TCR-Engineered T-Cell Immunotherapy for Epithelial Ovarian Cancer Enhanced by TGFbeta Blockade and Epigenetic Modulation
Abstract
Patients with epithelial ovarian cancer (EOC) in advanced stage, and with tumors that have become resistant to chemotherapeutic drugs, have few treatment options that can provide durable clinical responses. Therefore, new treatment modalities to help those patients are much needed and this is the focus of this grant proposal. Recently, many novel treatments based on immunotherapy, the use of the immune system to specifically attack cancer cells, have been in development with very promising initial results. Indeed, immunotherapy is the only known modality that can provide long-term survival of, and even cure in some cases, patients with advanced metastatic cancer, though the number of patients that respond is relatively low. One of the well-studied reasons that explains this low number of responses is that the tumor, including ovarian cancer, can produce factors that suppress or inhibit the immune system, so when the immune cells (such as T lymphocytes, also called T cells) go to attack the cancer cells, they encounter these suppressive factors in the tumor environment and cannot work efficiently to eradicate the tumor. One very important factor is TGFbeta. Our hypothesis is that blocking TGFbeta in the context of treatment that involves injection of "genetically engineered" immune T cells will render these T cells resistant to the negative effects of TGFbeta and therefore more capable of seeking and attacking cancer cells. We propose to "genetically engineer" these T cells by inserting genes that efficiently block the effect of TGFbeta along with a gene (T-Cell Receptor [TCR]) that can specifically recognize proteins that are expressed only in ovarian cancer cells and not in normal, non-cancer cells in adults. We will also add an epigenetic regulator drug (called decitabine) that can efficiently increase the expression of these specific proteins that will serve as targets by the TCR. In summary, this is a very innovative approach that combines multiple strategies to make this immunotherapy a very powerful modality against ovarian cancer. We will open a clinical trial to test the efficacy of these engineered T cells and we will analyze blood samples, tumor biopsies, and other tissues to look for the precise mechanisms of the responses by various immunological lab assays. Through our background experience in engineered T cell clinical trials, we learned that a critical issue is the lack of long-term specific T cell persistence and function. This present proposal will directly address this problem and provide a promising new and efficacious way to treat patients with ovarian cancer, which affects many in the military and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810300
Entities
People
- Richard Koya
Organizations
- United States Army