Trending topics and news in HCT and Cellular Therapy

Allogeneic Double-Negative T-Cell Therapy for Acute Myeloid Leukemia

In a review, published in Current Opinion in Pharmacology, researchers from the University of California, Los Angeles and their collaborators highlight CD3⁺CD4⁻CD8⁻ double-negative T cells (DNTs) as a promising off-the-shelf cellular therapy for acute myeloid leukemia (AML). This review highlights the potent anti-leukemic effects of allogeneic DNTs, their ability to avoid graft-versus-host disease (GVHD), and their synergy with existing AML therapies. DNTs have shown success both in preclinical studies and early clinical trials, suggesting they may fill a critical gap for patients with relapsed or refractory AML who are ineligible for intensive treatments like allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The rationale for DNT therapy stems from their unique immune profile: they lack both CD4 and CD8 co-receptors and do not express markers typical of NK or MAIT cells. These cells naturally exhibit antigen-independent cytotoxicity and can be expanded ex vivo from healthy donors using anti-CD3, IL-2, and the PI3Kδ inhibitor idelalisib. DNTs attack AML cells via perforin/granzyme-mediated mechanisms, and their activity is enhanced by cytokines like TNFα and IFNγ, which upregulate ligands such as NKG2D and ICAM-1 on AML targets. Importantly, they do not trigger GVHD and demonstrate persistence after infusion. A first-in-human phase I trial showed that infusions of allogeneic DNTs were well tolerated with no GVHD or neurotoxicity and produced complete remission in five of ten AML patients, four of whom remain in remission after three years.

DNTs also enhance the efficacy of chemotherapy and molecular-targeted agents like azacitidine and venetoclax, and they may potentiate graft-versus-leukemia effects post-transplant. Notably, CAR-DNTs have shown enhanced cytotoxicity in preclinical models and are emerging as safer alternatives to traditional CAR-T cells, particularly in patients who relapse after allo-HSCT. In a separate phase I trial of CAR19-DNTs for lymphoma, no severe immune toxicities were observed, and all patients at the highest dose responded. Furthermore, long-term remissions in other CAR-T trials have been associated with the persistence of CAR-expressing DNTs, suggesting these cells may drive durable outcomes. Taken together, DNTs represent a versatile, non-toxic and clinically scalable platform for AML immunotherapy, warranting further clinical investigation in larger trials.

Reference:

Tin E, Lee J, Zhang L. Allogeneic double-negative T-cell therapy for acute myeloid leukemia. Curr Opin Pharmacol. Published online May 10, 2025.

http://doi.org/10.1016/j.coph.2025.102537