肿瘤细胞治疗研究
英文原题：Overcoming fratricide of CD86 targeting CAR-T cells by defined logic-gate CAR strategy.
尽管在治疗多种血液系统恶性肿瘤方面取得了显著成功，但使用嵌合抗原受体（CAR）T细胞的细胞免疫疗法在治疗难治/复发性或髓系恶性肿瘤如AML、CML或多发性骨髓瘤时仍面临重大挑战。
尽管嵌合抗原受体（CAR）T细胞疗法治疗多种血液系统恶性肿瘤已取得显著成功，但用于复发/难治性或髓系恶性肿瘤（如AML、CML或多发性骨髓瘤）仍面临重大挑战。为应对这些疾病显著的异质性，研究者近期开始寻找合适的肿瘤相关抗原，并将B7蛋白家族表面抗原作为潜在CAR-T靶点。本文以靶向CD86为例，指出利用B7家族蛋白这一T细胞（活化）相关抗原群作为靶点时，CAR-T疗法存在重要陷阱。在一系列体内外实验中，我们证明预先活化的CD86特异性CAR-T细胞之间发生同类相残，显著降低其总体存活和肿瘤杀伤效力；靶向B7-H3/CD276的CAR也曾观察到类似情况。因此，我们提出一种明确的组合抗原识别概念：采用双链CAR-T细胞，通过CD19初级CAR活化及CD86条件性共刺激形成“与”门机制，以克服疗效严重受限的问题。
Despite its remarkable success in the treatment of several hematological malignancies, cellular immunotherapy using chimeric antigen receptor (CAR) T cells faces significant challenges when treating refractory/relapsed or myeloid malignancies such as AML, CML or multiple myeloma. To overcome the pronounced heterogeneity of such diseases, the search for suitable tumor-associated antigens recently led to surface antigens of the B7 protein family as potential CAR-T cell targets. Using the example of CD86-targeting, we highlight a considerable pitfall of CAR-T therapy which utilizes B7-family proteins as a prominent group of T cell (activation) associated antigens. In a consistent set of in vitro and in vivo experiments we could demonstrate that fratricide among pre-activated CD86-specific CAR-T cells strongly reduces their overall survival and efficacy in tumor killing as recently shown for B7-H3/CD276-targeting CARs. Therefore, we propose a defined combinatorial antigen recognition concept via dual-chain CAR-T cells that incorporate an "AND-gate" mechanism through CD19 primary CAR activation and CD86 conditional co-stimulation to circumvent a severely limited outcome.
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