Inhibition of Akt promotes immunologic memory in tumor-infiltrating lymphocytes isolated from patients with melanoma. Homo sapiens

Adoptive cell immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can result in complete regression of advanced melanoma in some patients, but the efficacy of this potentially curative therapy is limited by poor persistence of TIL after adoptive-transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in viral-specific murine models, but whether this approach may enhance features of memory (e.g. long-term persistence) in TIL which are characteristically exhausted and senescent is not established. Here we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy for melanoma. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of anti-tumor T cells and improve the efficacy of cellbased immunotherapy for metastatic cancer. Overall design: Human TIL from 3 patients (biological replicates) were cultured independently in triplicate (technical replicates). TIL were stimulated with agonistic CD3 (OKT3) and irradiated allogeneic feeders (200:1 ratio) with high dose IL-2 in the presence (n=12) or absence (n=12) of Akt inhibitor (1uM).