Fate Therapeutics said today it has won a $4 million California Institute for Regenerative Medicine (CIRM) grant toward advancing one of its off-the-shelf engineered natural killer (NK) cell cancer immunotherapies into a first-in-human clinical trial.

FT516 is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to uniformly express a novel CD16 Fc receptor that has been modified to enhance its binding affinity to immunoglobulin G (IgG) antibodies and prevent the receptor’s shedding from the surface of NK cells upon activation, which can otherwise diminish the cells’ antitumor activity.

In preclinical studies, FT516 has shown potent and persistent antitumor activity in vitro and in vivo in multiple tumor cell recognition and killing assays, including in combination with various IgG antibodies, Fate Therapeutics said.

Fate Therapeutics said it plans to develop FT516 as a treatment for multiple types of tumors, both alone and in combination with an FDA-approved, tumor-targeting monoclonal antibody (mAb) therapy.

“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,” Fate Therapeutics president and CEO Scott Wolchko said in a statement.

The first-in-human study is expected to evaluate the safety and tolerability of multiple dosing cycles of FT516 in combination with mAb therapy—which CIRM said will be Herceptin® (trastuzumab)—to augment the drug’s ability to kill breast cancer cells.

2019 Trial Planned

The grant is the second awarded in recent months toward R&D of Fate Therapeutics iPSC-derived NK cell cancer immunotherapies. On November 30, CIRM awarded $5.15 million to Dan S. Kaufman, M.D., Ph.D., of University of California, San Diego School of Medicine, toward a research collaboration with the company focused on developing treatments for blood cancers.

Fate Therapeutics’ latest grant comes from CIRM’s late-stage preclinical funding program, which aims to fund the final stages of research required to file an Investigational New Drug (IND) application with the FDA.

Other activities planned for the grant funding, CIRM detailed on its website, include completing the manufacturing process control and release assay development, completing engineering and process qualification and clinical manufacturing runs, and completing clinical trial database construction and clinical site identification and study initiation.

“CIRM funding will enable us to complete our IND-enabling studies and the manufacturing of our clinical product,” Wolchko said in CIRM’s statement announcing the grant. “Our goal is to launch a clinical trial in 2019 using the City of Hope CIRM Alpha Stem Cell Clinic.”

Marketed by Genentech, a member of the Roche Group, Herceptin is a HER2/neu receptor antagonist indicated for HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

FT516 has had preclinical success in combination with Herceptin, according to the company, with the combo showing enhanced antitumor activity in vivo, compared to mice treated with trastuzumab alone, in a HER2+ ovarian cancer model.

Additional Preclinical Combination Studies

The cell therapy also showed positive preclinical results combined with two other marketed cancer treatments. The combination of FT516 and Eli Lilly’s Erbitux® (cetuximab) exhibited superior antibody-dependent cell-mediated cytotoxicity (ADCC) compared to conventional NK cells sourced from peripheral blood and cord blood, in an in vitro killing assay of a human ovarian cancer cell line.

Erbitux is indicated in combination with radiation therapy for squamous cell carcinoma of the head and neck, and alone for K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing colorectal cancer.

And when combined with the Genentech/Biogen co-marketed Rituxan® (rituximab), the cell therapy showed a dose-dependent killing response in vitro in a CD20+ human lymphoblast-derived B-lymphocyte cell line killing assay, Fate Therapeutics said.

Rituxan is a CD20-directed cytolytic antibody whose approved indications include two cancers, non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.

“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,” stated CIRM president and CEO Maria T. Millan, M.D.

Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of more than 90 issued patents and 100 pending patent applications. The portfolio broadly covers the generation and engineering of iPSCs and the production of NK and T-cell cancer immunotherapies from clonal master iPSC lines—as well as compositions and methods for making iPSCs, including engineering their biological properties using CRISPR (clustered regularly interspaced palindromic repeats) and other nucleases, and for producing cells of the hematopoietic lineage, including NK cells, from iPSCs.

The company also holds an exclusive license from the University of Minnesota covering iPSC-derived NK cells expressing targeting receptors, including chimeric antigen receptors for human therapeutic use, and modified CD16 Fc receptors.

NK cells naturally express CD16, a potent activating receptor that enables binding of NK cells to the Fc portion of IgG antibodies. Once activated through CD16, NK cells can orchestrate a broad adaptive immune response by lysing antibody-coated tumor cells and secreting immune signaling cytokines, such as interferon gamma. But CD16 expression on NK cells can lead to downregulation in cancer patients, which can lead to loss of NK cell antitumor activity.

Dr. Millan noted that Fate Therapeutics’ approach to cancer immunotherapy based on adoptive transfer of healthy allogeneic donor NK cells has not been associated with 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.”

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