Fate Therapeutics, Inc. announced the publication of preclinical study results demonstrating the successful generation, durable anti-tumor response, and functional persistence of TCR-CAR+ iPSC-derived CD8aß T cells from induced pluripotent stem cells (iPSCs). The CD8aß T cells were derived from a single engineered iPSC integrating a novel chimeric antigen receptor (CAR) transgene into the T-cell receptor alpha constant (TRAC) locus, ensuring complete bi-allelic disruption of T-cell receptor (TCR) expression and promoting uniform CAR expression. The discoveries were made under a multi-year research collaboration between the Company and 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, and were published this week in Nature Biomedical Engineering.

The mass production of TCR-CAR+ CD8aß T cells from master engineered iPSC lines is a promising approach for development of off-the-shelf, cell-based cancer immunotherapies. Through a systematic assessment of factors that affect T-cell lineage commitment and induce adaptive T-cell formation, the researchers discovered that integrating the CAR construct into the TRAC locus delayed its expression and drove T-cell lineage commitment, and that regulation of CAR signaling strength promoted the generation of CD4+CD8+ double-positive cells mimicking thymic development in the absence of a TCR. Subsequent stimulation of the CAR matured the double-positive population into single-positive CD8aß T cells with a phenotype highly correlated with peripheral blood CD8aß effector T cells and distinct from ?d T cells and natural killer cells.

Preclinical studies showed that iPSC-derived TCR-CAR+ CD8aß T cells were able to repeatedly lyse tumor cells in vitro and durably control leukemia in vivo, with persistence in the bone marrow, spleen, and blood, in a systemic NALM6 leukemia model. The Company is conducting a multicenter Phase 1 study of FT819, the first T-cell therapy manufactured from a clonal master iPSC line to undergo clinical investigation. The product candidate's clonal engineered master iPSC line is created from a single iPSC that has a novel CD19-targeted 1XX CAR construct integrated into the TRAC locus, ensuring complete bi-allelic disruption of TCR expression to prevent graft-versus-host disease and promoting uniform CAR expression for enhanced anti-tumor activity.

Dose escalation is currently ongoing in single-dose and multi-dose escalation cohorts for relapsed /refractory B-cell malignancies.