FT516 Shows Promising Preliminary Efficacy, Safety in B-cell Lymphoma

Paolo Strati, MD

FT516, an off-the-shelf natural killer (NK) cell therapy, demonstrated a complete response (CR) rate of 55% and an objective response rate (ORR) of 73% for patients with relapsed/refractory B-cell lymphoma, according to phase 1 findings presented at the 2021 ASCO Annual Meeting.

The preliminary findings with a median follow-up of just 79 days were from 11 patients enrolled across higher doses of FT516, with 4 receiving 90 million cells per dose and 7 receiving 300 million cells per dose. Each received up to 6 doses of the NK cell therapy and all patients also received lymphodepleting chemotherapy and a single dose of rituximab (Rituxan). In general, the therapy was safely administered in an outpatient setting and there were no treatment discontinuations due to adverse events (AEs) or dose-limiting toxicity (DLT). No cases of cytokine release syndrome, neurotoxicity, or graft-vs-host disease were observed in the study.

"Eight of 11 patients treated at 90 million cell dose or higher achieved an objective response, including 4 out of 5 patients who were refractory to their last treatment," principal investigator Paolo Strati, MD, assistant professor in lymphoma and myeloma at MD Anderson Cancer Center, said in a video that accompanied the poster. "Dose escalation is ongoing with a 900 million cell dose in combination with rituximab in relapsed/refractory B cell lymphoma."

FT516 is derived from a clonal master induced pluripotent stem cell (iPSC) line, which has been engineered with a high affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor. The enhancements made to CD16 are meant to prevent downregulation, enhance binding to tumor-target antibodies, and maximize antibody-dependent cellular cytotoxicity (ADCC). Preclinical models demonstrated prolonged survival of the NK cells with the CD16 modification compared with non-modified NK cells.

The phase 1 study enrolled 13 total patients, with 2 treated at a lower dose and 11 treated at 90 million cells or greater. The median age across all patients was 65 years and most had a diffuse large B cell lymphoma (DLBCL) or transformed non-Hodgkin lymphoma histology (46.2%). The next most common histology was high-grade Burkitt-cell lymphoma (BCL) or Burkitt-like histology (23.1%). Most patients were stage IV at study entry (76.9%), apart from 3 who were either stage III (n = 2) or unknown (n = 1). Approximately two-thirds had bulky disease (69.2%).

Patients had received a median of 3 prior treatments (range, 1-7), this included a median of 2 prior anti-CD20 regimens. Approximately half of patients were refractory to their prior treatment (46.2%) and 38.5% had received a prior CD19-directed CAR T-cell therapy. Conditioning therapy was administered with fludarabine and cyclophosphamide plus 1 dose of rituximab after which FT516 was administered on days 1, 8, and 15 with 6-MIUs of interleukin-2 after each dose. There were 2 cycles of treatment planned in the study, with lymphodepletion being optional in the second cycle based on hematologic recovery.

Of the 11 patients who received 90 million cells or higher, 8 achieved an objective response, with 6 being CRs. Overall, 4 of 5 patients who were refractory to their most recent prior treatment responded to FT516, with 3 of these responses being CRs. Two of the 4 patients previously treated with CAR T-cell therapy experienced a CR.

The ASCO presentation contained a patient case study of a 36-year-old male patient with high-grade BCL or Burkitt-like histology who was refractory to prior therapies but had responded with a CR of 2 months to CAR T-cell therapy, which was followed by progression. At study entry the patient had stage III disease with triple-hit rearrangements of MYC, BCL2, and BCL6 genes. Following treatment with FT516, the patient experienced a CR with resolution of FDG-avid disease. There was an 85% reduction in the sum of the product of diameters for target lesions.

The most common all-cause grade ≥3 AEs observed in the study were neutrophil count decrease (46.2%), neutropenia (30.8%), febrile neutropenia (23.1%), platelet count decrease (15.4%), pyrexia (7.7%), and hypotension (7.7%). None of these events were considered related to treatment with FT516. There were no patient withdrawals due to AEs in the study and FT516 was primarily administered in the outpatient setting with no mandatory hospitalization required.

“These additional data from our phase 1 study of FT516 administered off-the-shelf in the outpatient setting continue to reinforce its differentiated safety profile and underscore its potential clinical benefit,” Wayne Chu, MD, senior vice president of Clinical Development of Fate Therapeutics, the company developing the therapy, said in a statement. “Based on the favorable therapeutic profile of FT516 that continues to emerge and the potential to treat patients on-demand without delay, we plan to initiate multiple indication-specific, dose-expansion cohorts for patients with B-cell lymphomas to broadly assess FT516 in combination with CD20-targeted monoclonal antibody regimens, including those used as standard-of-care in earlier-line settings.”

Strati P, Bachanova V, Goodman A, et al. 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). J Clin Oncol. 39, 2021 (suppl 15; abstr 7541).