Simon Sylvain, Bugos Grace, Prins Rachel, Rajan Anusha, Palani Arulmozhi, Heyer Kersten, Stevens Andrew, Zeng Longhui, Thompson Kirsten A, Atilla Pinar A, Price Jason P, Kluesner Mitchell G, Jaeger-Ruckstuhl Carla A, Shabaneh Tamer B, Olson James M, Su Xiaolei, Riddell Stanley R
Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Department of Immunology, University of Washington, Seattle, WA, USA.
Nat Cancer. 2025 Apr;6(4):647-665. doi: 10.1038/s43018-025-00927-0. Epub 2025 Mar 17.
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.
表达嵌合抗原受体（CAR）的T细胞的过继性转移在B细胞恶性肿瘤中是有效的。然而，癌细胞中靶抗原水平低或完全缺失，从而逃避CAR T细胞的检测，这种情况导致复发。这些逃避机制凸显了对具有更高敏感性和多特异性的受体的需求。我们引入了一种合成嵌合T细胞受体（ChTCR），与CAR和先前的杂交TCR设计相比，它具有更高的抗原敏感性，并且易于用于双特异性靶向。ChTCR复制天然TCR的结构，形成经典免疫突触并表现出类似TCR的信号传导。在雌性小鼠体内根除具有异质性抗原表达的肿瘤时，表达双特异性ChTCR（Bi-ChTCR）的T细胞比双特异性CAR T细胞更有效。Bi-ChTCR结构具有弹性，可设计用于靶向B细胞和多发性骨髓瘤抗原对。这些发现为对抗肿瘤异质性和预防复发提供了一种广泛适用的策略。
