Chimeric antigen receptor (CAR) T cells are a promising strategy in treating single antigen cancers, like acute lymphoblastic leukemia. However, treating solid tumors remains a challenge due to tumor heterogeneity. By using synthetic Notch (synNotch) receptors in combination with CAR, T cells can be engineered to identify heterogeneous tumors using multi-antigen sensing. Mouse T cells were engineered to express synNotch receptors specific to myelin oligodendrocyte glycoproteins (MOG) and chimeric antigen receptors specific to epidermal growth factor receptors (EGFR). Co-culture assays were used to assess synNotch activation, induced CAR expression, and anti-tumor activity of synNotch-CAR T cells. SynNotch-CAR T cells significantly cleared cancer cells expressing EGFR when MOG was present, demonstrating the functionality of combinatorial antigen sensing in T cell therapy. Even more so, synNotch-CAR T cells did not kill EGFR-expressing cells when MOG was absent, indicating the ability of these T cells to avoid off-target toxicity. These findings will inform future in vivo studies using syngeneic mouse models and nod to the clinical impact of synNotch-CAR T cells as a favorable treatment for solid tumors.