To investigate the feasibility of dual-antigen specificity using combined TCR and CAR engineering in T cells.
  • To assess the efficacy of dual-specific T cells in preventing antigen escape in multiple myeloma (MM).
  • To evaluate the recognition and activity of T cells engineered with both a TCR and a CAR.

Main Methods:

  • Generation of CD8 T cells engineered to express a transgenic TCR targeting BOB1 peptide (HLA-B*07:02) and a BCMA-targeting CAR.
  • Characterization of T cells, termed TRaCR T cells, for dual-antigen recognition.
  • Evaluation of TRaCR T cell efficacy in an in vivo model of heterogeneous multiple myeloma.

Main Results:

  • TRaCR T cells demonstrated dual specificity, recognizing target cells resistant to either BOB1 TCR or BCMA CAR T cells alone.
  • In the presence of both antigens, CAR-mediated recognition was preferential, impairing TCR-mediated recognition.
  • This preferential CAR engagement resulted in a survival advantage for BCMA-negative tumor cells in a heterogeneous MM model.

Conclusions:

  • Dual antigen specificity can be installed on T cells using combined TCR and CAR engineering.
  • Preferential engagement of one targeting mechanism (CAR) over another (TCR) can occur, impacting therapeutic efficacy.
  • Caution is advised when applying TRaCR T cell strategies to heterogeneous tumors due to potential for antigen escape and tumor cell survival.
Keywords:
BCMACAR T cellsCD19TCR engineered T cell therapyantigen escapecellular therapycombination therapiesmulti-antigen targetingmultiple myeloma

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