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Cancer Therapy: Preclinical

BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice

Chengwen Liu, Weiyi Peng, Chunyu Xu, Yanyan Lou, Minying Zhang, Jennifer A. Wargo, Jie Qing Chen, Haiyan S. Li, Stephanie S. Watowich, Yan Yang, Dennie Tompers Frederick, Zachary A. Cooper, Rina M. Mbofung, Mayra Whittington, Keith T. Flaherty, Scott E. Woodman, Michael A. Davies, Laszlo G. Radvanyi, Willem W. Overwijk, Gregory Lizée and Patrick Hwu
Chengwen Liu
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Weiyi Peng
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Chunyu Xu
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Yanyan Lou
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Minying Zhang
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Jennifer A. Wargo
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Jie Qing Chen
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Haiyan S. Li
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Stephanie S. Watowich
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Yan Yang
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Dennie Tompers Frederick
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Zachary A. Cooper
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Rina M. Mbofung
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Mayra Whittington
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Keith T. Flaherty
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Scott E. Woodman
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Michael A. Davies
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Laszlo G. Radvanyi
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Willem W. Overwijk
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Gregory Lizée
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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Patrick Hwu
Departments of 1Melanoma Medical Oncology and 2Immunology, Center for Cancer Immunology Research; 3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Divisions of 4Surgical Oncology and 5Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts
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DOI: 10.1158/1078-0432.CCR-12-1626 Published January 2013
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Abstract

Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAF-mutant tumors.

Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen–independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples.

Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model.

Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell–based immunotherapy for the treatment of patients with melanoma. Clin Cancer Res; 19(2); 393–403. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received May 18, 2012.
  • Revision received November 8, 2012.
  • Accepted November 13, 2012.
  • ©2012 American Association for Cancer Research.
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Clinical Cancer Research: 19 (2)
January 2013
Volume 19, Issue 2
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BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice
Chengwen Liu, Weiyi Peng, Chunyu Xu, Yanyan Lou, Minying Zhang, Jennifer A. Wargo, Jie Qing Chen, Haiyan S. Li, Stephanie S. Watowich, Yan Yang, Dennie Tompers Frederick, Zachary A. Cooper, Rina M. Mbofung, Mayra Whittington, Keith T. Flaherty, Scott E. Woodman, Michael A. Davies, Laszlo G. Radvanyi, Willem W. Overwijk, Gregory Lizée and Patrick Hwu
Clin Cancer Res January 15 2013 (19) (2) 393-403; DOI: 10.1158/1078-0432.CCR-12-1626

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BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice
Chengwen Liu, Weiyi Peng, Chunyu Xu, Yanyan Lou, Minying Zhang, Jennifer A. Wargo, Jie Qing Chen, Haiyan S. Li, Stephanie S. Watowich, Yan Yang, Dennie Tompers Frederick, Zachary A. Cooper, Rina M. Mbofung, Mayra Whittington, Keith T. Flaherty, Scott E. Woodman, Michael A. Davies, Laszlo G. Radvanyi, Willem W. Overwijk, Gregory Lizée and Patrick Hwu
Clin Cancer Res January 15 2013 (19) (2) 393-403; DOI: 10.1158/1078-0432.CCR-12-1626
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Clinical Cancer Research
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