使用双功能小分子的转基因CAR-T细胞重定向 - 中国病毒学论坛|我们一直在坚持！

Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent antitumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion and terminate their response. Herein, we demonstrate that a bifunctional small molecule "switch" consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity toward folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirection by folate-FITC. Anti-FITC-CAR-T cell activation and proliferation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ultimately lead to increased safety for CAR-T cell immunotherapy.

CAR-T细胞技术具有一个潜在的抗肿瘤效应，而且变成一个治疗癌症的有前景的方式。然而，虽然具有有效性，但是CAR-T细胞技术面对着安全性的挑战，主要是无法控制它们激活和扩张的能力，并且有效的终止它们的反应。在这篇文章中，我们描述了一个双功能小分子开关，由叶酸偶联的异硫氰酸荧光素（叶酸FITC）构成，对FITC标记的叶酸受体（FR）过表达的肿瘤细胞，可以重定向和调节CAR-T细胞活性。研究显示，这个系统对于FR阳性细胞具有高度的细胞毒性，而对FR阴性细胞没有活性，这就说明叶酸FITC CAR-T具有特异性和重定向能力。anti-fitc-car-t细胞的活化和增殖是严格依赖于叶酸-FITC和FR-阳性细胞的存在，并且与叶酸-FITC开关的剂量有关。这种新型的治疗模式可能会最终增加CAR-T免疫治疗的安全性。