TY - JOUR
T1 - Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics
AU - Crompton, Joseph G.
AU - Sukumar, Madhusudhanan
AU - Roychoudhuri, Rahul
AU - Clever, David
AU - Gros, Alena
AU - Eil, Robert L.
AU - Tran, Eric
AU - Hanada, Ken Ichi
AU - Yu, Zhiya
AU - Palmer, Douglas C.
AU - Kerkar, Sid P.
AU - Michalek, Ryan D.
AU - Upham, Trevor
AU - Leonardi, Anthony
AU - Acquavella, Nicolas
AU - Wang, Ena
AU - Marincola, Francesco M.
AU - Gattinoni, Luca
AU - Muranski, Pawel
AU - Sundrud, Mark S.
AU - Klebanoff, Christopher A.
AU - Rosenberg, Steven A.
AU - Fearon, Douglas T.
AU - Restifo, Nicholas P.
N1 - Publisher Copyright:
© 2014 AACR.
PY - 2015/8/8
Y1 - 2015/8/8
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-14-2277
DO - 10.1158/0008-5472.CAN-14-2277
M3 - Article
C2 - 25432172
AN - SCOPUS:84921044688
SN - 0008-5472
VL - 75
SP - 296
EP - 305
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -