Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable successes in patients with hematologic malignancies, yet its effectiveness against solid tumors remains limited. Observations in pre-clinical models suggest that Vα24-invariant natural killer T cells (NKTs) may be more effective than conventional T cells for cell-based cancer immunotherapy. Specifically, NKTs traffic more effectively to tumor sites, can kill or reprogram tumor-associated macrophages and other suppressive myeloid cells, activate NK cells, and stimulate tumor-specific CD8 T cells. To take advantage of these properties for clinical applications, we established cGMP-compliant methods to manufacture CAR-NKT cells at clinical scale and initiated two CAR-NKT clinical trials: in children with neuroblastoma (NCT03294954) and in patients with B cell malignancies (NCT03774654). Notably, the latter trial employs an allogeneic (off-the-shelf) product, leveraging the fact that NKT cells are not alloreactive, a characteristic that can be achieved in T cells only through HLA matching or genetic engineering. I will present interim results from both clinical trials, with an emphasis on evaluating safety and antitumor activity. Additionally, I will discuss laboratory correlates of response, which promise to deepen our understanding of human NKT cell biology and pave the way for the development of innovative NKT-based therapeutic approaches for the treatment of cancer and other diseases.