Work

SAR445419 Off-the-Shelf Natural Killer Cells Are Safe and Show Efficacy Signal in Relapsed/Refractory Acute Myeloid Leukemia.

Year: 2024

Type: article

Abstract: Natural Killer (NK) cells are cytotoxic lymphocytes that exert an anti-tumor effect in an MHC-I independent manner but are dysfunctional and reduced in number in patients with leukemia. As NK alloreactivity and NKG2C expression play critical roles in mediating anti-tumor effects, we identified ‘ideal’ NK cell donors, using human leukocyte antigen (HLA) and Killer immunoglobulin receptor (KIR) genotyping, to generate SAR445419 (SAR’419). SAR’419 contains hyperactive NK cells expanded ex vivo using PM21 particles expressing membrane-bound interleukin-21 and 4-1BB ligand from the plasma membranes of feeder cells. SAR’419 is then cryopreserved for immediate ‘off-the-shelf’ administration to recipients. Here, we report our initial experience in a Phase I trial of these off-the-shelf, alloreactive, hyper functional NK cells, SAR’419 (provided by Sanofi) as immunotherapy for relapsed/refractory AML. SAR’419 was completely HLA-mismatched between donor and recipients. Patients were treated at two dose levels of SAR’419 (DL1: 1x10e7 cells/kg; DL2: 3x10e7 cells/kg) following administration of Fludarabine 30 mg/m2/day & Cytarabine 2 g/m2/day on days -6 to -2. After chemotherapy, SAR’419 is infused thrice weekly for 2 weeks for a total of 6 doses (Clinicaltrials.gov: NCT04220684). Once a month maintenance dosing is permitted for patients achieving CR/CRi/PR who are not candidates for allogenic transplant. Persistence of SAR’419 was determined by flow cytometry using haplotype-discriminating anti-HLA antibodies (Figure 1). As of October 2023, 6 patients (3 in DL1 and 3 in DL2) have been treated. All patients had relapsed/refractory AML with at least two prior lines (range, 2-4) of treatment. Each patient received the first SAR’419 dose as an inpatient and were discharged to receive the remaining 5 doses as an outpatient. One patient received 5 doses and the rest received 6 doses of SAR’419 administered over 2 weeks. A complete remission was obtained by one participant (relapsed post-allograft) receiving a dose of 1x10e7 cells/kg and as of the cutoff date, has received 10 months of maintenance SAR’419 NK cells, remaining in morphologic, immunophenotypic and molecular remission. No infusion-related reactions, neurotoxicity or graft versus host disease was observed. Correlative studies to be presented on this initial cohorts include assessment of in vivo expansion and persistence (HLA-specific flow and/or next-generation sequencing-based molecular STR chimerism), serum cytokines, and NK cell product phenotype (mass cytometry) and function (cytotoxicity and cytokine production). Cryopreserved, third-party, donor-derived NK cells (SAR’419) are well tolerated and feasible in relapsed/refractory AML patients as induction and maintenance treatments. Completely HLA-mismatched NK cells can persist and expand to high levels in vivo with an efficacy signal noted at 1x10e7 cells/kg.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2023.12.296