Journal Article

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

Ding, Cornelia C. K., Chan, Emily, Wiita, Arun P., Lee, John K., Feng, Felix Y., Yip, Elizabeth, Berman, Sarah C., Gokturk Ozcan, Gamze, Solit, David B., Chang, Kevin, Chu, Carissa E., Delavan, Henry M., Al-Ahmadie, Hikmat, Liao, Sheng-You, Rosenberg, Jonathan E., Kasap, Corynn, Steri, Veronica, Koshkin, Vadim S., Lodha, Roshan, Basar, Merve, Teo, Min Yuen, Porten, Sima P., Chou, Jonathan, Zhu, Jun, Friedlander, Terence W., Carretero-Gonzalez, Alberto

2025

Overview

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. Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 631/67/1059/2325 / 631/67/1059/2326 / 631/67/589/1336 / 64/60 / 692/4028 / 692/4028/67/589/1336 / 96 / 96/106 / 96/31 / Agonists / Animals / Antibodies / Antibodies, Monoclonal / Antigens / Antitumor agents / Biopsy / Bladder / Bladder cancer / Cancer / Candidates / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - metabolism / Cell Line, Tumor / Cell therapy / Chimeric antigen receptors / Conjugates / Cytotoxicity / Diabetes mellitus / Female / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immunotherapy, Adoptive - methods / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Nectins / Peptides / Peroxisome proliferator-activated receptors / PPAR gamma - agonists / PPAR gamma - genetics / PPAR gamma - metabolism / Proteins / Ratios / Receptors / Receptors, Chimeric Antigen - genetics / Receptors, Chimeric Antigen - immunology / Receptors, Chimeric Antigen - metabolism / Rosiglitazone / Rosiglitazone - pharmacology / Science / Science (multidisciplinary) / Signal Transduction / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Therapeutic targets / Tumors / Up-Regulation / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - immunology / Urinary Bladder Neoplasms - metabolism / Urinary Bladder Neoplasms - pathology / Urinary Bladder Neoplasms - therapy / Urothelial carcinoma / Xenograft Model Antitumor Assays / Xenotransplantation