Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer
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.
Article Details
Authors (26)
Kevin Chang
Henry M. Delavan
Elizabeth Yip
Corynn Kasap
Jun Zhu
Wuxi EliTe Solar Co., Wuxi, China.
Roshan Lodha
Sheng-You Liao
Sarah C. Berman
Alberto Carretero-Gonzalez
Merve Basar
Gamze Gokturk Ozcan
Min Yuen Teo
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
David B. Solit
Jonathan E. Rosenberg
Genitourinary Oncology Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
Hikmat Al-Ahmadie
Cornelia C. K. Ding
Emily Chan
Veronica Steri
Sima P. Porten
Vadim S. Koshkin
Division of Hematology/Oncology, Department of Medicine University of California‐San Francisco San Francisco California USA
Terence W. Friedlander
Felix Y. Feng
John K. Lee
Arun P. Wiita
Carissa E. Chu
Jonathan Chou
Helen Diller Family Comprehensive Cancer Center, University of California