Chang Kevin, Delavan Henry M, Yip Elizabeth, Kasap Corynn, Zhu Jun, Lodha Roshan, Liao Sheng-You, Berman Sarah C, Carretero-Gonzalez Alberto, Basar Merve, Gokturk Ozcan Gamze, Teo Min Yuen, Solit David B, Rosenberg Jonathan E, Al-Ahmadie Hikmat, Ding Cornelia C K, Chan Emily, Steri Veronica, Porten Sima P, Koshkin Vadim S, Friedlander Terence W, Feng Felix Y, Lee John K, Wiita Arun P, Chu Carissa E, Chou Jonathan
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA.
Nat Commun. 2025 Sep 10;16(1):8215. doi: 10.1038/s41467-025-62710-0.
With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4, and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients.
随着抗体药物偶联物恩杂鲁胺（EV）的获批，NECTIN4已成为尿路上皮癌（UC）中一个名副其实的治疗靶点。在此，我们报告了一种针对NECTIN4的嵌合抗原受体（CAR）T细胞的研发情况，该细胞对表达一系列内源性NECTIN4的细胞具有反应性，在高表达细胞中活性增强。我们证明，对管腔分化至关重要的PPARγ途径在转录水平上控制NECTIN4，并且PPARγ激动剂罗格列酮可启动并增强NECTIN4的表达，从而增加对NECTIN4-CAR T细胞介导杀伤的敏感性。NECTIN4-CAR T细胞即使对EV耐药细胞也具有强大的抗肿瘤活性，这些细胞在很大程度上保留NECTIN4表达，包括在EV后活检队列中。我们的结果阐明了UC细胞用于控制NECTIN4表达的一种可用于治疗的机制，并提出了利用PPARγ激动剂与UC中靶向NECTIN4的药物进行合理联合的治疗方法，以及为EV难治性患者提供未来潜在的治疗选择。
