Repurposing Diabetes Drugs to Enhance CAR T Cell Therapy for Bladder Cancer

Urothelial carcinoma (UC), a prevalent form of bladder cancer, remains a significant health challenge, causing over 16,000 deaths annually in the United States. Despite advances in treatment, the prognosis for metastatic UC is still poor, with a five-year survival rate between 5% and 10%. A promising development involves repurposing existing medications to improve immunotherapy outcomes.

Currently, enfortumab vedotin (EV), an FDA-approved antibody-drug conjugate, targets NECTIN4, a protein expressed on bladder cancer cells, serving as a frontline treatment for advanced UC. While EV shows a response rate of around 40%, resistance in some patients limits long-term remission and survival benefits. To address this, researchers at UCSF have developed a chimeric antigen receptor (CAR) T cell therapy targeting NECTIN4 and investigated ways to boost its effectiveness.

The team discovered that the PPAR gamma pathway, involved in fat metabolism regulation, influences NECTIN4 expression on tumor cells. Notably, established diabetes drugs like rosiglitazone and pioglitazone activate PPAR gamma, leading to increased NECTIN4 levels. By using these drugs, the researchers could 'prime' the tumor cells, making them more receptive to NECTIN4-specific CAR T cells.

Their studies found that many bladder tumors resistant to EV still retain NECTIN4 expression. Priming tumors with rosiglitazone enhanced the efficacy of CAR T cell therapy in both cell cultures and animal models. This approach effectively turns low-expressing tumors into high-expressing ones, increasing their vulnerability to targeted treatment.

This research provides a basis for combining diabetes medications with immunotherapy to improve outcomes in bladder cancer patients. Continued development and clinical testing of this strategy could expand the therapeutic options for resistant UC cases, potentially leading to longer-lasting remissions and improved survival rates.

Source: Medical Xpress