Identifying Biomarkers and Dissecting Combinatorial Synergies to Improve Immune Checkpoint Inhibitor Response in Bladder Cancer

Project: Research project

Project Details


An important function of the human immune system is to protect against the development of cancers and to clear pre-cancerous and early cancerous lesions before they progress. This is evidenced by the fact that immunocompromised individuals more frequently develop cancers that are more likely to progress to advanced stages. The discovery of a relationship between the immune system and cancer became the basis for the most promising class of cancer treatments in a generation: immunotherapy. The underlying premise of these treatments is that we can 're-train' the immune system to recognize and clear cancer from the body.

Though immunotherapy has demonstrated remarkable promise in bladder cancer, with multiple randomized controlled clinical trials confirming its benefit, the benefit remains limited to a minority of patients–only about one in five. This is the problem we aim to address in this proposal. Our primary objective is to improve immunotherapy so that it works more effectively for all patients with bladder cancer. We have several secondary objectives in this proposal. We are exploring new drug targets that may lead to more effective 're-training' of the immune system, paving the way for the next generation of immunotherapies. We are using animal models to learn more about anti-bladder cancer immunity and to explore the mechanisms behind the sporadic effectiveness of immunotherapy in bladder cancer. Finally, we will leverage the enormous potential of artificial intelligence to integrate clinical and biological data and help us better match bladder cancer patients to the right combination of therapies tailored to their disease.

This proposal will unite and amplify the capabilities of a team of investigators engaged in bladder cancer treatment and translational research, driving towards better treatments for patients. The three initiating and partnering principle investigators include clinical, translational ('bench to bedside'), and computational scientists with a specific focus on improving outcomes in bladder cancer. Dr. Mian is physician/scientist at the Cleveland Clinic who has been exploring the role of immunotherapy combined with radiation to improve organ preservation in patients with localized bladder cancer and has a special focus on aggressive treatment resistant variants of bladder cancer. Dr. Gupta is a medical oncologist and bladder cancer clinical trialist who has been running clinical trials to study the optimal sequencing of immunotherapy with chemotherapy in early and advanced bladder cancer. Dr. Hwang is a computational biologist with an expertise in machine learning (AI) and its application to the integration of clinical and biological data in bladder cancer. Together, this team, along with a talented group of collaborating surgeons, oncologists, pathologists, scientists, and trainees, has the synergistic expertise to address the important and highly impactful objectives of this proposal.

Our study design applies a multi-dimensional approach to address critical unanswered questions related to the limited efficacy of bladder cancer immunotherapy. We will use preclinical models and clinical trial specimens to study specific populations of white blood cells of the human immune system (myeloid cells) that suppress antitumor immunity and block tumor clearance by the immune system. We will explore tumor and immune proteins that control myeloid cell function. We will use unique murine models of bladder cancer to explore the function of these proteins and, importantly, to test better therapies with the near-term goal of translating them into the clinic where they can benefit patients. Finally, our innovative study integrates artificial intelligence algorithms to build computational tools to aid clinicians and scientists in selecting the best tailored treatment approaches.

This proposal addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of bladder cancer (fourth most common cancer diagnosed in the VA Health System) and immunotherapy and FY19 PRCRP Military Health Focus Areas by addressing gaps in bladder cancer diagnosis, prognosis, and treatment that may impact mission readiness and the health and well-being of military members. By improving our ability to tailor immunotherapy, this research will accelerate the movement of promising ideas related to prognosis, treatment, and survivorship directly towards clinical applications with immediate impact for military members and the general public.

Effective start/end date1/1/19 → …


  • Congressionally Directed Medical Research Programs: $623,580.00


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