CAR-NK and CAR-NKT Cell Therapies Show Promise Across Multiple Cancer Types

Three recent studies highlight advances in chimeric antigen receptor (CAR)-engineered natural killer (NK) and natural killer T (NKT) cell therapies, with findings spanning a phase II clinical trial in B-cell non-Hodgkin lymphoma, preclinical models of endometrial cancer, and laboratory optimization of costimulatory domains in CAR-NK cells.

Results from a phase II, open-label, multicenter study (NCT05020015) evaluating single-dose TAK-007, a cryopreserved, allogeneic, cord blood-derived, off-the-shelf CD19-directed CAR-NK cell therapy expressing interleukin-15 (IL-15), in heavily pretreated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) were published in Blood Cancer Discovery. The primary objectives were to determine the safety, tolerability, and recommended phase II dose (RP2D). The RP2D was 800 × 10⁶ CD19-directed CAR+ viable NK cells. In the safety population (N = 26), Grade ≥3 treatment-emergent adverse events occurred in 92.3%, most commonly neutropenia (73.1%), leukopenia (50.0%), anemia (38.5%), and thrombocytopenia (38.5%). No dose-limiting toxicities, graft-versus-host disease (GvHD), or TAK-007-related immune effector cell-associated neurotoxicity syndrome occurred; TAK-007-related cytokine release syndrome was limited to Grade 1–2 (11.5%). Across the 800 × 10⁶ dose escalation and expansion cohorts, the overall response rate (ORR) was 60.9% (complete response, 34.7%; partial response, 26.1%); the ORR was 50.0% in large B-cell lymphoma and 77.8% in indolent NHL. Median progression-free survival was 2.0 months in large B-cell lymphoma and 5.6 months in indolent NHL. Circulating tumor DNA-negative responses were achieved in five patients. TAK-007 demonstrated a manageable safety profile and preliminary activity in heavily pretreated R/R B-cell NHL; further studies are needed to optimize outcomes by refining manufacturing protocols.

In a separate preclinical study, researchers at UCLA developed a CAR-NKT cell therapy that eliminated tumors in models of endometrial cancer. The study, published in Experimental Hematology & Oncology, found that CAR-NKT cell therapy outperformed existing immunotherapies in targeting and destroying endometrial cancer cells, particularly in aggressive subtypes. Endometrial cancer is the most common gynecologic cancer in the United States, and survival rates have declined over recent decades. Aggressive forms such as uterine papillary serous carcinoma represent about 10% of diagnoses but account for nearly 40% of deaths. The investigational therapy uses invariant natural killer T cells engineered with a chimeric antigen receptor targeting mesothelin, a protein found on endometrial cancer cells. These CAR-NKT cells are designed to detect and destroy tumors through three simultaneous pathways, unlike conventional CAR-T cell therapies that rely on a single recognition mechanism. In mouse models, the therapy achieved complete tumor elimination and prolonged survival, whereas conventional CAR-T cells provided only partial and temporary tumor control before the cancer returned. Additional testing in patient tumor samples and patient-derived tumor cell lines supported these findings. The CAR-NKT therapy demonstrated stronger cancer-killing activity than current immunotherapy approaches, including in difficult-to-treat forms such as uterine papillary serous carcinoma. The therapy uses an off-the-shelf platform, with CAR-NKT cells produced from donated blood stem cells in a scalable manufacturing process. Because NKT cells are naturally compatible with different immune systems, a single donation can generate enough cells for thousands of treatments. In preclinical testing, the engineered cells did not trigger graft-versus-host disease. The therapy remains in the preclinical stage and has not yet been tested in humans. Researchers have completed preclinical studies and are preparing to submit applications to the U.S. Food and Drug Administration to begin clinical trials.

Meanwhile, researchers at the Ribeirão Preto Blood Center and the Center for Cell-Based Therapy (CTC) conducted a study using the NK-92 cell line to test new models of CARs with specific costimulatory domains, such as 2B4 and DAP12. The tests showed that these components helped make the cells "ready to attack," thereby increasing their ability to destroy tumors. The results were published in Frontiers in Immunology. The research demonstrates that combining optimized co-stimulation with reversible pharmacological control can enhance the potency and efficiency of CAR-NK therapies. The research also evaluated using the drug dasatinib temporarily to control the activation of these cells. In animal models, CAR-NK cells with 2B4-DAP12, pretreated with dasatinib, showed better tumor control compared to traditional versions.