Identifying Biomarkers of Response and Resistance to Immunotherapy in Bladder Cancer
Abstract
Bladder cancer is the fourth most common cancer in the United States, with an estimated 80,470 new cases and 17,670 deaths in 2019. Metastatic bladder cancer is inevitably fatal. Localized bladder cancer can be treated with removal of bladder, but over 50% patients will eventually recur and develop metastatic disease. Over the past 40 years, there had been no therapy advances in bladder cancer up until recently, when immunotherapy agents were approved for metastatic bladder cancer. Development of immunotherapy provided a glimmer of hope for patients with bladder cancer as previously, there were no approved treatments after failure of standard chemotherapy. Immunotherapy agents train our immune system to fight cancer and have the potential to provide durable and effective responses in bladder cancer. Unfortunately, only 1 out of every 4 bladder cancer patients will respond to immunotherapy, and in the clinical setting, we do not have the tools to accurately predict who will and who will not respond to immunotherapy. As a result, patients are offered immunotherapy when chances are more likely than not that they will not respond, thus subjecting patients to an ineffective therapy at the cost of serious physical and financial toxicity. Mechanisms of resistance and response to immunotherapy are poorly understood, and there is a critical need to develop reliable and comprehensive biomarkers that will help us identify, in the clinic, which patients are most likely to benefit from immunotherapy. We want to systematically study the immune microenvironment in the tumors and determine the biomarkers that can predict response and resistance to immunotherapy. We will also study the genomic features seen in tumors from bladder cancer patients and develop a combined signature using machine learning algorithms. The ultimate goal of our research is to develop immunologic and genomic algorithms can provide information at the point of care in clinic as well as inform development of novel clinical trials using immunotherapy alone or in combination with chemotherapy. Our research proposal is innovative and unique as it will study tissue samples from patients who received chemotherapy alone, immunotherapy alone, and a combination of chemotherapy and immunotherapy for localized bladder cancer who received pre-operative treatment followed by cystectomy (removal of bladder). The key aspect of our proposal is that we have pretreatment and post-treatment matching tissues available which will help us study the specific effect of each treatment approach and provide clues as to why some patients respond while others have no response at surgery. Our research team consists of basic and clinical scientists with an expertise in immunotherapy and chemotherapy in bladder cancer. Dr. Shilpa Gupta is a medical oncologist and bladder cancer clinical researcher at Cleveland Clinic foundation who has expertise in bladder cancer immunotherapy trials. Dr. Peter Black is a physician scientist at University of British Columbia who is studying novel targets in bladder cancer and role of immunotherapy and biomarkers of response and resistance to chemotherapy and immunotherapy. This proposal specifically addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of bladder cancer and immunotherapy and FY19 PRCRP Military Health Focus Areas by addressing critical gaps in optimizing bladder cancer treatment and can diminish the morbidity and mortality from bladder cancer affecting active duty Service members, Veterans, and other military beneficiaries. By developing composite predictive biomarkers, we will be able to identify patients who will and will not respond to immunotherapy, thus offering effective therapies to those who will benefit and sparing ineffective therapies in those who will not benefit.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010877
Entities
People
- Shilpa Gupta
Organizations
- Cleveland Clinic
- United States Army