A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-Shelf, Third-Party Natural Killer Cells for Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

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 & able to tolerate intensive chemo & sensitive to Cytarabine will receive Fludarabine 30 mg/m²/day (days -6 to -2) & Cytarabine 2 g/m²/day (days -6 to -2). Patients >60 yrs or <60 yrs & unable/unwilling to tolerate intensive chemo or disease insensitive to Cytarabine will receive Fludarabine 30 mg/m²/day (days -5 to -2) & Decitabine 20 mg/m²/day (days -6 to -2). All patients subsequently receive a total of 6 infusions of NK cells administered thrice weekly for two weeks (between day 0-21). Three NK cell dose-levels: 1x10⁷, 3x10⁷ & 1x10⁸ cells/kg/dose will be explored to determine MTD (maximal tolerated dose). Between 3-18 patients/cohort/dose for MTD determination, plus an additional 10 patients/dose in an expansion phase may be enrolled (maximum 28/cohort = 56 total subjects). Patients will be followed up to day 56 from first NK cell infusion. Primary objectives are to determine the recommended phase 2 dose and overall response rate (CR, CRi & MLFS). Secondary objectives will explore PFS, OS & MRD negativity, cell counts, infectious complications, and patients proceeding to transplant. Enrollment in both cohorts is ongoing. Clinical trial information: NCT04220684.