Preliminary results of a phase I trial of FT516, an off-the-shelf natural killer (NK) cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line expressing high-affinity, non-cleavable CD16 (hnCD16), in patients (pts) with relapsed/refractory (R/R) B-cell lymphoma (BCL).

Abstract

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received > 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.

iPSC-Derived Natural Killer Cell Therapies - Expansion and Targeting

“…Additional trials using NK cells engineered to improve targeting of tumors and NK cell expansion have been initiated (15,(51)(52)(53). For example, a recent trial utilizing adoptive transfer of ex vivo expanded, HLA-mismatched, CB-NK cells engineered to express both an anti-CD19 CAR and secreted IL-15 were used to treat 11 patients with CD19-positive relapsed or refractory B cell malignancies and demonstrated objective response in 73% of the patients (15).…”

“…Multiple recent studies have genetically engineered iPSCs to create iPSC-NK cells with enhanced expansion, in vivo persistence and tumor killing capability are being explored (52,79,80). Many of these technologies were first developed and tested in PB-NK cells and/or CB-NK cells and subsequently translated into iPSC-derived NK cells.…”

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma

“…Finally, iPSCs have recently become an attractive source of CAR-NK cells for their unlimited proliferative capacity ( 71 , 72 ). Indeed, CAR-engineered iPSCs can be induced to differentiate in vitro into hematopoietic progenitor cells and then into CAR-NK cells ( 72 ).…”

“…Finally, iPSCs have recently become an attractive source of CAR-NK cells for their unlimited proliferative capacity ( 71 , 72 ). Indeed, CAR-engineered iPSCs can be induced to differentiate in vitro into hematopoietic progenitor cells and then into CAR-NK cells ( 72 ). Notably, from a limited number of iPSCs it is possible to obtain a large number of CAR-modified NK cells, even characterized by a homogeneous phenotype ( 73 ).…”

Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

“…FT516 is under evaluation in a Phase 1 study (clinicaltrials.gov: NCT04023071) as a monotherapy for acute myeloid leukaemia (AML) and in combination with CD20-specific monoclonal antibody therapy in patients with advanced B-cell lymphoma. Preliminary clinical results obtained in lymphoma patients in combination with rituximab have recently been published (Strati et al 2021 ). Patients received two cycles of treatment consisting of lymphodepletion (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 , each for 3 days), a single dose of rituximab followed by three weekly cycles of FT516 (dose range 30–900 × 10 6 cells) accompanied by IL-2 (six million IU after each dose of FT516).…”