Vα24-invariant Natural Killer T cells (NKTs) preferentially localize to the tumor site in neuroblastoma and other types of cancer and have natural antitumor properties that make them attractive as a carrier of tumor-specific chimeric antigen receptors (CARs). We previously demonstrated that adoptively transferred NKTs expressing GD2-specific CARs (CAR.GD2) can effectively localize to the tumor site and mediate antitumor activity in a xenogenic model of neuroblastoma in NSG mice. In this study, we explored whether expression of IL-15, the main homeostatic cytokine for NKTs, within CAR.GD2 would further enhance NKT-cell in vivo persistence and therapeutic efficacy. So, we synthesized CAR.GD2 constructs with a costimulatory CD28 or 41BB endodomain with or without IL-15. NKTs that were transduced with CD28/IL-15 and 41BB/IL-15 CARs secreted similar levels of IL-15 and significantly improved NKT-cell in vitro expansion compared with IL-15-less CARs in response to repeated stimulation with neuroblastoma cells. After transfer to NSG mice with human neuroblastoma xenografts, NKTs expressing IL-15-containing CARs persisted significantly longer compared with those expressing IL-15-less CARs. NKTs expressing CD28/IL-15 CAR underwent a progressive in vivo expansion at the sites of neuroblastoma metastases. Indeed, the frequency of CD28/IL-15 CAR NKTs reached 30% of bone marrow cells two months after a single injection. Nonetheless, human NKTs did not accumulate in normal murine tissues and did not induce xeno-GvHD. Treatment with CD28/IL-15 CAR NKTs on day 7 after tumor injection resulted in the median survival of 70 days compared to the range of 42 - 53 days in untreated control and groups treated with unmodified NKTs or NKTs expressing other CAR.GD2 constructs (P < 0.001). Thus, a combined use of CD28 costimulatory endodomain and IL-15 in the CAR design enables potent in vivo expansion and anti-tumor activity of CAR.GD2 NKTs cells that should be considered for immunotherapy of neuroblastoma and other solid tumors.