Fate Therapeutics announced the U.S. Food and Drug Administration (FDA) has cleared the Company’s Investigational New Drug (IND) application for FT538, the first CRISPR-edited, iPSC-derived cell therapy. FT538 is an off-the-shelf natural killer (NK) cell cancer immunotherapy that is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three functional components to enhance innate immunity: a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor; an IL-15/IL-15 receptor fusion (IL-15RF); and the elimination of CD38 expression. The Company plans to initiate clinical investigation of three once-weekly doses of FT538 as a monotherapy in acute myeloid leukemia (AML) and in combination with daratumumab, a CD38-directed monoclonal antibody therapy, for the treatment of multiple myeloma.

“We are very pleased to expand the clinical application of our proprietary iPSC product platform to multiple myeloma, where rates of relapse remain high,” said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. “Clinical data suggest that deficiencies in NK cell-mediated immunity, which are evident even at the earliest stages of myeloma, continue to accumulate through disease progression. We believe administration of FT538 to patients can restore innate immunity, and that the anti-cancer effect of certain standard of care treatments, such as monoclonal antibodies, can be more effective when combined with the engineered functionality of FT538.”

The three functional components of FT538 are designed to boost the innate immune response in cancer patients, where endogenous NK cells are typically diminished in both number and function due to prior treatment regimens and tumor suppressive mechanisms. In preclinical studies, FT538 has shown superior NK cell effector function, as compared to endogenous NK cells, with the potential to confer significant anti-tumor activity to patients through multiple mechanisms of action including:

• Expression of the hnCD16 Fc receptor, which improves antibody-dependent cellular cytotoxicity, a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells;

• Expression of the IL-15RF cytokine complex, which promotes NK cell survival and persistence and induces trans-activation of endogenous NK cells and CD8 T cells; and

• Elimination of CD38 expression, which enhances innate effector function, including granzyme and perforin levels and resistance to oxidative stress, and prevents anti-CD38 antibody-mediated NK cell death.

The first-in-human, multi-center, dose-escalation Phase 1 clinical trial of FT538 is designed to determine the maximum tolerated dose (MTD) of three once-weekly doses of FT538 in up to 105 adult patients across four dose cohorts (100M cells per dose; 300M cells per dose; 900M cells per dose; and 1.5B cells per dose). The study will assess two treatment regimens: Regimen A as a monotherapy in patients with relapsed / refractory AML; and Regimen B in combination with daratumumab, an FDA-approved anti-CD38 monoclonal antibody, in patients with relapsed / refractory multiple myeloma who have failed at least two lines of therapy. In addition, the Company may initiate a third treatment regimen in combination with elotuzumab, an FDA-approved anti-SLAMF7 monoclonal antibody, in patients with relapsed / refractory multiple myeloma who have failed at least two lines of therapy starting at one dose level below the MTD of Regimen B. For all regimens, multiple indication- or dose-specific dose-expansion cohorts of up to 15 patients per cohort may be enrolled to further evaluate the clinical activity of FT538.