Retroviral genetic modification of PBLs to optimize expansion for cell therapy

Division Of Basic Sciences - Nci

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Abstract

Cytotoxic T cells respond to antigen by reprogramming their metabolism to support cellular proliferation, differentiation and effector functions. These changes are induced by changes in gene expression induced by intracellular signaling pathways including the PI3K-AKT pathway and the MAP kinase (MAPK) pathway. These pathways are essential for T cell function, but oncogenic alterations in cancers stimulate proliferation through these same networks. Gain of function mutations in PIK3CA or KRAS can drive gastrointestinal cancers; many tumors also exhibit loss of function mutations in PTEN, a tumor suppressor and negative regulator of PI3K signaling. Preclinical studies have suggested that combining immune-based approaches with inhibitors of the PI3K or MAPK pathways can promote anti-tumor immune responses and inhibit tumor growth. Despite a substantial body of preclinical evidence supporting this approach, there has been little discernible success at translation. Between these studies there are conflicting results, and it is not clear whether the effects are specific to T cells, cancer cells, both or neither. In order to better understand how these shared pathways influence interactions between the adaptive immune system and cancer cells, we propose to investigate phosphatases that regulate the PI3K and MAPK pathways in a clinically relevant adoptive cell transfer model.