Posted: Tuesday, December 12, 2023
Jonathan Chou, MD, PhD, of the University of California, San Francisco, and colleagues developed a preclinical in vitro model of bladder cancer to investigate the mechanisms of and strategies to overcome resistance to the nectin-4–targeted antibody-drug conjugate enfortumab vedotin-ejfv. Their findings, which were presented during the 2023 Society of Urologic Oncology (SUO) Annual Meeting (Poster 66), suggested that insensitivity to this agent may be primarily attributed to its payload drug rather than a loss of nectin-4 expression. Enfortumab vedotin has been approved in the United States in the treatment of metastatic urothelial carcinoma.
Using the RT112 bladder cancer cell line, which expresses high levels of nectin-4, the investigators developed a model of resistance. Second-generation chimeric antigen receptor (CAR) T cells were engineered with a single-chain fragment variable comprising the variable regions of both the heavy and light chains of enfortumab.
RT112 cells exposed to “cycles” of treatment with escalating concentrations of enfortumab vedotin (range, 0.5–30 µg/mL) were found to yield a generation of cells that exhibited a fourfold to fivefold elevation in IC50 (half maximal inhibitor concentration) values for the agent. Compared with the parental cells, these RT112 cells resistant to enfortumab vedotin demonstrated similar surface nectin-4 levels and increased surface TROP-2 levels.
Reduced sensitivity to the payload drug of enfortumab vedotin, monomethyl auristatin E (vedotin), was observed in the resistant cells. However, they demonstrated increased sensitivity to the Trop-2–directed antibody-drug conjugate sacituzumab govitecan-hziy. Enfortumab vedotin–resistant and parental RT112 cells seemed to be equally susceptible to killing by nectin-4–directed CAR T cells.
“Nectin-4 remains a relevant target, even after cells develop enfortumab vedotin resistance,” the investigators concluded. “Treatment using sacituzumab govitecan represents an alternative strategy after resistance.”
Disclosure: No information regarding conflicts of interest was provided.