TYRP1 directed CAR T cells control tumor progression in preclinical melanoma models

Molecular Therapy: Oncology Pub Date : 2024-08-22 DOI:10.1016/j.omton.2024.200862

Christopher S. Hackett, Daniel Hirschhorn, Meixian S. Tang, Terence J. Purdon, Yacine Marouf, Alessandra Piersigilli, Narasimhan P. Agaram, Cailian Liu, Sara E. Schad, Elisa de Stanchina, Sarwish Rafiq, Sebastien Monette, Jedd D. Wolchok, Taha Merghoub, Renier J. Brentjens

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Abstract

Despite therapeutic efficacy observed with immune checkpoint blockade in advanced melanoma, many tumors do not respond to treatment, representing a need for new therapies. Here, we have generated chimeric antigen receptor (CAR) T cells targeting TYRP1, a melanoma differentiation antigen expressed on the surface of melanomas, including rare acral and uveal melanomas. TYRP1-targeted CAR T cells demonstrate antigen-specific activation and cytotoxic activity and against human melanomas independent of the MHC alleles and expression. In addition, the toxicity to pigmented normal tissues observed with T lymphocytes expressing TYRP1-targeted TCRs was not observed with TYRP1-targeted CAR T cells. Anti-TYRP1 CAR T cells provide a novel means to target advanced melanomas, serving as a platform for the development of similar novel therapeutic agents and as a tool to interrogate the immunobiology of melanomas.

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TYRP1 引导的 CAR T 细胞可控制临床前黑色素瘤模型的肿瘤进展

尽管免疫检查点阻断疗法对晚期黑色素瘤有疗效，但许多肿瘤对治疗没有反应，因此需要新的疗法。在这里，我们生成了以TYRP1为靶点的嵌合抗原受体（CAR）T细胞，TYRP1是一种表达在黑色素瘤（包括罕见的尖锐湿疣和葡萄膜黑色素瘤）表面的黑色素瘤分化抗原。以 TYRP1 为靶点的 CAR T 细胞对人类黑色素瘤具有抗原特异性激活和细胞毒性活性，不受 MHC 等位基因和表达的影响。此外，表达 TYRP1 靶向 TCR 的 T 淋巴细胞对色素正常组织的毒性在 TYRP1 靶向 CAR T 细胞中没有观察到。抗TYRP1 CAR T细胞为靶向晚期黑色素瘤提供了一种新的手段，可作为开发类似新型治疗药物的平台和研究黑色素瘤免疫生物学的工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Molecular Therapy: Oncology

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