Ju-Fang Chang, Jack H Landmann, Tien-Ching Chang, Mehmet Emrah Selli, Yangdon Tenzin, John M Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar Gupta, John F DiPersio, Alex S Holehouse, Nathan Singh
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引用次数: 0
Abstract
Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T-cell activation causes T-cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T-cell response, we designed MHC-independent T-cell receptors (miTCR) by linking antibody variable domains to T-cell receptor constant chains. Using predictive modeling, we observed that this standard "cut and paste" approach to synthetic protein design resulted in myriad biochemical conflicts at the hybrid variable-constant domain interface. Through iterative modeling and sequence modifications, we developed structure-enhanced miTCRs which significantly improved receptor-driven T-cell function across multiple tumor models. We found that 41BB costimulation specifically prolonged miTCR T-cell persistence and enabled improved leukemic control in vivo compared with classic CAR T cells. Collectively, we have identified core features of hybrid receptor structure responsible for regulating function. Significance: Improving the durability of engineered T-cell immunotherapies is critical to enhancing efficacy. We used a structure-informed design to evolve improved miTCR function across several models. This work underscores the central role of synthetic receptor structure in T-cell function and provides a framework for improved receptor engineering.
基于嵌合抗原受体(CAR)的疗法开创了合成细胞免疫疗法,但其长期疗效仍然有限。新出现的数据表明,CAR 驱动的 T 细胞活化失调会导致 T 细胞功能障碍和治疗失败。为了重新精确激活内源性 T 细胞反应,我们将抗体可变域与 TCR 常链连接,设计出了不依赖 MHC 的 T 细胞受体(miTCRs)。通过预测建模,我们发现这种标准的 "剪切和粘贴 "合成蛋白质设计方法会在可变结构域与恒定结构域的混合界面上产生无数的生化冲突。通过迭代建模和序列修改,我们开发出了结构增强型 miTCR,在多个肿瘤模型中显著改善了受体驱动的 T 细胞功能。我们发现,与传统的 CAR T 细胞相比,41BB 成本刺激特异性地延长了 miTCR T 细胞的存活时间,并改善了体内的白血病控制。总之,我们确定了混合受体结构中负责调节功能的核心特征。
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.