决定异体 CAR T 细胞排斥与扩增的细胞和分子机制
Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion.
我们评估了11例接受单一批次cemacabtagene ansegedleucel(cema-cel)治疗的大B细胞淋巴瘤患者,cemacabtagene ansegedleucel是一种异体抗CD19 CAR T产品。
英文原题:CAR-T cells targeting CD155 reduce tumor burden in preclinical models of leukemia and solid tumors.
这些发现提示,CD155 可被 CD155 CAR-T 细胞安全有效地靶向,代表一种创新的细胞治疗策略,有望将其应用范围扩展至急性髓系白血病和多种实体瘤,从而降低细胞免疫治疗的成本,尤其是在同种异体、通用型、即用型 CAR-T 细胞疗法走向临床之际。
CAR-T细胞是强效但价格高昂的癌症免疫治疗手段。虽然其靶向血液系统恶性肿瘤的应用已较成熟,但使用单一CAR-T疗法同时治疗血液系统和实体瘤、从而降低成本的做法仍未得到充分探索。本研究发现,CD155是一种随肿瘤进展而上调的黏附分子,可作为白血病及实体瘤CAR-T治疗靶点。我们利用Berkeley Lights Beacon平台产生的人源和小鼠抗CD155抗体构建CAR-T细胞。这些CAR-T细胞具有强效抗肿瘤活性,可在急性髓系白血病、非小细胞肺癌和胰腺癌临床前模型中显著降低肿瘤负荷。为减少潜在的异体排斥,我们使用保留疗效的人源化抗CD155抗体序列制备CAR-T细胞。此外,靶向小鼠CD155的鼠源CAR-T细胞在免疫功能完整小鼠中产生的毒副作用有限,显示出良好的安全性。这些发现提示,CD155 CAR-T细胞可安全有效地靶向CD155,是一种创新细胞疗法,有望扩展至AML及多种实体瘤,从而降低细胞免疫治疗成本;异体通用现货型CAR-T疗法进入临床后尤有此潜力。
CAR-T cells are a powerful yet expensive tool in cancer immunotherapy. Although their use in targeting hematological malignancies is well established, using a single CAR-T cell therapy to treat both hematological and solid tumors, which can reduce cost, remains largely unexplored. In this study, we identified CD155, an adhesion molecule that is upregulated during tumor progression, as a target for CAR-T cell therapy in both leukemia and solid tumors. We engineered CAR-T cells using human and mouse anti-CD155 antibodies generated from a Berkeley Lights' Beacon platform. These CAR-T cells demonstrated potent antitumor activity, significantly reducing tumor burden in preclinical models of acute myeloid leukemia, non-small cell lung cancer, and pancreatic cancer. To reduce potential allogeneic rejection, we generated CAR-T cells using humanized anti-CD155 antibody sequences that retained efficacy. Additionally, murine CAR-T cells targeting mouse CD155 exhibited limited toxic side effects in immunocompetent mice, highlighting the favorable safety profile of this therapy. These findings suggest that CD155 can be targeted by CD155 CAR-T cells safely and effectively, representing an innovative cellular therapeutic strategy that has the potential to expand its scope across both AML and multiple solid tumors, thereby lowering the cost of cellular immunotherapy, especially as allogenic, universal, and off-the-shelf CAR-T cell therapies advance to the clinic.
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