Project 5: Memory-like NK cell augmented hematopoietic cell transplantation for AML
The long-term goal of this project is to develop novel NK cell-based therapeutic strategies that will lead to clinical benefit for patients with leukemia. Hematopoietic cell transplantation was the first curative cellular immunotherapy for leukemia. These clinical remissions are achieved through immune response by the donor’s immune system, in particular, T cell and natural killer (NK) cells. The aim of this project is to test the ability of functionally-amplified donor NK cells, transferred into the patient, to eliminate leukemia. We identified a highly translatable strategy to induce memory-like natural killer (NK) cells using combined interleukin (IL)-12, IL-15, and IL-18 pre-activation, which results in multiple enhanced anti-leukemia properties. First-in-human phase 1 testing performed at Washington University demonstrated the safety, feasibility, and capability of memory-like NK cell therapy from an MHC-haploidentical donor to induce complete remissions in patients with relapsed or refractory acute myeloid leukemia (AML). Further, donor memory-like NK cells expanded in the patients, trafficked to the bone marrow, and exhibited potent anti-leukemia functions. However, since donor NK cells are foreign cells to the patient (allogeneic), they are eventually rejected by the patient’s immune system, resulting in only a brief 2- to 3-week window of opportunity for the NK cells to eliminate leukemia. To address this barrier of NK cell persistence, we hypothesized that augmenting MHC-haploidentical hematopoietic cell transplantation with same-donor memory-like NK cells would provide an ideal immune compatible environment that would allow for long term memory-like NK cell response. This Project tests this hypothesis in a phase 2 clinical trial of hematopoietic cell transplantation, followed within days by same-donor memory-like NK cell infusion for patients with AML not in remission. The safety, feasibility, and ability to achieve remission and improve leukemia-free survival will be tested in this high-risk subset of AML patients. In addition, cutting-edge immunomonitoring will be used to track memory-like NK cells in patients, and discovery mechanisms of response and resistance to this immunotherapy. These studies will lead to new strategies to enhance NK cell anti-leukemia responses.