Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.

Abstract

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be 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 virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that 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. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer.

• Authors: Joseph G Crompton, Madhusudhanan Sukumar, Rahul Roychoudhuri, David Clever, Alena Gros, Robert L Eil, Eric Tran, Ken-Ichi Hanada, Zhiya Yu, Douglas C Palmer, Sid P Kerkar, Ryan D Michalek, Trevor Upham, Anthony Leonardi, Nicolas Acquavella, Ena Wang, Francesco M Marincola, Luca Gattinoni, Pawel Muranski, Mark S Sundrud, Christopher A Klebanoff, Steven A Rosenberg, Douglas T Fearon, Nicholas P Restifo
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 2 Pg. 296-305 (Jan 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25432172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Humans
• Immunologic Memory
• Immunotherapy, Adoptive (methods)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, pathology)
• Melanoma (immunology, therapy)
• Melanoma, Experimental (immunology, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Transgenic
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, immunology)
• Random Allocation
• Tumor Cells, Cultured