Kidney cancer affects nearly 75,000 people each year in the United States, and is especially common among Veterans. Advanced kidney cancer, which generally cannot be cured by surgery, is responsible for nearly 15,000 deaths each year in the United States alone. More recently, a new type of therapy called "immune checkpoint inhibition" has become the new standard treatment for patients with advanced kidney cancer. These drugs work by "cutting the brakes" on the immune system, allowing a patient's own immune system to recognize and eliminate kidney cancer cells in the body. While these medications have helped many people with advanced kidney cancer, unfortunately for most patients, the therapy either stops working or never works from the beginning. Therefore, key challenges include (1) understanding why these treatments work for some patients but not for others, and (2) designing new types of treatments to "steer" the immune toward the tumor, to help patients who are not currently benefitting from immune checkpoint inhibition. I believe that a better understanding of how immune cells recognize kidney cancer will help to address these important questions.

My prior training in immunology (to understand how immune checkpoint inhibition works), genomic medicine (to understand what changes or "mutations" occur in a tumor, and how those changes might be a target for the immune system), and clinical oncology (to evaluate and treat patients with kidney cancer) enables me to begin to answer these fundamental questions. My career goal is to lead my own laboratory focused on better understanding kidney cancer, and developing new types of treatments that harness the immune system to attack kidney cancer cells. I would also like to continue to treat patients with kidney cancer, learning about the most important questions directly from patients, addressing those questions in the laboratory, and ultimately using that knowledge to improve the lives of patients with the disease. My proposed research study and career development plan will allow me to learn important scientific skills and build a network of collaborators (doctors, scientists, and patients) that will be needed for me to achieve these goals. Further, through my participation in the Academy of Kidney Cancer Investigators (AKCI), I hope to learn from both experienced kidney cancer researchers and next-generation innovators. I also hope to contribute my own ideas and experience in immunology, new scientific technologies, clinical trial design, and clinical oncology toward the growth of the AKCI.

Together with a collaborative team, I plan to use novel scientific tools to investigate how the immune system recognizes and kills cancer cells in patients with advanced kidney cancer who are treated with immune checkpoint inhibition (and specifically, drugs that target and "cut" a particular immune system brake, called PD-1). I plan to first identify the targets on tumor cells (also called "antigens"), i.e., the elements of a kidney cancer cell that can be recognized by the immune system. I will then determine whether the immune cells that can get into a tumor are actually capable of recognizing and acting on these antigens. Finally, using larger groups of tumors from patients in clinical trials, I will examine whether any of the identified tumor antigens, or specific types of immune cells found in a tumor, are associated with a better response to immune checkpoint inhibition (i.e., does it help patients to live longer).

This work will contribute to our knowledge of how the immune system effectively recognizes and eliminates kidney cancer. This information will be most important for patients with advanced kidney cancer (and particularly the most common subtype, clear cell kidney cancer), who are mostly treated with immune checkpoint inhibition as part of their initial therapy. By the end of the grant period, this project can help understand why some tumors are resistant (i.e., do not shrink) to these standard therapies. This information will be helpful even in the short term, as it could help match the right treatment to the right patient by identifying which tumors are likely or unlikely to respond to immune checkpoint inhibition.

Importantly, I hope to utilize the findings of this study to help design new types of immune-based therapies for advanced kidney cancer that are designed to specifically attack the identified tumor antigens. I am already heavily involved in a first-in-disease personalized vaccine clinical trial in kidney cancer that attempts to steer the immune system to target patient-specific cancer mutations. With this prior experience, and with the identification of new tumor antigens, I would aim to rapidly translate the findings of this current study into clinical trials. Overall, the results of this project will have direct implications on the design of future kidney cancer clinical trials that will investigate novel, antigen-targeting therapies.