Characterizing the immune infiltrate in muscle-invasive urothelial carcinoma

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Project Summary Urothelial carcinoma is a common, aggressive, morbid, and understudied disease. Many patients are not cured with the current standard of care for localized muscle-invasive urothelial carcinoma, which is neoadjuvant combination cisplatin-based chemotherapy followed by radical cystectomy. But overall survival is significantly longer in patients who obtain a pathologic complete response to neoadjuvant chemotherapy, suggesting that intensification of systemic therapy will improve survival. It is critical that we develop reliable predictive biomarkers that can select patients that will or will not have a complete pathologic response to receive, respectively, either chemotherapy or an intensified peri-operative regimen. Preliminary evidence in urothelial carcinoma and other cancers suggests that infiltrating immune cells play a role in treatment response, but this has not been rigorously studied in muscle-invasive urothelial carcinoma. In this study, we will interrogate pre- and post-treatment samples from a completed, pivotal phase II clinical trial, harnessing our expertise in spatial transcriptomics and proteomics to interrogate differential gene and protein expression in tumor, immune, and stromal cells in annotated tissue specimens before and after neoadjuvant chemotherapy with or without a checkpoint inhibitor. Specifically, we will evaluate baseline CD8:FOXP3 ratio and responses to therapy (Aim 1), determine the effect of neoadjuvant therapy on CD8:FOXP3 ratio (Aim 2), and leverage the full capacity of spatial transcriptomic/proteomic assays to develop and evaluate the performance of novel predictive biomarkers of response to neoadjuvant therapy (Aim 3). This study will result in predictive biomarkers while concurrently profiling the immune infiltrate composition and how it is influenced by treatment. The ultimate goal is to design rational combination or sequential peri-operative regimens for biomarker-driven clinical trials to improve patient survival and cure rates. The project will provide the candidate, Katharine Collier, MD, MSc, MSE, MS, with training in rigorous quantitative methods, cutting-edge spatial molecular analyses, and high-dimensional biomarker development. The proposal capitalizes on Dr. Collier’s quantitative background in Chemical Engineering, clinical training in Medical Oncology, and formal training in clinical trial design, while providing an opportunity to gain additional skills and knowledge in multi-omics techniques and data analyses, preclinical studies, leadership, presentations, and grant writing. Dr. Collier is committed long-term to improving outcomes for patients with genitourinary cancers as a translational physician-scientist. Dr. Collier will be supported by an experienced mentorship team (Amir Mortazavi, MD, Zihai Li, MD, PhD, Daniel Stover, MD, Steven Clinton, MD, PhD), skilled collaborators, the rich academic environment of the Ohio State University Comprehensive Cancer Center, and an invested institution committed to providing protected time and resources for career development and research. This award will ensure Dr. Collier’s successful transition to independence as a physician-scientist and translational researcher improving outcomes for patients with genitourinary cancers.