Therapeutic Activation of Immunogenic Cell Death to Improve Immunotherapy for Kidney Cancer
Abstract
Despite recent advances in kidney cancer treatment, kidney cancer remains the eighth most common cancer with ~63,000 new cases and ~14,000 fatalities each year in the United States alone, devastating patients, their families, and friends, and communities, among whom many are current or former military personnel. Renal cell carcinoma (RCC) accounts for > 90% of cancers detected in the kidney, encompassing a large heterogeneous group of cancers derived from renal tubular epithelial cells. RCC is highly heterogeneous in many aspects, including subtypes, inter-tumors, intra-tumors, and clinical outcomes. Clear cell renal cell carcinoma (ccRCC) is the most common (70%-75% of kidney cancer) and aggressive subtype of renal cell carcinoma. In fact, metastatic ccRCC accounts for most of the kidney cancer mortality. Although metastatic ccRCC is refractory to conventional chemotherapy, marked therapeutic advances have been made over the past 15 years. The recent approvals of immune checkpoint inhibitors (a type of immunotherapy) for ccRCC have revolutionized kidney cancer care. These drugs are thought to work through activating the body s own immune cells, especially cytotoxic T lymphocytes, which then recognize and kill tumor cells. Remarkably, ~30% of ccRCC patients have a partial response to immune checkpoint inhibitors, among whom ~10% have a complete remission. However, this exceptional clinical outcome is rare and comes with life-threatening toxicities. Hence, it is of paramount importance to develop novel strategies to enhance the response to immune checkpoint inhibitors and make more patients benefit from immunotherapy. In this proposal, a team of physicians, cancer biologists, immunologists, computational biologists, and statisticians will work together to address the most critical challenges in kidney cancer immunotherapy, taking advantage of existing expertise in our team and emerging new technologies. Our goal is to improve the immunotherapy of kidney cancer through activation of a specific type of cancer cell death, which can provoke an immune response to dying cells and activate immune cells to attack other viable cancer cells. Activation of this specific type of cell death can enhance the sensitivity of cancer cells to immunotherapy and generate long-term antitumor immunity against tumor recurrence. To this end, we have performed comprehensive screenings of more than 1,000 drugs and identified several promising drugs that can activate this specific type of cell death in kidney cancer. We plan to test these drugs in mouse models of kidney cancer to demonstrate their abilities to enhance and improve immunotherapy for kidney cancer. Notably, the drugs we identified either have U.S. Food and Drug Administration approvals or are entering clinical trials. Hence, our study can be translated into clinics immediately, which will transform the treatment of kidney cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210835
Entities
People
- Emily Cheng
Organizations
- Sloan-Kettering Institute
- United States Army