Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy

Klebanoff CA, Crompton JG, Leonardi AJ, Yamamoto TN, Chandran SS, Eil RL, Sukumar M, Vodnala SK, Hu J, Ji Y, Clever D, Black MA, Gurusamy D, Kruhlak MJ, Jin P, Stroncek DF, Gattinoni L, Feldman SA, Restifo NP (2017)

Publication Type: Journal article

Publication year: 2017

Journal

JCI Insight American Society for Clinical Investigation

Book Volume: 2

Article Number: e95103

Journal Issue: 23

DOI: 10.1172/jci.insight.95103

Abstract

Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype. Critically, this intervention did not compromise cell yield. Mechanistically, disruption of AKT signaling preserved MAPK activation and promoted the intranuclear localization of FOXO1, a transcriptional regulator of T cell memory. Consequently, AKT signaling inhibition synchronized the transcriptional profile for FOXO1-dependent target genes across multiple donors. Expression of an AKT-resistant FOXO1 mutant phenocopied the influence of AKT signaling inhibition, while addition of AKT signaling inhibition to T cells expressing mutant FOXO1 failed to further augment the frequency of CD62L-expressing cells. Finally, treatment of established B cell acute lymphoblastic leukemia was superior using anti-CD19 CAR–modified T cells transduced and expanded in the presence of an AKT inhibitor compared with conventionally grown T cells. Thus, inhibition of signaling along the PI3K/AKT axis represents a generalizable strategy to generate large numbers of receptor-modified T cells with an early memory phenotype and superior antitumor efficacy.

Involved external institutions

Memorial Sloan Kettering Cancer Center US United States (USA) (US) National Cancer Institute (NCI) US United States (USA) (US) US National Institutes of Health (NIH) US United States (USA) (US)

How to cite

APA:

Klebanoff, C.A., Crompton, J.G., Leonardi, A.J., Yamamoto, T.N., Chandran, S.S., Eil, R.L.,... Restifo, N.P. (2017). Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight, 2(23). https://doi.org/10.1172/jci.insight.95103

MLA:

Klebanoff, Christopher A., et al. "Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy." JCI Insight 2.23 (2017).

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