Haploidentical hematopoietic cell transplantation as a platform for natural killer cell immunotherapy

Abstract An innovative approach is crucially needed to manage relapse after allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematological malignancies. This review explores key aspects of haploidentical HCT with post‐transplant cyclophosphamide, highlighting the potential and suitability of this platform for natural killer (NK) cell immunotherapy. NK cells, known for their unique abilities to eliminate cancer cells, can also exhibit memory‐like features and enhanced cytotoxicity when activated by cytokines. By discussing promising results from clinical trials, the review delves into the recent major advances: donor‐derived NK cells can be expanded ex vivo in large numbers, cytokine activation may enhance NK cell persistence and efficacy in vivo, and post‐HCT NK cell infusion can improve outcomes in high‐risk and/or relapsed myeloid malignancies without increasing the risk of graft‐versus‐host disease, severe cytokine release syndrome, or neurotoxicity. Looking ahead, cytokine‐activated NK cells can be synergized with immunomodulatory agents and/or genetically engineered to enhance their tumor‐targeting specificity, cytotoxicity, and persistence while preventing exhaustion. The ongoing exploration of these strategies holds promising preliminary results and could be rapidly translated into clinical applications for the benefit of the patients.