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Background: Natural Killer (NK) cells are cytotoxic lymphocytes that are able to exert an anti-tumor effect in an MHC-I independent manner, but are dysfunctional and reduced in number in patients with leukemia. Several studies have shown therapeutic potential for related donor NK cells expanded and/or activated ex vivo when administered to cancer patients, including patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, personalized, donor-derived cell therapies require time for donor identification, manufacturing and product release, resulting in patient attrition. As NK alloreactivity and NKG2C expression play critical roles in mediating anti-tumor effects, we identified 'ideal' NK cell donors (in partnership with "Be the Match Biotherapies") for collection. Human leukocyte antigen (HLA) and Killer immunoglobulin receptor (KIR) genotyping were done to screen and select donors. Following this, a sample was collected from donors to expand NK cells under small-scale conditions. If donor NK cells showed robust expansion, they proceeded with apheresis. To ensure these therapeutic cells would be readily-available, we established a third-party NK cell bank through scalable, affordable mass-production with membrane-bound IL-21 feeder cells (FC21), and cryopreserved large numbers of these NK cells for immediate 'off-the-shelf' administration to recipients. Here, we report our initial experience in a Phase I trial of these off-the-shelf (OTS) alloreactive NK cells as immunotherapy for patients with relapsed/refractory AML and MDS. Methods: Patients were treated at Dose level 1, to allow infusion at a dose of 1 x 10e7 NK cells/ kg. Each dose level had two cohorts, stratified by age. Patients were enrolled into Cohort 1 (patients Results: 6 patients (3/cohort) were treated at the first dose level of 1x10 7 NK cells/kg/dose. All 6 patients had relapsed/refractory AML and had received at least two prior lines of treatment. One patient (005) withdrew from the study prior to infusion of NK cells. 6 patients received the first NK cell dose as an inpatient and were discharged to receive the remaining 5 doses as an outpatient. 5 patients tolerated infusion of all 6 doses of NK cells administered over 2 weeks. One patient (006) developed a Cytokine response (CRS) - like syndrome in the context of streptococcus bacteremia and received only one dose of NK cells. Symptoms suggestive of CRS responded fully with steroids and patient was able to successfully wean off steroids and discharged to the outpatient setting. One patient proceeded to allogeneic hematopoietic cell transplant. No infusion-related reactions, neurotoxicity or graft versus host disease was observed. In vivo persistence/expansion NK cells were superior with FLU/CY lymphodepletion (cohort 1). Conclusions: Cryopreserved, third-party donor-derived NK cells are safe and feasible in relapsed/refractory AML patients, and even at this first dose level, completely HLA-mismatched NK cells can persist and expand to high levels in vivo. Figure 1 Figure 1. Disclosures Vasu: Kiadis, Inc.: Research Funding; Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Walker: Newave: Other: clinical trial support; Geron: Other: clinical trial support; Novartis: Other: clinical trial support. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding. Lee: Kiadis Pharma: Divested equity in a private or publicly-traded company in the past 24 months, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Courier Therapeutics: Current holder of individual stocks in a privately-held company.

Background: Allogeneic transplantation (allo-HCT) is an effective treatment for many patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). With HCT the long term disease free survival (DFS) rate is approximately 60% for patients transplanted in first remission. After relapse, the rate falls to approximately 40% if the patients are in remission at the time of HCT. However, many patients present with refractory chemo-resistant disease, relapse during or shortly after induction therapy, or develop complicating comorbidities due to prolonged induction. For most such relapse-refractory (R/R) AML patients, allo-HCT is not an option. These patients have a dire prognosis with only 5-10% long term DFS. Natural Killer (NK) cells are cytotoxic lymphocytes that are able to identify tumors and exert an anti-tumor effect in an MHC-I independent manner. However, NK cells from patients with cancer can be dysfunctional and reduced in number. To overcome that, NK cells expanded ex vivo to yield high numbers of cells could provide a cellular therapeutic option for cancer patients, including patients with AML/MDS. The therapeutic potential of ex vivo membrane-bound IL-21 expanded NK cells (FC21-NK) from a haploidentical donor has been established in patients with poor prognosis AML/MDS undergoing a haploidentical HCT. Besides obtaining sufficient cell numbers, having them readily available for patients is another major obstacle for adoptive NK cell immunotherapy. Patients with aggressive disease need prompt intervention yet the manufacture of patient-specific NK cells exceeds three weeks. As NK alloreactivity plays a critical role in mediating anti-tumor effects, we identified KIR and HLA-mismatched 'ideal' donors (selected through "Be The Match Biotherapies"). Using lymphocytes from these donors, we have established a third-party NK cell bank to ensure readily-available immune cell therapies that allows scalable, affordable mass-production of large numbers of NK cells suitable for banking & immediate 'off-the-shelf' administration to a broad population of recipients. This trial is to determine the safety of FC21 expanded Off-the-shelf (OTS), Third-party donor-derived NK cells for relapsed/refractory AML patients. Methods: This phase 1 study follows a 3+3 design to investigate the safety of FC21-expanded, third-party, OTS NK cells for treatment of patients with primary refractory or relapsed AML or myelodysplastic syndrome. Active GvHD is excluding. Patients aged ≥18 or ≤80 years are enrolled into two cohorts: those 60 yrs or Disclosures Vasu: Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Bhatnagar:KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. O'Donnell:Kiadis Pharma: Other: Licensing of intellectual property. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.