Chimeric Antigen Receptor (CAR) T cell therapy has shown promise in treating hematological cancers but faces challenges in solid tumors, particularly in expanding and persisting in the periphery. To address this, we designed a dual-targeted CAR T cell against peripheral B cells (anti-CD19) and solid tumor antigen (anti-mesothelin, MSLN) to maintain MSLN CAR T cell persistence and increase anti-tumor efficacy. We first assessed our technology in immunocompetent C57BL/6 mice where we established two syngeneic flank tumor models of pancreatic ductal adenocarcinoma (PDAC), ranging in immunogenicity, as well as an additional melanoma model. Ultimately, we find enhanced B cell driven expansion in the blood, increased anti-tumor efficacy, and higher levels of early activation without increasing downstream dysfunction or toxicity compared to single CAR T cells. We have also identified the importance of B cell driven responses and alternative mechanisms of trafficking, likely owing to antigen engagement in the spleen. To translate our findings into human CAR T cells in NOD scid gamma (NSG) mice, we developed two novel models for CD19⁺ B cells in the periphery through donor matched T cells transduced with truncated CD19 antigen (T-APCs) or B cell expansion. Our findings suggest that CD19⁺ B cells, as opposed to our T-APC model, uniquely enhances dual CAR T cell efficacy in PDAC xenograft models, highlighting the importance of B cell costimulation during CAR T cell activation. In our immunocompetent models, dual CAR T cells were also able to induce B cell aplasia without the need for lymphodepletion, underscoring its potential applications in autoimmunity where lymphodepletion remains an even greater therapeutic hurdle. Together our work suggests that dual-targeted CAR T cells are a successful strategy to enhance CAR T cell expansion and anti-tumor efficacy while uncovering unanticipated mechanistic applications in cancer and beyond.