On May 20, 2020 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported that 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 (Press release, Fate Therapeutics, MAY 20, 2020, View Source [SID1234558311]). 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.

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"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.

FT538 is the fourth off-the-shelf, iPSC-derived NK cell product candidate from the Company’s proprietary iPSC product platform cleared for clinical investigation by the FDA. The Company has initiated clinical manufacture of FT538 at its GMP facility in San Diego, CA.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.