Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in treating hematologic malignancies; however, its efficacy against solid tumors remains limited. Preclinical studies suggest that Vα24-invariant natural killer T (NKT) cells may offer advantages over conventional T cells for cell-based cancer immunotherapy. NKTs exhibit enhanced tumor trafficking, the ability to eliminate or reprogram tumor-associated macrophages and other immunosuppressive myeloid cells, and the capacity to activate NK cells and prime tumor-specific CD8⁺ T cell responses. To harness these properties for clinical application, we developed cGMP-compliant methods for large-scale manufacturing of CAR-NKT cells and launched two clinical trials: one in children with neuroblastoma (NCT03294954) and another in patients with B cell malignancies (NCT03774654). Notably, the latter trial uses an allogeneic (off-the-shelf) product, taking advantage of the non-alloreactive nature of NKT cells, an attribute that in T cells typically requires HLA matching or genetic engineering. In this presentation, I will share results from both trials, focusing on safety and antitumor activity. I will also highlight laboratory correlates of response that provide insights into human NKT cell biology and inform the development of next-generation NKT-based therapies for cancer and other diseases.