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Ex vivo Expansion of Tumor-reactive T Cells by Means of Bryostatin 1/Ionomycin and the Common Gamma Chain Cytokines Formulation
Published on: January 14, 2011
Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics
Joseph G Crompton1, Madhusudhanan Sukumar2, Rahul Roychoudhuri3
1National Cancer Institute (NCI), NIH, Bethesda, Maryland. Department of Surgery, University of California Los Angeles, Los Angeles, California. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. joe.crompton@nih.gov sukumarm2@mail.nih.gov restifo@nih.gov.
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.
Insights
Pharmacologic inhibition of Akt enhances tumor-infiltrating lymphocytes (TIL) persistence and antitumor immunity. This novel immunometabolomic approach improves adoptive cell therapy for metastatic cancer.
Area of Science:
- Immunology
- Cancer Therapy
- Cell Biology
Background:
- Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) shows promise for advanced cancer.
- Poor TIL persistence limits ACT efficacy.
- Akt inhibition promotes memory in virus-specific T cells, but its effect on exhausted TIL is unknown.
Purpose of the Study:
- To investigate if pharmacologic Akt inhibition enhances memory features in TIL.
- To determine if Akt inhibition improves TIL persistence and antitumor immunity.
Main Methods:
- Pharmacologic Akt inhibition was used to expand TIL.
- Transcriptional, metabolic, and functional properties of expanded TIL were analyzed.
- TIL persistence was assessed in immunodeficient mice.
- Antitumor immunity was evaluated in a mouse model of cell-based immunotherapy.
Main Results:
- Akt inhibition enabled TIL expansion with memory T cell characteristics.
- Akt inhibition enhanced TIL persistence in vivo.
- Akt inhibition augmented CD8 T cell antitumor immunity in a mouse model.
Conclusions:
- Pharmacologic Akt inhibition is a novel immunometabolomic strategy.
- This approach enhances the persistence and function of antitumor T cells.
- Akt inhibition holds potential for improving cell-based immunotherapy efficacy in metastatic cancer.
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