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 and Jonathan Chou ()
Additional contact information
Kevin Chang: University of California
Henry M. Delavan: University of California
Elizabeth Yip: University of California
Corynn Kasap: University of California
Jun Zhu: University of California
Roshan Lodha: University of California
Sheng-You Liao: University of California Los Angeles
Sarah C. Berman: University of California
Alberto Carretero-Gonzalez: University of California
Merve Basar: Memorial Sloan Kettering Cancer Center
Gamze Gokturk Ozcan: Memorial Sloan Kettering Cancer Center
Min Yuen Teo: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Jonathan E. Rosenberg: Memorial Sloan Kettering Cancer Center
Hikmat Al-Ahmadie: Memorial Sloan Kettering Cancer Center
Cornelia C. K. Ding: University of California
Emily Chan: University of California
Veronica Steri: University of California
Sima P. Porten: University of California
Vadim S. Koshkin: University of California
Terence W. Friedlander: University of California
Felix Y. Feng: University of California
John K. Lee: University of California Los Angeles
Arun P. Wiita: University of California
Carissa E. Chu: University of California
Jonathan Chou: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62710-0

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