Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.

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Publication Details

Journal
Nature Cancer
Published
2025-03-17
DOI
https://doi.org/10.1038/s43018-025-00927-0
Citations
14
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
14.64

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article

Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy

Mitchell G. Kluesner, Sylvain Simon, A Stevens, Tamer B. Shabaneh et al.
14 citations
Nature Cancer
CAR-T cell therapy research
14.64
article

Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy

Mitchell G. Kluesner, Sylvain Simon, A Stevens, Tamer B. Shabaneh, Rachel Prins, Kersten Heyer, Anusha Rajan, Kirsten A. Thompson, Xiaolei Su, James M. Olson, Grace Bugos, Carla A. Jaeger-Ruckstuhl, Longhui Zeng, Stanley R. Riddell, Pınar Ataca Atilla, Jason P. Price, Arulmozhi Palani
article en
14 citations

Abstract

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.

Nature CancerVol. 6(4)
Seattle Children's Hospital (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), University of Washington (US), Yale Cancer Center (US), Yale University (US), Fred Hutch Cancer Center (US)
Bristol-Myers Squibb, Leukemia and Lymphoma Society, Fred Hutchinson Cancer Research Center, University of Washington, Mark Foundation For Cancer Research, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 1%
CAR-T cell therapy research
14.64
DOIOpen Access PDFOpenAlex
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