Derepression of Human Endogenous Retrovirus and Implications for Immunotherapy for Clear Cell Renal Cell Carcinoma
Abstract
The American Cancer Society predicts that 76,080 new cases of kidney cancer will be diagnosed in the United States in 2021 and that approximately 13,780 patients will die from the disease. Most of these deaths will be the result of metastatic spread to distant organs. Seventy percent of kidney cancers are categorized as clear cell renal cell carcinomas (ccRCC) and over 90% of ccRCCs contain a defective (mutated) version of the VHL gene. Therefore, developing therapies to target kidney cancers with faulty VHL function is of great interest. If successful, this could impact over 40,000 patients annually in the U.S. alone. Immunotherapy has contributed greatly to kidney cancer management. Historically, cytokines, which are small proteins that boost immune system in a general way, have been used to treat advance stage disease. However, the side-effects are too serious for most patients to bear, and only 10%-15% of patients benefit from such therapies. In the past decade, scientists developed more sophisticated therapies to boost a patient s own immune system in a specific way to more efficiently recognize and destroy cancer cells. One example is drugs called immune checkpoint inhibitors (such as antibodies that bind to proteins PD-L1 and CTLA-4 on tumor cells). However, less than 50% of the patients respond to such therapies and we do not have molecular tools to predict which patients will respond. More recently, another form of immunotherapy has been developed in which patient immune cells (specifically T cells) can be engineered in the laboratory to produce a receptor on their cell surface (chimeric antigen receptor, or CAR, for short) that will bind to a specific protein (antigen) on the surface of the cancer cell. The binding of CAR to the antigen causes the T cell to kill the cancer cell. CAR-T cell therapy has achieved great success in blood cancers but has failed in solid tumors, partly because we have not identified suitable antigens that are expressed specifically on solid tumor cells but not on normal cells. The goal of my proposal is to identify such ccRCC-specific antigens that could form the basis for new CAR-T cell therapies. In one clinical trial, certain immune cells from family members were given to ccRCC patients to help combat their cancer. In one patient who achieved complete response to such therapy, researchers identified T cells that recognized an antigen derived from one human endogenous retrovirus (hERV) and that killed the patient s ccRCC cells efficiently. hERVs are remnants of exogenous retroviruses that were integrated into human genome millions of years ago. They are silenced in normal tissues and sometimes aberrantly expressed in cancer cells, as was true in this case. There is currently a phase 1 clinical trial using engineered T cells to recognize this particular hERV. This is a great example of one normally silenced hERV being expressed specifically in ccRCC due to VHL inactivation. The expressed hERV-derived protein fragment (peptide) allows a patient s cytotoxic T cells to recognize and destroy tumor cells and leave normal tissues untouched. There are believed to be about 3,000 hERVs in the genome, which is a great reservoir for tumor-specific antigen discovery. Therefore, I propose to systematically understand which of these 3,000 hERVs are highly expressed in VHL-inactivated ccRCCs but silenced in VHL-competent normal tissues. Many hERVs have been so damaged over the course of evolution that they no longer can give rise to proteins, which is required if they are going to serve as antigens. I will systematically look for hERVs that are not only active when VHL is inactive but also can give rise to peptides. Then I aim to discover which hERV-derived peptides that are specific to ccRCCs are presented by cancer cells and are reactive with T cells. The next step is to engineer T cells to recognize such hERV-derived peptides to achieve high efficiency and specif
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210096
Entities
People
- Qinqin Jiang
Organizations
- Dana–Farber Cancer Institute
- United States Army