Simon Sylvain, Bugos Grace, Prins Rachel, Rajan Anusha, Palani Arulmozhi, Heyer Kersten, Stevens Andrew, Zeng Longhui, Thompson Kirsten, Price Jason P, Kluesner Mitchell K, Jaeger-Ruckstuhl Carla, Shabaneh Tamer B, Olson James M, Su Xiaolei, Riddell Stanley R
Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Res Sq. 2024 Apr 22:rs.3.rs-4253777. doi: 10.21203/rs.3.rs-4253777/v1.
The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.
合成嵌合抗原受体（CAR）的表达可重定向T细胞的抗原特异性，正在改变血液系统恶性肿瘤和自身免疫性疾病的治疗方式[1-7]。在癌症中，持久疗效常常受到表达低水平或缺乏靶抗原的肿瘤逃逸的限制[8-12]。这些临床结果强调需要具有高敏感性和多特异性的免疫受体来改善治疗结果。目前的单特异性和双特异性CAR不能如实地重现T细胞受体（TCR）的功能，并且需要肿瘤细胞上有高抗原水平才能识别[13-17]。在此，我们描述了一种新型的合成嵌合TCR（ChTCR），它表现出卓越的抗原敏感性，并且易于适应双特异性靶向。双特异性ChTCR模仿TCR结构，形成经典免疫突触，并表现出类似TCR的近端信号传导。与表达优化双特异性CAR的T细胞相比，表达双特异性ChTCR的T细胞在体内更有效地消除了具有异质性抗原表达的肿瘤。双特异性ChTCR结构具有弹性，可设计用于靶向多种B细胞谱系和多发性骨髓瘤抗原。我们的研究结果确定了一种广泛适用的方法，用于工程化T细胞以靶向具有异质性抗原表达的血液系统恶性肿瘤，从而克服当前CAR-T疗法后最常见的复发机制。
