Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer Journal Article

   


Authors: Chang, K.; Delavan, H. M.; Yip, E.; Kasap, C.; Zhu, J.; Lodha, R.; Liao, S. Y.; Berman, S. C.; Carretero-Gonzalez, A.; Basar, M.; Ozcan, G. G.; Teo, M. Y.; Solit, D. B.; Rosenberg, J. E.; Al-Ahmadie, H.; Ding, C. C. K.; Chan, E.; Steri, V.; Porten, S. P.; Koshkin, V. S.; Friedlander, T. W.; Feng, F. Y.; Lee, J. K.; Wiita, A. P.; Chu, C. E.; Chou, J.
Article Title: Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer
Abstract: <p>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 PPAR gamma pathway, critical for luminal differentiation, transcriptionally controls NECTIN4, and that the PPAR gamma 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 PPAR gamma agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients.</p>
Keywords: recognition; reveals; efficacy; tumor-antigen; target; pioglitazone; proliferator-activated receptors; enfortumab vedotin
Journal Title: Nature Communications
Volume: 16
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2025-09-10
Start Page: 8215
Language: English
ACCESSION: WOS:001570546600002
DOI: 10.1038/s41467-025-62710-0
PROVIDER: wos
PMCID: PMC12423289
PUBMED: 40931013
Notes: Article -- Source: Wos
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MSK Authors
  1. David Solit
    784 Solit
  2. Hikmat Al-Ahmadie
    668 Al-Ahmadie
  3. Jonathan Eric Rosenberg
    525 Rosenberg
  4. Min Yuen Teo
    107 Teo
  5. Gamze Gokturk Ozcan
    12 Gokturk Ozcan
  6. Carissa Ellen Chu
    15 Chu
  7. Merve Basar Yerebakan
    14 Basar Yerebakan
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