A Phase II Clinical Trial of "Off-the-Shelf" NK Cells with Allogeneic Stem Cell Transplantation to Decrease Disease Relapse in Patients with High-Risk Myeloid Malignancies

Background Acute myeloid leukemia, myelodysplastic syndrome, and TKI resistant CML continue to be among the most aggressive forms of blood cancer. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains one of the most effective treatments available. Much of the benefit of AlloSCT is due to the immune-mediated graft-versus-leukemia effect to prevent relapse. Nevertheless, disease relapse remains the most important cause of treatment failure after alloSCT. A potential solution to reduce the risk of relapse may be found in Natural Killer (NK) cells, which have a demonstrable ability to eliminate leukemic and virally infected cells. However, naturally produced NK cells seen in patients early post-transplant are functionally impaired. A potential solution would be to provide donor-derived, expanded and activated NK cells in the peri-transplant setting. Natural killer cells are a unique class of lymphocytes, with cytotoxic, and immunoregulatory function which can mediate potent anti-leukemia effects. NK cells are regulated by Killer-cell Immunoglobulin-like Receptors (KIR) receptor-ligand interactions and mediate cytotoxicity. Alloreactive NK cells have been reported to enhance engraftment, reduce GVHD and prevent relapse of leukemia post transplant. This study will utilize NK cells from third party donors as adjuvant treatment to eradicate leukemia and prevent disease relapse after transplantation. Study Design and Methods Our clinical trial is registered as NCT05115630. Inclusion criteria includes age 18 to 65 years old, weighing at least 42 kg, with High risk AML, MDS, or TKI-resistant/intolerant CML who have either an HLA matched related donor, HLA matched unrelated donor, a haploidentical related donor, or a one antigen mismatched unrelated donor. HLA matching includes HLA A, B, C, and DR-B1. Exclusion criteria include patients who are HIV positive or has active hepatitis B or C, uncontrolled infections, liver cirrhosis, CNS involvement within 3 months prior to the transplant, or positive pregnancy test in a woman with child bearing potential. We will also exclude any patient with inability to comply with medical therapy or follow-up, patient with a known history of allergic reactions to any constituents of the product, including a known history of allergic reactions to cellular products or DMSO, other malignancy/cancer diagnosis <2 years ago. We will also exclude any patient requiring systemic corticosteroids with prednisone dose >10 mg or equivalent or who has KDS-1001 Donor specific antibodies (dsa) >5000 MFI units, or has KDS-1001 Donor anti-C1q positive. Statistical considerations and exploratory endpoints This is a single-arm Phase II trial of 3rd party natural killer (NK) cells at a fixed dose added to an allogeneic stem cell transplant for AML/MDS/CML. The goal is to reduce the risk of relapse of the malignancy post transplant, and to improve relapse free survival. The primary endpoint is the adverse event Failure = [graft failure, grade 3-4 GVHD, relapse or non-relapse death within 100 days post-transplant]. The stopping rule for time-to-failure (defined as graft failure, gr 3-4 GHVD, or non-relapse death) will be implemented to avoid waiting 100 days (3 months) to evaluate each patient to perform safety monitoring. The design will be based on T with 3 months follow-up, applying the design of Thall et al. Possibly right-censored values of T for patients treated in the trial will be monitored continuously throughout the trial. The accrual rate is expected to be approximately 2 patients per month, with each patient's follow-up continued until all patients have been followed for 3 months from their date of first NK cell administration. The distributions of time to failure and RFS time will be estimated using the method of Kaplan and Meier. Exploratory analyses with immunophenotyping for NK cell chimerism and persistence will be done as feasible. Immune reconstitution studies or additional future research may be performed.