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Expression of Genes Involved in T-cell Function and Hematopoietic Stem Cell Engraftment Significantly Increased
Fate Therapeutics, Inc. (Nasdaq:FATE), a biopharmaceutical company engaged in the discovery and development of adult stem cell modulators to treat orphan diseases, released preclinical data today highlighting the pharmacological properties of ex vivo programmed hematopoietic cells sourced from mobilized peripheral blood at the 56th Annual Meeting and Exposition of the American Society of Hematology (ASH). Using a newly-identified combination of two small molecule modulators, scientists from Fate Therapeutics demonstrated that both T-cells and CD34+ cells from mobilized peripheral blood can be modulated ex vivo, with preclinical evidence pointing to the programmed hematopoietic cells having improved therapeutic potential.
“While hematopoietic stem cell transplantation has proven curative potential, a significant need remains to reduce the morbidity and mortality associated with the procedure, including the risk of T-cell mediated complications such as viral infections, graft vs. host disease and delayed immune reconstitution,” said Christian Weyer, M.D., M.A.S., President and Chief Executive Officer of Fate Therapeutics. “We are excited that our ex vivo programming platform has identified a combination of small molecule modulators that promote the supra-physiologic activation of genes implicated in the cell cycle, immune tolerance and anti-viral properties of T-cells, as well as in the survival, proliferation and engraftment potential of CD34+ cells. We believe these findings form a compelling scientific basis to support the clinical evaluation of ex vivo programmed mobilized peripheral blood in patients undergoing hematopoietic stem cell transplantation for the treatment of hematologic malignancies.”
The data are being presented today during a poster presentation entitled “Ex Vivo Modulation of Mobilized Peripheral Blood: Characterization of HSC and T-Cell Responses to Small Molecule Modulation,” and expand and build upon the clinical development of the Company’s lead product candidate, PROHEMA®. PROHEMA, an ex vivo programmed hematopoietic cellular therapeutic which uses FT1050 (16,16 dimethyl prostaglandin E2 , or dmPGE2) to pharmacologically modulate umbilical cord blood, is currently being investigated in a Phase 2 clinical trial in adult patients and a Phase 1b clinical trial in pediatric patients with hematologic malignancies undergoing umbilical cord blood transplantation. As part of its continuing evaluation of the modulatory effects of FT1050 on hematopoietic cells, Fate Therapeutics identified a second small molecule modulator, referred to as FT4145, that synergizes with FT1050 to further enhance the pharmacological properties and the in vivo therapeutic potential of CD34+ cells and T-cells.
Gene expression analysis of CD34+ cells sourced from mobilized peripheral blood co-modulated with FT1050 and FT4145 showed a ~60-fold increase in the expression of the key homing receptor CXCR4, and ex vivo programmed CD34+ cells demonstrated a statistically significant increase in engraftment in preclinical models as compared to unmodulated cells. Additionally, genome-wide expression analysis of the T-cell compartment of mobilized peripheral blood, including CD8+, CD4+ and regulatory T-cells, revealed the induction of genes involved in cell cycle (e.g., CCND1, CCNE1), immune tolerance (e.g., DUSP5, FLT1) and anti-viral properties (e.g., CD55, EFNB2). Additionally, following a five-day culture in the presence of activating beads, T-cells co-modulated with FT1050 and FT4145 were found to have reduced proliferation rates and decreased cell-surface protein expression of ICOS, a key T-cell activation marker, relative to unmodulated cells.
Collectively, these preclinical findings point to the therapeutic potential for ex vivo programmed hematopoietic cells to mitigate T-cell mediated complications and improve outcomes in patients undergoing hematopoietic stem cell transplant with mobilized peripheral blood as a cell source. Mobilized peripheral blood is the predominant cell source used in hematopoietic stem cell (HSC) transplantation.
