Adoptive Cell Therapy of cancer using T cells is entering mainstream practice after years
as a research method. Central to the efficacy of this “living therapy” is the function of the
T cells transferred. T-cells, like other primary tissue cells, undergo differentiation and
death. Clinical and preclinical data shows that lesser differentiated, less glycolytic, and
more proliferative-capable cells used for the adoptive transfer yield superior tumor
responses.
This introductory section will describe discoveries which elucidate and control T-cell
differentiation and function for the improvement of adoptive cell therapy. Namely by use
of inhibition of the PI3k/AKT pathways, and through the discovery of a dual function of
death and differentiation by the canonical death receptor Fas, which can be parsed apart
with a mutation from valine to cysteine at the 194 position (C194V), differentiation can be
withheld while leaving cell proliferation unhindered during T-cell stimulation and
expansion. The data also reveals that the differentiation signal caused by extracellular Fas
ligation passes through AKT, revealing both Fas and AKT as points of intervention for
targeting differentiation along the same pathway.
From further investigation, this introduction will describe the effect of AKT inhibition on
T-cell differentiation on a transciptional and metabolic level. The data reveals AKT
inhibition promoted FOXO1 intranuclear organization, which creates a more naive-like
phenotype to the cells, and lower glycolytic status, another phenotype associated with
persistent and long-lived cells. Furthermore, this control of AKT and Fas in T-cells yields
benefits in several modalities of pre-clinical models of adoptive T-cell immunotherapy of
cancer, in both use of a chimeric antigen receptor (CAR) and with use of Tumor
Infiltrating Lymphocytes (TIL). Finally, the real-world applicability of the finding
including the use of AKT inhibition in current approved Adoptive T-cell immunotherapies
will be discussed
