Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, 08035, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Monforte de Lemos, Madrid, 28029, Spain.
Nat Commun. 2024 Nov 18;15(1):9589. doi: 10.1038/s41467-024-53265-7.
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.
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，已显示出对某些血液恶性肿瘤的治疗成功。然而，这种策略对实体瘤没有效果。在这里，我们描述了针对 p95HER2 的 CAR T 细胞的开发，p95HER2 是在 HER2 扩增的实体瘤中发现的肿瘤特异性抗原。这些 CAR T 细胞对表达 p95HER2 的细胞系显示出强大的活性，但对患者来源的异种移植瘤的疗效有限。由于 p95HER2 始终可检测到过表达 HER2 的肿瘤细胞上，但不能检测到正常水平表达 HER2 的肿瘤细胞上，因此我们用针对 HER2 和 CD3 的亲和力优化的双特异性抗体武装 p95HER2 特异性 CAR T 细胞，以便仅将它们重定向至 HER2 扩增的细胞。p95HER2.CAR T 细胞和 HER2 x CD3 双特异性抗体的组合导致三种 HER2 阳性患者来源的小鼠异种移植瘤模型中的完全消退。这种组合代表了一种有前途的策略，可以将 T 细胞重定向至一组 HER2 阳性肿瘤。
