Phase I Study of FT516, an Off-the-Shelf iPSC-Derived NK Cell Therapy, in Combination with Rituximab in Patients with Relapsed/Refractory B-Cell Lymphoma

Background: Allogeneic natural killer (NK) cell therapies have documented anti-tumor activity in patients with relapsed/refractory (R/R) hematologic malignancies, including B-cell lymphoma (BCL), and may offer an improved safety profile characterized by the absence of cytokine release syndrome (CRS) and neurologic toxicity compared with T-cell therapies (Liu et al. 2020). However, limited availability of suitable donors, relatively short in vivo persistence, and manufacturing constraints limiting the ability to consistently deliver multiple doses remain barriers to maximizing the clinical benefit of NK cell therapy.

FT516 is a first-of-kind, off-the-shelf, NK cell therapy manufactured from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of NK cells for multi-dose treatment and immediate patient access. FT516 expresses a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor, which has been demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity in combination with an anti-CD20 monoclonal antibody (Zhu et al. 2020).

Methods: Primary objectives of the study are to determine the recommended Phase II dose of FT516 in combination with rituximab (R) or obinutuzumab (G) in R/R BCL and to evaluate safety and tolerability in patients (pts) with R/R BCL. Key secondary objectives include evaluation of FT516 anti-tumor activity by Lugano Classification and pharmacokinetics when combined with R or G in R/R BCL.

The ongoing dose-escalation stage assesses FT516 for up to 2 cycles, each consisting of 3 days of conditioning chemotherapy (cyclophosphamide [CY] 500 mg/m ² and fludarabine [FLU] 30 mg/m ²), a single-dose of R (375 mg/m ²), and 3 weekly doses of FT516 (30-900 million cells per dose) each with IL-2 support (6 MIU). FT516 may be administered in the outpatient setting with no mandatory hospitalization.

Following dose escalation, further investigation of safety and efficacy will be conducted as follows: FT516 + R or G following FLU/CY in pts with R/R diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma (FL) who have not received prior CAR T-cell therapy; FT516 + R following FLU/CY in pts with R/R BCL who have previously received CAR T-cell therapy; and FT516 + R following bendamustine.

Results: As of 07 July 2021, 13 pts (2 at 30 million cells per dose, 4 at 90 million cells per dose, and 7 at 300 million cells per dose) were enrolled and had at least 3 months of follow-up or discontinued. Pts had DLBCL, including transformed indolent (7 pts), high-grade BCL (HGBCL, 3 pts), low-grade FL (2 pts), or marginal zone lymphoma (1 pt), and received a median of 3 prior lines of therapy and a median of 2 prior lines containing CD20-targeted therapy. Ten of 13 pts received both planned treatment cycles (6 doses of FT516); 3 pts discontinued after a single cycle due to disease progression.

No dose-limiting toxicities, FT516-related serious adverse events, or FT516-related Grade ≥3 adverse events (AEs) were observed. No CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. Grade ≥3 AEs occurring in ≥2 pts were neutrophil count decreased (6 pts), neutropenia (5 pts), febrile neutropenia (3 pts), and thrombocytopenia (2 pts).

Eight of the 11 pts (72%) treated with ≥90 million FT516 cells achieved an objective response. Seven pts achieved complete response (CR), including 2 pts whose disease progressed following treatment with autologous CD19 CAR T-cell therapy. Two pts treated at the lowest dose of 30 million FT516 cells experienced progressive disease.

Of the 8 responders, 5 continue in remission at between 4.6 and 9.5 months. One pt with primary refractory triple-hit HGBCL that had progressed after 7 prior regimens, including CAR T-cell therapy, continues in CR with minimal residual disease negativity by local ctDNA analysis 4.9 months from initiation of FT516 treatment.

Conclusions: Administration of up to 6 doses of FT516 cells in combination with R appears safe and tolerable up to 300 million cells per dose, without CRS, ICANS, or GvHD. Deep responses were observed in heavily pretreated pts, with several with ongoing CR at data cutoff. Updated clinical and translational results of ongoing dose escalation will be presented at the conference.