Project Summary Solid tumors are the most common cause of cancer death in the United States. Chimeric antigen receptor (CAR) T cells have revolutionized the care of relapsed and refractory B cell malignancies but have not yet mediated substantial benefit for patients with solid tumors. CARs redirect the powerful anti-tumor activity of a T cell against a tumor cell by targeting an antigen expressed on its surface. In solid cancers, most target antigens are shared with normal, vital tissues, and therefore CARs can mediate dangerous and potentially fatal toxicity. This has prevented widespread application of CAR T cells to solid tumors. The current generation of CAR T cells is unable to differentiate between tumor tissue and normal tissue largely because they rely on a single input/single output system that activates whenever the T cell finds its target. We have generated a novel mechanism to direct the CAR T cell response only when multiple antigens are present, greatly enhancing our ability to generate a programmed immunotherapeutic response against solid tumors. Optimization and application of this platform will greatly enhance the number of potential targets for CAR T cells, a paradigm shifting technology poised to mediate significant clinical benefit for patients with solid tumors. This strategy will also prove essential to effectively use CAR T cells to treat other cancers, such as myeloid malignancies, and diseases as diverse as autoimmunity and fibrosis. The novel system proposed here has the potential to redefine the landscape for programmable cellular therapies.

Project Narrative Solid tumors are responsible for the majority of cancer deaths in the United States. Researchers have been unable to widely employ CAR T cells, an effective form of cancer immunotherapy, to solid tumors due to a lack of tumor specific antigen targets and the risk of toxicity when target antigens are shared with normal, vital tissues. This project will optimize innovative and completely novel receptors capable of logic-gated control of CAR T cells, greatly enhancing their safety and tumor specificity, opening the door to effective therapy of solid tumors.