On April 1, 2019 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported late-breaking preclinical data highlighting the Company’s unmatched ability to mass produce uniformly engineered chimeric antigen receptor (CAR) T cells for off-the-shelf cancer immunotherapy at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia (LB-073/18: Generation of Novel Single Cell-derived Engineered Master Pluripotent Cell Line as a Renewable Source for Off-the-shelf TCR-less CAR T Cells in support of First-of-kind Clinical Trial) (Press release, Fate Therapeutics, APR 1, 2019, View Source [SID1234534823]).
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The Company’s proprietary approach to CAR T-cell therapy utilizes a one-time genetic modification event followed by high-throughput selection of a single gene-edited induced pluripotent stem cell (iPSC). In contrast to repeatedly engineering large populations of patient- or donor-derived T cells which results in batch-to-batch and cell-to-cell variability, the Company has shown that a single gene-edited iPSC can be maintained as a clonal master engineered iPSC line which can be repeatedly used for production of uniformly engineered CAR T cells.
"The efficiency, accuracy, and uniformity of genetic modifications have the potential to impact the safety and efficacy of CAR T-cell therapy. We know that, when engineering a population of T cells, current gene-editing technologies create genomic heterogeneity and result in undesired byproducts, such as DNA mutagenesis and translocations. The selection of a single gene-edited cell for the derivation of a clonal master engineered iPSC line ensures that the effects of gene editing can be fully characterized and that only engineered T cells meeting rigorous quality standards are administered to patients," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics.
New preclinical data presented today at AACR (Free AACR Whitepaper) for FT819, the Company’s universal, off-the-shelf CAR19 T-cell product candidate being developed under a collaboration with Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., demonstrate the production of clonal master engineered iPSC lines having complete elimination of T-cell receptor (TCR) expression and insertion of a novel 1XX CAR signaling domain into the T-cell receptor alpha (TRAC) locus. These synthetic features are intended to mitigate the risk of graft-versus-host disease, a severe life-threatening condition that occurs when donor T cells attack a patient’s healthy tissue, and to regulate CAR expression to enhance the therapeutic profile of CAR T cells.
Scientists from the Company and MSK are using clonal master engineered iPSC lines under the collaboration to overcome the complexity, heterogeneity, and substantial costs associated with engineering T cells from a patient or a donor. As proof-of-principle for the therapeutic advantages arising from selecting a single gene-edited cell for the production of CAR T-cell therapy, the scientists engineered a population of 545 cells using CRISPR-directed gene editing and found that only about 5% of cells contained both bi-allelic disruption of the TCR and insertion of the CAR into the TRAC locus. Upon further characterization for off-target genomic modifications and functional performance, only about 2% of the cell population were determined to meet the Company’s standards for genomic integrity and overall quality.
Previously published work by Dr. Sadelain in the journal Nature has shown that directing a CD19-specific CAR to the TRAC locus enhances T-cell potency, and that TRAC-targeted CAR T cells vastly outperform conventionally-generated CAR T cells in a mouse model of acute lymphoblastic leukemia (View Source). Additionally, Dr. Sadelain has shown in published work described in the journal Nature Medicine that the third-generation 1XX CAR signaling domain balances T-cell effector and memory programs, resulting in CAR T cells with potent activity and longer durability (View Source).
Fate Therapeutics has exclusively licensed from MSK foundational intellectual property covering the production and composition of iPSC-derived T cells for human therapeutic use. Additionally, in May 2018, the Company expanded its existing license agreement with MSK to include certain patents and patent applications relating to a novel 1XX CAR construct and off-the-shelf CAR T cells, including the use of CRISPR and other innovative technologies for their production. In addition, Fate Therapeutics 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.
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 in repeat doses to mediate 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 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 to treat many patients. As a result, the Company’s platform is uniquely capable of addressing the limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is fraught with batch-to-batch and cell-to-cell variability that can affect safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 100 issued patents and 100 pending patent applications.