间皮质靶向CAR-T细胞局部注射治疗具有潜在和长期的CD4依赖... - 中国病毒学论坛|我们一直在坚持！

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. Following intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced anti-tumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intra-tumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication or persistence. The remarkable ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through “regional distribution centers.” Based on these results, we are opening a phase I clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

CAR-T细胞移植治疗恶性血液系统肿瘤获得成功，若要转到实体肿瘤的治疗必须克服几个障碍，包括低效率的T细胞对肿瘤的浸润以及功能持久性不足。利用一个原位模型准确的模仿胸膜恶性肿瘤，我们评估了使用M28z CAR的间皮质靶向CAR-T细胞的两种给药途径。我们发现，向胸膜内注射CAR-T细胞大大优于全身注射CAR-T细胞，可以需要少30倍的m28z T细胞来诱导长期完全的缓解。在胸腔内注射T细胞之后，在体内抗原诱导的T 细胞迅速活化，CAR-T细胞扩增并且功能性分化，产生了抗肿瘤活性并能持续200天。T细胞局部注射也促进了胸外肿瘤有效的消除。这个治疗的有效性取决于早期CD4+T细胞活化，与较高的肿瘤内CD4／CD8细胞比例和CD28依赖的CD4 + T细胞介导的细胞毒作用有关。相反的，静脉注射的CAR-T细胞，即使在胸腔肿瘤积累相同的数量，也没有起到相对应的活性、肿瘤根除或持久性。胸腔内注射T细胞的有效性支持了这么一个观点：通过区域性注射中心可以进行最优化的CAR-T细胞治疗。基于这些结果，我们正开放一个I期临床试验，评估原发或继发胸膜恶性肿瘤患者胸腔内注射间皮素靶向T细胞的安全性。