Enhancing the Immunogenicity of Nectin-4 Targeted Therapy for the Treatment of Aggressive Bladder Cancer
Abstract
Scientific Rationale: Bladder cancer is the fifth most common cancer overall in the United States, with approximately18,000 deaths attributed to this devastating disease in 2021. For over 3 decades, the standard treatment for bladder cancer that has high risk of progressing has remained cisplatin-based chemotherapy, which has substantial toxicity (side effects). Recently, cancer researchers are trying to find treatments that will be less toxic than cisplatin-based chemotherapy and also more effective, improving survival and other patient outcomes. Their efforts have often focused on immunotherapy treatments. However, more than 70% of bladder cancer patients do not respond to existing immunotherapy treatments; new treatments are needed. The Food and Drug Administration recently approved a targeted chemotherapy for bladder cancer called enfortumab vedotin (EV). EV binds to a bladder cancer-specific marker called nectin-4. In a clinical trial combining EV and an immunotherapy called pembrolizumab, patients cancers decreased in size 73% of the time using this potent combination treatment. This exciting data suggests that combining immunotherapy with EV might improve bladder cancer outcomes, but the effects of EV on the immune system are not yet fully understood. The aims of this proposal are to (1) understand how EV alters the immune response to bladder cancer and (2) to develop a novel cellular therapy targeting nectin-4 for the treatment of bladder cancer. To understand how EV alters the immune system, we will analyze blood and tissue samples from a fully-funded clinical trial in which patients are receiving combination EV and pembrolizumab. The first aim will use correlative analyses on the blood and tissue samples to help determine which biomarkers (blood and tumor-specific factors in an individual patient) are associated with the patient responding to this new treatment. The second aim of this proposal focuses on developing new ways to target nectin-4 to develop even better treatments for bladder cancer. One approach is to introduce a tumor-specific receptor, called a chimeric-antigen receptor (CAR), into patients own T cells. Reprogrammed CAR T cells specific to nectin-4 can be reinfused into the patient to eliminate cancer. We have designed several CAR receptors specific to nectin-4, and we will test the safety and activity of these receptors in mouse models of bladder cancer. Dr. Aggen s career goals are to define novel mechanisms of response and resistance to immunotherapy and to develop the next generation of immunotherapies for bladder cancer. His proposed translational studies will define blood and tumor tissue biomarkers associated with response and resistance to EV treatment, and will potentially identify new therapeutic vulnerabilities for targeting nectin-4. This work may also identify new therapeutic targets besides nectin-4. Dr. Aggen s long-term career goal is to develop cellular therapies for bladder cancer. The proposed studies will provide the preclinical (laboratory-based) foundation to translate a nectin-4 targeted cell therapy into the clinical setting, and further position him as a leader in the key Topic Area of bladder cancer. The translational studies in Aim 1 will directly benefit metastatic bladder cancer patients by identifying biomarkers associated with EV treatment response to guide selection of the least toxic, most effective treatment for their advanced cancer. We also anticipate identifying markers of resistance for future therapeutic approaches. The proposed biopsies and tissue collections will be performed in the context of a clinical trial, and all biopsy and tissue collections would have been performed anyhow as standard-of-care treatment. There are no additional research biopsies for patients on this study. The preclinical CAR-T studies in Aim 2 have potential applications to treat the full spectrum of bladder cancer, from localized to advanced disease. This proposal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210155
Entities
People
- David H Aggen
Organizations
- Sloan-Kettering Institute
- United States Army