On December 9, 2017 Fate Therapeutics, Inc. (NASDAQ:FATE), a biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported the generation of chimeric antigen receptor (CAR)-targeted CD8αβ+ T cells from a clonal engineered master pluripotent cell line (MPCL) (Press release, Fate Therapeutics, DEC 9, 2017, View Source [SID1234522462]). The clonal engineered MPCL was created from an induced pluripotent stem cell (iPSC), which was modified in a one-time engineering event using CRISPR/Cas9 to both insert a CAR into the T-cell receptor α constant (TRAC) locus and eliminate T-cell receptor (TCR) expression. The groundbreaking development enables the renewable production of CAR-targeted, TCR-null CD8αβ+ T cells that are not restricted to an individual patient for off-the-shelf administration.
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The breakthrough was reported today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition by scientists from the laboratories of Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center and Fate Therapeutics. In September 2016, Fate Therapeutics and Memorial Sloan Kettering Cancer Center launched a multi-year partnership led by Dr. Sadelain to develop off-the-shelf T-cell product candidates using clonal engineered MPCLs. The collaborators are currently conducting preclinical studies and finalizing current good manufacturing practice protocols for the development of CAR-targeted, TCR-null T-cell immunotherapies. A first-in-human clinical trial of FT819, a CAR19 T-cell product candidate derived from a clonal engineered MPCL with complete elimination of TCR expression and TRAC-regulated CAR expression, is being planned.
"The use of a clonal engineered master pluripotent cell line enables cost-effective manufacture, timely availability and reliable off-the-shelf delivery of targeted T-cell cancer immunotherapy without patient restriction," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Additionally, unlike conventional allogeneic CAR T-cell approaches that involve billions of heterogeneous engineering events to modify the genomic function of primary T cells, an engineered iPSC clone is defined by a single uniform engineering event. As a result, a T-cell product generated from a clonal engineered master pluripotent cell line is homogeneous with respect to genomic modification and cell product composition. This revolutionary approach has the potential to mediate safer, more effective pharmacologic activity, including in combination with cycles of other cancer treatments."
In February 2017, Dr. Sadelain and colleagues published a set of preclinical studies in the journal Nature using primary T cells demonstrating that directing a CD19-specific CAR to the TRAC locus with CRISPR/Cas9 resulted in uniform CAR expression and enhanced T-cell potency as compared to conventional CAR T cells. Scientists from the laboratories of Sadelain and Fate Therapeutics advanced the observation by instead engineering iPSCs and generating CD8αβ+ T cells from a clonal engineered MPCL with a CD19-targeted CAR inserted into the TRAC locus and complete elimination of TCR expression. The collaborators demonstrated that the CAR-targeted, TCR-null CD8αβ+ T cells display antigen-specific anti-tumor potency, including cytokine release and targeted cellular cytotoxicity.
Fate Therapeutics has built an extensive intellectual property portfolio broadly covering the genomic engineering of iPSCs and off-the-shelf engineered T- and NK cell cancer immunotherapies. Its proprietary portfolio includes compositions and methods for editing iPSCs to modify their biological properties using CRISPR and other nucleases, including the use of CRIPSR to insert a CAR in the TRAC locus for endogenous transcriptional control, and for manufacturing cells of all hematopoietic lineages from iPSCs including T cells. In addition, the Company has an exclusive license from Memorial Sloan Kettering covering iPSC-derived T cells expressing chimeric antigen receptors for human therapeutic use, and maintains an option to exclusively license intellectual property arising from all research and development activities under the collaboration.
About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (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. 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 pluripotent cell line (MPCL). Similar to master cell lines used for the manufacture of monoclonal antibodies, clonal MPCLs can serve as a renewable cell source for the consistent and repeated manufacture of homogeneous cell products with the potential to treat many different diseases and many thousands of patients in an off-the-shelf manner. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 90 issued patents and 100 pending patent applications.