Adoptive Cell Therapy Against Triple-Negative Breast Cancer Using a Novel tMUC1 Antibody-Derived CAR

The project addresses two overarching challenges: (1) Increase the survival rate associated with metastatic triple-negative breast cancer (TNBC). (2) Improve treatment of TNBC by replacing therapies that have life-threatening side effects with ones that are safe and effective. The objective is to design immune therapy that will safely treat patients with TNBC. We will use a novel and exciting technology to engineer T cells (the body's immune cells that fight infections) to target a protein called tumor-specific MUC1 (tMUC1) that is present on 94% of human TNBC cells. tMUC1 is the tumor form of normal MUC1 (nMUC1), which is expressed by all epithelial cells in our body. Therefore, it is imperative to target the tMUC1 specifically, and not the nMUC1. We have developed and patented an antibody that only targets tMUC1 and spares nMUC1. We will use functional fragments of this antibody to engineer the T cells. When injected in the body, these engineered T cells will seek out tMUC1 on TNBC cells, become activated, and kill the tumor cells. This type of targeted therapy has worked in blood cancers very effectively and is now being explored for solid tumors such as TNBC. This is because there are few proteins that can be safely targeted on TNBC cells. TNBC cells do not express Her2 neu, estrogen, or progesterone. Although other antigens on TNBC cells are being explored for targeted therapy, thus far, MUC1 remains the strongest contender. A National Cancer Institute (NCI)-launched pilot project to prioritize cancer antigens to target for immunotherapy ranked MUC1 as the second most optimal target. Although there are other MUC1 antibodies that can be used, these antibodies cannot distinguish tMUC1 from nMUC1 effectively. This is extremely critical, as we do not want to attack normal healthy cells and create a toxic environment. The choice of antibody and target has to be ideal for such a therapy to work. From all the data collected thus far, we believe that we have such a combination of antibody (TAB 004) and target (tMUC1). Our data prove that the fragments of TAB004 are ideally suited for development of CAR-engineered T cells. We propose to study the effectiveness and toxicity of this therapy in several appropriate mouse models that mimic the human disease and have an active immune system. We will also test the therapy on freshly isolated primary human TNBC tumor explants from patients that have chemo-refractory disease. If successful, we will quickly move to the clinic to conduct a pilot study in eligible patients with treatment refractory TNBC. Such therapies have the potential of controlling disease progression, prolonging time to recurrence, and ultimately, even serving as a cure. It must be emphasized that such therapies can be highly toxic if the antibody fragments used to engineer the T cells are not highly specific to the tumor. This project will enable us to evaluate if there are any toxicity issues. If the therapy works, it will revolutionize treatment for patients with TNBC. Impact: We have all the appropriate tools to conduct this study in a very timely fashion. The project is highly translational. Although high risk, if successful, it will be a breakthrough new treatment for patients with treatment refractory TNBC and accelerate progress toward a clinical trial. We have the clinical collaborations and scientific expertise to conduct such a pilot trial.