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- W2891206508 abstract "Adoptive Cell Therapy of cancer using T cells is entering mainstream practice after yearsas a research method. Central to the efficacy of this “living therapy” is the function of theT cells transferred. T-cells, like other primary tissue cells, undergo differentiation anddeath. Clinical and preclinical data shows that lesser differentiated, less glycolytic, andmore proliferative-capable cells used for the adoptive transfer yield superior tumorresponses.This introductory section will describe discoveries which elucidate and control T-celldifferentiation and function for the improvement of adoptive cell therapy. Namely by useof inhibition of the PI3k/AKT pathways, and through the discovery of a dual function ofdeath and differentiation by the canonical death receptor Fas, which can be parsed apartwith a mutation from valine to cysteine at the 194 position (C194V), differentiation can bewithheld while leaving cell proliferation unhindered during T-cell stimulation andexpansion. The data also reveals that the differentiation signal caused by extracellular Fasligation passes through AKT, revealing both Fas and AKT as points of intervention fortargeting differentiation along the same pathway.From further investigation, this introduction will describe the effect of AKT inhibition onT-cell differentiation on a transciptional and metabolic level. The data reveals AKTinhibition promoted FOXO1 intranuclear organization, which creates a more naive-likephenotype to the cells, and lower glycolytic status, another phenotype associated withpersistent and long-lived cells. Furthermore, this control of AKT and Fas in T-cells yieldsbenefits in several modalities of pre-clinical models of adoptive T-cell immunotherapy ofcancer, in both use of a chimeric antigen receptor (CAR) and with use of TumorInfiltrating Lymphocytes (TIL). Finally, the real-world applicability of the findingincluding the use of AKT inhibition in current approved Adoptive T-cell immunotherapieswill be discussed." @default.
- W2891206508 created "2018-09-27" @default.
- W2891206508 creator A5062574740 @default.
- W2891206508 date "2018-04-01" @default.
- W2891206508 modified "2023-09-28" @default.
- W2891206508 title "Cell to cell signaling via AKT causes T cell differentiation and collapse of tumour stroma" @default.
- W2891206508 hasPublicationYear "2018" @default.
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