Ex Vivo Interleukin-12-Priming During CD8+ T Cell Activation Dramatically Improves Adoptive T Cell Transfer Antitumor Efficacy in a Lymphodepleted Host
- 30 April 2012
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American College of Surgeons
- Vol. 214 (4), 700-707
- https://doi.org/10.1016/j.jamcollsurg.2011.12.034
Abstract
Background Clinical application of adoptive T cell therapy has been hindered by an inability to generate adequate numbers of nontolerized, functionally active, tumor-specific T cells, which can persist in vivo. In order to address this, we evaluated the impact of interleukin (IL)-12 signaling during tumor-specific CD8 + T cell priming in terms of persistence and antitumor efficacy using an established B16 melanoma tumor adoptive therapy model. Study Design B6 mice were injected subcutaneously with B16 melanoma tumor cells. On day 12 of tumor growth, mice were preconditioned with cyclophosphamide (4mg dose, intraperitoneally), and 1 day later were treated by adoptive transfer of tumor-specific pmel-1 CD8 + T cells primed ex vivo 3 days earlier with both IL-12 and antigen (hGP100 25-33 peptide) or antigen only. Tumors were measured biweekly, and infused donor T cells were analyzed for persistence, localization to the tumor, phenotype, and effector function. Results Adoptive transfer of tumor-specific CD8 + T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced antitumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-γ (IFNγ). Conclusions Our findings demonstrate that ex vivo priming of tumor-specific CD8 + T cells with IL-12 dramatically improves their in vivo persistence and therapeutic ability on transfer to tumor-bearing mice. These findings can be directly applied as novel clinical trial strategies.Keywords
This publication has 41 references indexed in Scilit:
- Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cellsJCI Insight, 2005
- Extensive Replicative Capacity of Human Central Memory T CellsThe Journal of Immunology, 2004
- IL-12 Priming during In Vitro Antigenic Stimulation Changes Properties of CD8 T Cells and Increases Generation of Effector and Memory CellsPublished by The American Association of Immunologists ,2004
- Adoptive-cell-transfer therapy for the treatment of patients with cancerNature Reviews Cancer, 2003
- Tumor Regression and Autoimmunity after Reversal of a Functionally Tolerant State of Self-reactive CD8+ T CellsThe Journal of Experimental Medicine, 2003
- Generation of Tumor-Infiltrating Lymphocyte Cultures for Use in Adoptive Transfer Therapy for Melanoma PatientsJournal of Immunotherapy, 2003
- Signal 3 Determines Tolerance versus Full Activation of Naive CD8 T CellsThe Journal of Experimental Medicine, 2003
- The Roles of IL-12 in Providing a Third Signal for Clonal Expansion of Naive CD8 T CellsThe Journal of Immunology, 2002
- A Novel Transcription Factor, T-bet, Directs Th1 Lineage CommitmentCell, 2000
- Use of Tumor-Infiltrating Lymphocytes and Interleukin-2 in the Immunotherapy of Patients with Metastatic MelanomaNew England Journal of Medicine, 1988