Background: Efficacy of chimeric antigen receptor T cells (CAR-T) is dependent on their in vivo survival and expansion following adoptive transfer. Here, we show that constitutive expression of the MyD88/CD40 (MC) fusion protein dramatically enhances CAR-T proliferation resulting in improved antitumor efficacy against Her2⁺ solid tumors. Importantly, CAR-T cell levels and cytokine-related toxicity can be controlled by graduated administration of rimiducid to activate the inducible iCaspase-9 (iC9) suicide gene without detriment to tumor control. Methods: T cells were modified with a tricistronic retrovirus encoding iC9, a Her2-specific CAR (Her2.ζ) and constitutively active MC (iC9-Her2.ζ-MC), or control vectors (iC9-Her2.ζ and iC9-Her2.CD28.ζ) and compared for cytotoxicity, cytokine production and proliferation in coculture assays against Her2⁺ breast (SK-BR-3), ovarian (A2780, SKOV-3), gastric (N87, Kato III, SNU-1) and pancreatic (HPAC) cancer cell lines. CAR-T efficacy was assessed in NSG mice engrafted with tumor cell lines followed by i.t. or i.v. injection of T cells. Rimiducid was given i.p. at 0.5 mg/kg. Results: Her2-redirected T cells showed that in vitro, MC costimulation resulted in increased IL-2 production ( > 65-fold compared to iC9-Her2.CD28.ζ) which corresponded to enhanced proliferation and tumor elimination. In tumor xenograft models, iC9-Her2.ζ-MC CAR-T cells were more effective at eliminating large Her2⁺ tumors compared to conventional CAR-T constructs (Her2.ζ and Her2.28.ζ). Bioluminescent imaging also showed robust engraftment and proliferation of CAR-T cells co-expressing MC. Importantly, cytokine-related toxicity could be completely resolved while maintaining anti-tumor efficacy by partial elimination of iC9-Her2.ζ-MC CAR-T cells through systemic administration of rimiducid. Conclusions: MC represents a broadly applicable, potent T cell costimulatory signaling molecule in CAR-T cells, resulting in higher IL-2 production, improved survival and greater proliferative capacity. CARs containing MC demonstrate enhanced efficacy in vivo while retaining the safety profile through the iC9 suicide gene.