Background 

Bladder cancer is one of the most common cancers in the United States and causes about 16,000 deaths every year. When bladder cancer spreads to other parts of the body (called metastatic bladder cancer), it becomes very hard to treat, and most patients do not survive beyond five years. 

A newer treatment called enfortumab vedotin (EV) has helped some patients. It works by attaching a powerful cancer-killing drug to an antibody that targets a specific protein on bladder cancer cells called NECTIN4. This medicine has been an important step forward, but it doesn’t work for everyone. Even when cancer cells still have NECTIN4, they sometimes stop responding to EV. Researchers believe we need new ways to attack NECTIN4 to help more patients, especially those whose cancers have become resistant to this drug. 

What the Study Proposes to Address 

This project explores a new treatment approach called CAR T-cell therapy for bladder cancer. CAR T-cell therapy works by taking a person’s own immune cells, changing them in the lab so they can recognize and attack cancer cells, and then putting them back into the patient’s body. 

The research team has created eight new versions of CAR T cells that specifically target the NECTIN4 protein found on bladder cancer cells. They’ve already seen that these modified immune cells can destroy bladder cancer cells in the lab. 

In this study, the researchers will test how well each of the eight NECTIN4 CAR T-cell designs works against different types of bladder cancer cells, including those that have become resistant to EV. They’ll then choose the two most promising ones and test them in mice with bladder cancer, including tumors that were grown from real patients—some from minority groups who are often underrepresented in research. 

Why This Research is Important 

If successful, this study could lead to an entirely new kind of treatment for people with advanced bladder cancer. By targeting NECTIN4 with CAR T-cell therapy, doctors could treat both patients who have never received EV and those whose cancers no longer respond to it. 

This work will also help scientists better understand how to make personalized, immune-based therapies for bladder cancer. Ultimately, the findings from this study could lay the groundwork for a future clinical trial in people—and move us closer to bringing this powerful new treatment option to patients who urgently need better care. 

Final Report Summary

This research focuses on a new way to treat bladder cancer by targeting a protein called NECTIN4, which is often found on bladder cancer cells. A current drug, enfortumab vedotin (EV), already attacks NECTIN4, but many patients eventually stop responding to it. To find a new option, the researchers built special immune cells, called CAR T cells, that are designed to recognize and destroy NECTIN4 on cancer cells. 

The team discovered that another pathway in the cell, controlled by something called PPARγ, can actually turn on NECTIN4. When they used a drug called rosiglitazone to boost this pathway, it made cancer cells show more NECTIN4 on their surface, making them easier targets for the CAR T cells. Importantly, these new CAR T cells were effective even in cancers that no longer responded to EV, because those tumors still kept NECTIN4. 

The scientists tested this approach in models of bladder cancer, including cancers that spread to the lungs, and saw strong tumor-killing effects. Their findings open the door to combining NECTIN4-targeted therapies with drugs that boost NECTIN4, offering hope for new treatment strategies, especially for patients who no longer benefit from current drugs. 

Chang, K., Delavan, H. M., Zhu, J., Kasap, C., Yip, E., Lodha, R., Liao, S.-Y., Porten, S., Friedlander, T., Koshkin, V., Feng, F., Wiita, A., Lee, J., Chu, C. E., & Chou, J. (2024). Abstract PR008: Modulating the PPARγ pathway to augment NECTIN4-targeting chimeric antigen receptor (CAR) T cell therapy. Clinical Cancer Research, 30(10_Supplement), PR008–PR008. https://doi.org/10.1158/1557-3265.BLADDER24-PR008

Chang, K., Delavan, H.M., Yip, E. et al. Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer. Nat Commun 16, 8215 (2025). https://doi.org/10.1038/s41467-025-62710-0

Department of Defense, Peer Reviewed Cancer Research Program Career Development Award, 2025

Damon Runyon Clinical Investigator Award, 2025-2028, $600,000

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