Fate Therapeutics, Inc., a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s Investigational New Drug (IND) application for FT819, an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD19+ malignancies. FT819 is the first-ever CAR T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line, and is engineered with several first-of-kind features designed to improve the safety and efficacy of CAR T-cell therapy. The Company plans to initiate clinical investigation of FT819 for the treatment of patients with relapsed / refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL).
“The clearance of our IND application for FT819 is a ground-breaking milestone in the field of cell-based cancer immunotherapy. Our unique ability to produce CAR T cells from a clonal master engineered iPSC line creates a pathway for more patients to gain timely access to therapies with curative potential,” said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. “Four years ago, we first set out under our partnership with Memorial Sloan Kettering led by Dr. Michel Sadelain to improve on the revolutionary success of patient-derived CAR T-cell therapy and bring an off-the-shelf paradigm to patients, and we are very excited to advance FT819 into clinical development.”
FT819 was designed to specifically address several limitations associated with the current generation of patient- and donor-derived CAR T-cell therapies. Under a collaboration with Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, and Head, Gene Expression and Gene Transfer Laboratory at MSK, the Company incorporated several first-of-kind features into FT819 including:
- Use of a clonal master iPSC line as the starting cell source, which enables CAR T cells to be mass produced and delivered off-the-shelf for broad patient access;
- Incorporation of a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion in published work described in the journal Nature Medicine (https://doi.org/10.1038/s41591-018-0290-5);
- Insertion of the CAR transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR expression and enhanced T-cell potency in published work described in the journal Nature (https://doi.org/10.1038/nature21405); and
- Complete bi-allelic disruption of T-cell receptor (TCR) expression for the prevention of graft-versus-host disease (GvHD), a potentially life-threatening complication associated with allogeneic T-cell therapy.
The multi-center Phase 1 clinical trial of FT819 is designed to determine the maximum tolerated dose of FT819 and assess its safety and clinical activity in up to 297 adult patients across three types of B-cell malignancies (CLL, ALL, and NHL). Each indication will enroll independently and evaluate three dose-escalating treatment regimens: Regimen A as a single dose of FT819; Regimen B as a single dose of FT819 with IL-2 cytokine support; and Regimen C as three fractionated doses of FT819. For each indication and regimen, dose-expansion cohorts of up to 15 patients may be enrolled to further evaluate the clinical activity of FT819.
At the American Association for Cancer Research (AACR) Virtual 2020 Meeting, the Company presented preclinical data demonstrating FT819 is comprised of CD8αβ T cells with uniform 1XX CAR expression and complete elimination of endogenous TCR expression. Additionally, data from functional assessments showed FT819 has antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines that is comparable to that of healthy donor-derived CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia.
Fate Therapeutics has an exclusive license for all human therapeutic use to U.S. Patent No. 10,370,452 pursuant to its license agreement with MSK1, which patent covers compositions and uses of effector T cells expressing a CAR, where such T cells are derived from a pluripotent stem cell including an iPSC. In addition to the patent rights licensed from MSK, the Company owns an extensive intellectual property portfolio that broadly covers compositions and methods for the genome editing of iPSCs using CRISPR and other nucleases, including the use of CRISPR to insert a CAR in the TRAC locus for endogenous transcriptional control.