B7-H3-Specific Chimeric Antigen Receptor (CAR) T-Cell Immunotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC)
Abstract
Metastatic triple-negative breast cancer (mTNBC) is an aggressive type of breast cancer for which no effective therapy is currently available. This has prompted us to develop a strategy that can potentially eliminate mortality associated with mTNBC. We will use the immune system to target mTNBC cells. An important job of the immune system is to attack and destroy abnormal cells in our bodies. Some abnormal cells are able to escape from being recognized by the immune system and cancers develop. T cells are white blood cells that are part of the immune system that can identify and attack abnormal cells. Recent advances in cancer treatments are using the immune system T cells to attack cancers. We are developing a new way to attack breast cancer cells by modifying a person’s own immune system T cells to re-direct them to specifically kill mTNBC cells. The modified T cells can recognize a tumor antigen called B7-H3 that is found on most TNBC cells. An antigen is a substance on a cell that can be the target of an immune system response. The modified T cell therapy is referred to as “B7-H3.CAR.deltaEGFR T cell-based therapy.” The strategy we have designed aims not only to eradicate tumor cells, but also to be safe and well tolerated by patients with mTNBC. To this end, we have carefully selected as a target for the modified T cells a tumor antigen (B7-H3), which has minimal, if any, expression in normal tissues. This will minimize the chance of side effects due to the T cells attacking normal tissues. To prove this hypothesis, we are going to analyze cells from normal tissues and test them for their susceptibility to recognition by B7-H3.CAR.deltaEGFR T cells. The results of these experiments will provide additional evidence that the therapeutic strategy we have developed is likely to be safe in patients with mTNBC. Furthermore, in order to manage any potentially serious side effects, we have incorporated a safety switch in the modified T cells. The safety switch is a special gene in the modified T cells that will allow us to turn off the therapy if the CAR T cells proliferate in an abnormal way. Therefore, this strategy poses minimal risks for patients treated on our clinical trial. In this proposal, we will first confirm that B7-H3.CAR.deltaEGFR T cells have no detectable effect(s) on normal cells but eliminate TNBC cells. Moreover, we will validate our strategy with B7-H3.CAR.deltaEGFR T cells by performing in vitro co-culture studies under hypoxic conditions to mimic the tumor environment and by utilizing a clinically relevant mouse model. Then we will demonstrate that the safety switch gene works to turn off the therapy when prompted. Next, we will show we can manufacture the B7-H3.CAR.deltaEGFR T cells following Good Manufacturing Practice (GMP). GMP compliance follows the guidelines of agencies that regulate products for patient use to ensure they are made as safe as possible to use in humans. Finally, we will test the treatment in patients with mTNBC in a Phase 1 clinical trial. In the clinical trial, B7-H3.CAR.deltaEGFR T cells will be developed for each individual patient using their own blood samples. The purpose of the clinical trial is to determine the safe dosage of the B7-H3.CAR.deltaEGFR T cells administered to patients with mTNBC. We expect that our strategy utilizing B7-H3.CAR.deltaEGFR T cells is both safe and effective for patients with mTNBC. This should result in a major improvement in the outcomes of people with mTNBC and help to eliminate the mortality associated with this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010316
Entities
People
- Marcela V. Maus
Organizations
- Massachusetts General Hospital
- United States Army