NK cell therapy approaches clinic

SAN DIEGO—The California Institute for Regenerative Medicine (CIRM) has awarded a grant worth $4 million to Fate Therapeutics Inc., the latter company announced recently. The grant will support the advancement of FT516 into a first-in-human clinical trial. The goal of the study will be to determine safety and tolerability of FT516 together with an FDA-approved monoclonal antibody therapy in a variety of dosing cycles.

FT516 is a natural killer (NK) cell product candidate generated from a clonal master induced pluripotent stem cell line designed to uniformly express a novel CD16 Fc receptor. Fate Therapeutics is advancing the therapeutic as an off-the-shelf cancer immunotherapy. The plan is to develop FT516 against multiple tumor types as both a monotherapy and part of a combination regimen with a tumor-targeting monoclonal antibody therapy.

NK cells express the activating receptor CD16, which allows the cells to bind to the Fc portion of IgG antibodies, and once active, NK cells can release antibody-coated tumor cells and produce immune signaling cytokines to trigger a broad adaptive immune response. In individuals with cancer, expression of CD16 on NK cells is often significantly down-regulated, resulting in a decrease in anti-tumor activity. FT516 expresses a CD16 Fc receptor modified to prevent down-regulation and has been shown in in-vitro and in-vivo preclinical studies to result in potent and enduring anti-tumor activity.

“FT516 has the potential to address a significant unmet need for more efficacious treatments across multiple solid-tumor types by restoring a patient’s immune cell function and enhancing the therapeutic effect of monoclonal antibody therapy,” Scott Wolchko, president and CEO of Fate Therapeutics, commented in a press release. “We are honored that CIRM has recognized the potential therapeutic value of FT516 as well as the unique advantages of using clonal master iPSC lines to manufacture a well characterized, uniformly engineered cell product in large batches for off-the-shelf use.”

As noted by the company, Fate Therapeutics' iPSC product platform “enables large-scale generation of off-the-shelf, engineered, homogeneous cell products that can be administered in repeat doses to mediate more effective pharmacologic activity, including in combination with cycles of other cancer treatments.” Human iPSCs are engineered “in a one-time genetic modification event,” and a single iPSC is chosen for maintenance as the 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 generating homogeneous cell products in quantities that support the treatment of many thousands of patients in an off-the-shelf manner,” Fate Therapeutics explains on its website.

“CIRM is pleased to support the continued development of FT516 and Fate Therapeutics’ first-of-kind approach to off-the-shelf cancer immunotherapy using clonal master iPSC lines, which can serve as a renewable cell source for large-scale, cost-effective manufacture of well-characterized, uniform cell products,” said Dr. Maria T. Millan, president and CEO of CIRM. “The adoptive transfer of healthy allogeneic donor NK cells has been shown to be well tolerated in patients and has not been associated with the known risks of allogeneic T-cell immunotherapy such as graft-versus-host disease. This suggests that FT516 can be reliably administered without individual patient matching restrictions and used off-the-shelf to treat a large patient population.”

This news came scant days after Fate Therapeutics announced that the first patient had been treated in a study of one of its other NK cell cancer therapies. The DIMENSION study is evaluating FATE-NK100 for the treatment of advanced solid tumors, specifically the safety of the therapy and its maximum dose both as a monotherapy and when administered together with trastuzumab or cetuximab, FDA-approved targeted monoclonal antibody therapies. FATE-NK100 is a first-in-class, allogeneic donor-derived adaptive memory NK cell cancer therapy. According to the company, “Compelling clinical data indicate that NK cells mediate the therapeutic effect of monoclonal antibody therapy by recognizing and efficiently killing antibody-coated tumor cells via a potent immune response mechanism known as antibody-dependent cellular cytotoxicity (ADCC). The combination of FATE-NK100 and monoclonal antibody therapy is designed to enhance ADCC by administering an activated population of healthy allogeneic donor NK cells to augment the killing of antibody-coated tumor cells.”

This is the third clinical trial of FATE-NK100 at present. The other studies consist of VOYAGE, in which the therapy is being evaluated as a treatment for refractory or relapsed acute myelogenous leukemia, and APOLLO, in which it is being assessed in patients with ovarian cancer shown to be resistant to or recurrent on platinum-based treatment.