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Pre-clinical development and molecular characterization of an engineered type 1 regulatory T-cell product suitable for immunotherapy.
Pre-clinical development and molecular characterization of an engineered type 1 regulatory T-cell product suitable for immunotherapy. Cytotherapy Liu, J. M., Chen, P., Uyeda, M. J., Cieniewicz, B., Sayitoglu, E. C., Thomas, B. C., Sato, Y., Bacchetta, R., Cepika, A. M., Roncarolo, M. G. 2021Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic approach for many hematological disorders. However, allo-HSCT is frequently accompanied by a serious side effect: graft-versus-host disease (GVHD). The clinical use of allo-HSCT is limited by the inability of current immunosuppressive regimens to adequately control GvHD without impairing the graft-versus-leukemia effect (GvL) conferred by transplanted healthy immune cells. To address this, the authors have developed an engineered type 1 regulatory T-cell product called CD4IL-10 cells. CD4IL-10 cells are obtained through lentiviral transduction, which delivers the human IL10 gene into purified polyclonal CD4+ T cells. CD4IL-10 cells may provide an advantage over standard-of-care immunosuppressants because of the ability to suppress GvHD through continuous secretion of IL-10 and enhance the GvL effect in myeloid malignancies through targeted killing of malignant myeloid cells.Here the authors established a production process aimed at current Good Manufacturing Practice (cGMP) production for CD4IL-10 cells.The authors demonstrated that the CD4IL-10 cell product maintains the suppressive and cytotoxic functions of previously described CD4IL-10 cells. In addition, RNA sequencing analysis of CD4IL-10 identified novel transcriptome changes, indicating that CD4IL-10 cells primarily upregulate cytotoxicity-related genes. These include four molecules with described roles in CD8+ T and natural killer cell-mediated cytotoxicity: CD244, KLRD1, KLRC1 and FASLG. Finally, it was shown that CD4IL-10 cells upregulate IL-22, which mediates wound healing and tissue repair, particularly in the gut.Collectively, these results pave the way toward clinical translation of the cGMP-optimized CD4IL-10 cell product and uncover new molecules that have a role in the clinical application of CD4IL-10 cells.
View details for DOI 10.1016/j.jcyt.2021.05.010
View details for PubMedID 34404616