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Project

The Mechanism of Antitumor Immunity Induced by BCG Therapy for Bladder Cancer

Funder: Congressionally Directed Medical Research Programs

Funding period
USD 189 K
Funding amount
Abstract
PUBLIC ABSTRACT

My ultimate career goal as a cancer researcher is to become a faculty member and establish my own laboratory at a leading university or cancer research institute. The broad objectives of my research, both within this proposal and beyond into my career as an independent researcher, are to discover effective methods of harnessing the immune system to fight cancer. Immunotherapies have significant advantages over conventional chemotherapies in that they harness a patient's own immune cells to target their tumor specifically, rather than non-discriminately destroying all dividing cells, as is the case with most chemotherapies. Furthermore, immunotherapies can endow the immune system with specific memory of a tumor, allowing immune cells to seek and destroy tumor cells systemically, such as those that have metastasized to parts of the body far from the primary tumor, and often preventing their recurrence. The Horizon Award will advance my career as an independent cancer researcher by affording me my own funding to study the interactions of the immune system and a tumor through my work on BCG therapy for bladder cancer. BCG therapy is a well-established and widely successful immunotherapy for bladder cancer, however the specific mechanism by which BCG creates an immune response to bladder tumors remains unknown. The Horizon Award will allow me to pursue experiments that have the potential to make significant discoveries in this field. My goals under the Horizon Award are further supported by my researcher development plan, which includes mentoring from world-renowned cancer researchers, weekly seminars in immunology and cancer biology by experts from Memorial Sloan Kettering and outside institutions, and frequent hands-on opportunities to learn new and cutting-edge skills from experts in those techniques.



Having established that BCG therapy causes T cells to specifically target bladder tumor cells, and that tumor cells respond to interferon gamma stimulation by signaling through the transcription factor CIITA and ultimately expressing MHC Class II (a molecule capable of activating CD4 T cells), the scientific objectives of this research are to determine the ways in which BCG creates and enhances a T cell-mediated, tumor-specific immune response, and to shed new light on the positive and negative signals that are exchanged between T cells and tumor cells. The rationale underlying this proposal is that once completed, this work will provide a more complete understanding of the mechanism of BCG therapy for bladder cancer, enabling improvements for nonresponding bladder cancer patients, and providing a reference for the design and improvement of immunotherapies for other types of cancer based on what is learned.

The research proposed in this study has broad applicability to the field of tumor immunology and to the development of new tumor immunotherapies in that it aims to uncover the mechanisms of an immunotherapy that is already well established and highly successful in treating human cancer. With this in mind, the clinical risks resulting from these studies are minimal. At the conclusion of this work, we will be poised to exploit this knowledge to improve patient responses to the therapy for bladder cancer, most prominently to the benefit of non-responding patients, to minimize the side effects of BCG therapy, and to apply components of this knowledge to studies of other types of cancer. Furthermore, understanding the requirements for a successful response to BCG therapy at the level of both the tumor and the patient's immune system will potentially allow us to identify patients that are unlikely to respond to therapy in advance, and thus prescribe alternate methods of treatment better suited to their disease.



Bladder cancer is the 9th most common cancer in the United States. It affects predominantly males, and risk factors include exposure to radiation and chemicals, and smoking. Among these risk factors, smoking alone affects approximately 25% of all military personnel, but is even more prevalent in young Veterans, affecting 40% of those born between 1985 and 1989. Although more up-to-date statistics are not available, in 2007 bladder cancer comprised 3.6% of all cancers reported by the Department of Veterans Affairs, and in the United States more generally, estimates indicate 81,190 new cases of bladder cancer in 2018, in addition to 17,240 deaths. Despite its success over decades of clinical use, there remains a critical need to define the mechanism of BCG therapy in order to improve quality of life for non-responding patients, many of whom are service members forced to undergo cystectomy and endure the substantial financial burden of life-long care.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Immunization

  • RCDC

    Urologic Diseases

  • RCDC

    Vaccine Related

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical