Pre-clinical development and molecular characterization of an engineered type 1 regulatory T-cell product suitable for immunotherapy.
Cytotherapy
; 23(11): 1017-1028, 2021 11.
Article
em En
| MEDLINE
| ID: mdl-34404616
ABSTRACT
BACKGROUND AIMS:
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.METHODS:
Here the authors established a production process aimed at current Good Manufacturing Practice (cGMP) production for CD4IL-10 cells.RESULTS:
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.CONCLUSIONS:
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transplante de Células-Tronco Hematopoéticas
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Doença Enxerto-Hospedeiro
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article