Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA.
Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Blood Adv. 2023 May 9;7(9):1885-1898. doi: 10.1182/bloodadvances.2022008798.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematologic malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CART expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given T-cell receptor vβ (TCRvβ) family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvβ family members were designed and validated. Our results demonstrate that TCRvβ-family-specific CARTs (TCRvβ-CARTs) recognize and kill TCRvβ-expressing target cells. This includes specific self-depletion of the targeted cell subpopulation in the CART product and lysis of cell lines engineered to express a target TCRvβ family. Furthermore, TCRvβ-CARTs eliminated the dominant malignant TCRvβ clone in 2 patient samples. Finally, in immunodeficient mice, TCRvβ-CARTs eradicated malignant cells in a TCRvβ-dependent manner. Importantly, the nontargeted TCRvβ families were spared in all cases. Thus, TCRvβ-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.
外周 T 细胞淋巴瘤（PTCLs）是一组异质性的淋巴恶性肿瘤，由于治疗选择效果不佳且复发率高，预后较差。嵌合抗原受体 T 细胞（CART）疗法在某些血液恶性肿瘤中的成功使其成为 PTCL 的一种有吸引力的治疗选择。然而，潜在靶抗原在外周 T 细胞和恶性 T 细胞中的共同表达带来了挑战。目前的前瞻性 CART 方法导致高度的靶向、脱靶活性，导致 CART 扩增过程中的同型杀伤、体内健康 T 细胞耗竭以及患者免疫受损。为了限制脱靶靶向，我们试图开发一种针对特定 T 细胞受体 vβ（TCRvβ）家族的 CART 平台，该平台将赋予 CAR 修饰的 T 细胞识别和裂解克隆性恶性群体的能力，同时保留大多数健康 T 细胞。在这里，设计并验证了针对多个 TCRvβ 家族成员的 CAR 构建体。我们的结果表明，TCRvβ 家族特异性 CART（TCRvβ-CART）识别并杀死表达 TCRvβ 的靶细胞。这包括在 CART 产物中靶向细胞亚群的特异性自我耗竭以及表达靶 TCRvβ 家族的工程细胞系的裂解。此外，TCRvβ-CART 消除了 2 个患者样本中占主导地位的恶性 TCRvβ 克隆。最后，在免疫缺陷小鼠中，TCRvβ-CART 以 TCRvβ 依赖性方式根除恶性细胞。重要的是，在所有情况下，非靶向的 TCRvβ 家族都被幸免。因此，TCRvβ-CART 治疗为 PTCL 的高精度治疗提供了一种潜在选择，可限制健康 T 细胞的耗竭。
