FT596 and FT516 Off-the-shelf, iPSC-derived NK Cell Products Shows Promise in B-Cell Lymphoma

Treatment with off-the-shelf natural killer cell (NK) products derived from clonal master induced pluripotent stem cell (iPSC), FT516 and FT596, resulted in positive topline clinical data in a population of patients with B-cell lymphoma, according to a press release from developer Fate Therapeutics.¹

FT516 is engineered with a high-affinity, noncleavable CD16 Fc receptor that is designed to maximized antibody-dependent cytotoxicity. The compound has a notable antitumor mechanism that allows NK cells to recognize, bind, and kill cancer cells that have been coated with the antibody. Moreover, the FT596 product utilizes both the hnCD16 Fc receptor and a chimeric antigen receptor (CAR) targeting CD19. This allows for the multi-antigen targeting of tumor cells in addition to an IL-15 receptor fusion to further bolster NK cell activity and survival.

FT596, which is currently being assessed in a multicenter phase 1 trial (NCT04245722) in patients with relapsed/refractory B-cell lymphoma both alone and in combination with rituximab (Rituxan), enabled 10 of 14 patients to achieve an objective response. In total, 7 patients achieved a complete response (CR), including 2 out of 3 patients who received the FT596/rituximab combination following the use of CD19-targeted CAR T-cell therapy.

FT516, which is currently under investigation in a phase 1 study (NCT04023071) as monotherapy for acute myeloid leukemia and in combination with CD20-targeted monoclonal antibodies for advanced B-cell lymphoma, elicited an objective response in 8 of 11. Among the responders, 6 patients achieved a CR. Five responders continue to experience an ongoing response at a median of 5.2 months.

“We are very pleased with the interim safety, response rates, and durability of responses observed in our ongoing clinical studies of FT516 and FT596 for the treatment of patients with relapsed/refractory B-cell lymphomas. These data continue to demonstrate that our off-the-shelf, iPSC-derived NK cell product candidates can uniquely deliver substantial therapeutic benefit and expand patient access to cell-based cancer immunotherapies,” Scott Wolchko, president and chief executive officer of Fate Therapeutics, said in a press release.

The FT596 study is currently assessing the compound alone or with the addition of rituximab at 375 mg/m² following 3 days of conditioning chemotherapy, consisting of cyclophosphamide at 500 mg/m² and fludarabine at 30 mg/m². In total, 10 patients in the single-agent cohort and 10 in the combination cohort were evaluable for safety and efficacy as of the data cut off of June 25, 2021. This consisted of patients from 3 dose cohorts, including those receiving 30 million cells (n = 3), 90 million cells (n = 4), and 300 million cells (n = 3). Patients who enrolled on the study had received a median of 4 prior lines of therapy, with a median of 2.5 prior lines containing a CD20-targeted therapy. Among the 20 patients who were included in the study, 60% had aggressive B-cell lymphoma, 50% were refractory to their most recent therapy, and 35% had previously received a CD19-targeting CAR T-cell therapy.

The ongoing dose-escalation study is currently enrolling patients for the fourth single-dose cohort of 900 million cells in each arm.

In the clinical trial examining FT516, patients are treated with the compound for up to 2 cycles, with each cycle including conditioning chemotherapy (500 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine) plus a single 375 mg/m² dose of rituximab and 3 weekly doses of FT516 with IL-2 cytokine support. Notably, the regimen is designed to be administered in an outpatient setting. The trial is currently ongoing in the fourth multi-dose cohort of 900 million cells per dose.

When the interim data were presented at the 2021 American Society of Clinical Oncology Annual Meeting,² 11 patients had been treated with either 90 million cells per dose (n = 4) and 300 million cells per dose (n = 7). Those who enrolled had received a median of 3 previous lines of therapy, with 2 prior lines including CD20-targeted therapy. Eight of the 11 patients enrolled on the study had aggressive B-cell lymphoma, 5 were refractory to their most recent therapy, and 4 had previously undergone treatment with CD19-targeting CAR T-cell therapy.

Both regimens were well tolerated with no dose-limiting toxicities or reported incidences of graft-versus-host-disease or immune effector cell–associated neurotoxicity syndrome of any grade. Two patients in cohort 1 and 2 of the study treated with single-agent FT596 were reported to have experienced low-grade cytokine release syndrome.

“At this time, we are initiating multiple indication-specific, dose-expansion cohorts to broadly assess FT516 in combination with CD20-targeted monoclonal antibody regimens, including in patients that have experienced disease progression following autologous CD19-targeting CAR T-cell therapy. In addition, early clinical data with the single-dose FT596 treatment schedule have shown robust 30-day response rates and we look forward to further assessing both single-dose and multi-dose treatment regimens to validate its potential best-in-class therapeutic profile,” Wolchko concluded.

References

1. Fate Therapeutics Announces Positive Interim Clinical Data from its FT596 and FT516 Off-the-shelf, iPSC-derived NK Cell Programs for B-cell Lymphoma. News release. Fate Therapeutics. August 19, 2021. Accessed August 20, 2021. https://bit.ly/3D6JfL8
2. 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. 2021;39(suppl 15):7541. doi:10.1200/JCO.2021.39.15_suppl.7541