NY-ESO-1-specific TCR-engineered T cell immunotherapy for triple negative breast cancer
Abstract
Breast cancer is a major cause of death among women in the United States. This research proposal will focus on triple-negative breast cancer (TNBC) with the overarching challenge of eliminating mortality associated with metastatic breast cancer. TNBC is the most aggressive and difficult to treat subtype of metastatic breast cancer, with very limited treatment option due to lack of expression of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). The only option available for TNBC patients is chemotherapy, but it results in systemic side effects and ultimately relapses and death. Despite recent Food and Drug Administration approval of immunotherapy-based drugs ipilimumab (Yervoy) and more recently the programmed cell death (PD)-1 antibody, immunotherapy for TNBC is still lacking. Therefore, development of immunotherapy is urgently needed for the treatment of metastatic breast cancer. Cancer immunotherapy was named as "Breakthrough of the Year for 2013" by Science magazine. The rationale for cancer immunotherapy is to use and educate a patient s own immune cells to attack tumors. Tumor cells have cancer-specific antigens, which can be recognized by immune cells on cancer cells. Most cancer antigens are not specific and can be found in both cancer and normal tissues. One tumor antigen, NY-ESO-1, is highly specific and expressed in 30% of tumors from TNBC patients. NY-ESO-1 is expressed in cancer cells, but not in normal tissue, except testis. Therefore, this tumor antigen can be therapeutically targeted for immunotherapy with no toxic effects. The clinical applications of the proposal are that a patient s own immune cells will be engineered to express NY-ESO-1-specific T cell receptors (TCR), which mediate specific recognition of NY-ESO-1 on breast cancer cells, particularly on TNBCs. Recent clinical studies show that treatment of patients with immune cells with NY-ESO-1 TCR-engineered T cells has produced 55%-80% clinical response in metastatic synovial sarcoma, melanoma, and myeloma without any toxicity. However, it is unclear whether such immunotherapy is safe and effective in TNBC patients, and remains to be determined. The goals of this project are to develop therapeutic immunotherapy for TNBC patients using TCR-engineered T cells. Our central hypothesis is that treatment of TNBC patients with NY-ESO-1-transduced T cells is safe and will result in tumor regression and clinical benefits. We have been working on NY-ESO-1 and its development for cancer vaccines and immunotherapy for more than 15 years. Our recent studies demonstrate that T cell trafficking and persistence can be modulated through knockdown of specific regulatory proteins as well as T helper cells, a subset of immune cells. Because the clinical benefits of patients are correlated with the persistence and trafficking of NY-ESO-1-engineered T cells to tumor sites, we will determine whether antitumor immunity will be enhanced by improving immune cell trafficking to tumor sites and persistence within the tumor through genetic modification of immune cells (Aim 1). We will further improve antitumor immunity NY-ESO-1 TCR-engineered T cells by overcoming immune suppression in the tumor microenvironment and assess the potential toxicity associated with these modified T cells (Aim 2). Finally, we will test the safety and efficacy of NY-ESO-1 TCR immunotherapy in a Phase I clinical trial for a small number of TNBC patients (Aim 3), in collaboration with Dr. Chang and her clinical team. In this Phase I clinical trial, we will monitor the safety profile of TNBC patients after NY-ESO-1 TCR immunotherapy and evaluate clinical benefits, including partial and complete clinical response, and improvement of life quality and patient survival. Although it is safe and unlikely to observe severe toxicity, based on clinical trials of NY-ESO-1 TCR-engineered T cells in other cancer types, precaution m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610417
Entities
People
- Rongfu Wang
Organizations
- Houston Methodist Research Institute
- United States Army