Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer
- Kevin Chang
- Henry M. Delavan
- Elizabeth Yip
- Corynn Kasap
- Jun Zhu
- Roshan Lodha
- Sheng-You Liao
- Sarah C. Berman
- Alberto Carretero-Gonzalez
- Merve Basar
- Gamze Gokturk Ozcan
- Min Yuen Teo
- David B. Solit
- Jonathan E. Rosenberg
- Hikmat Al-Ahmadie
- Cornelia C. K. Ding
- Emily Chan
- Veronica Steri
- Sima P. Porten
- Vadim S. Koshkin
- Terence W. Friedlander
- Felix Y. Feng
- John K. Lee
- Arun P. Wiita
- Carissa E. Chu
- Jonathan Chou
2025-09-10
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.