肿瘤细胞治疗研究
英文原题：Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors.
利用双特异性抗体或嵌合抗原受体（CAR）将 T 淋巴细胞重定向以靶向肿瘤相关抗原或肿瘤特异性抗原，已在某些血液系统恶性肿瘤中取得治疗成功。
使用双特异性抗体或嵌合抗原受体（CAR）将T淋巴细胞重定向至肿瘤相关或肿瘤特异性抗原，已成功治疗某些血液系统恶性肿瘤，但对实体瘤疗效不佳。本文介绍靶向p95HER2的CAR T细胞开发；p95HER2是HER2扩增型实体瘤中存在的一种肿瘤特异性抗原。这些CAR T细胞对表达p95HER2的细胞系具有强效活性，但治疗患者来源异种移植瘤的效果有限。由于p95HER2在HER2过表达肿瘤细胞中始终可检出，而在HER2正常表达细胞中不存在，我们为p95HER2特异性CAR T细胞配备亲和力经优化、靶向HER2和CD3的双特异性抗体，使其仅重定向至HER2扩增细胞。p95HER2 CAR T细胞联合HER2×CD3双特异性抗体，可使3种HER2阳性患者来源小鼠异种移植肿瘤模型完全消退。这种联合策略有望将T细胞重定向至一部分HER2阳性肿瘤。
The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors.
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