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Cancer Immunol Res. 2014 Jul;2(7):643-54. doi: 10.1158/2326-6066.CIR-13-0215. Epub 2014 Apr 29.

Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.

Author information

1
Authors' Affiliations: Departments of Surgical Oncology and Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas;
2
Harvard-MIT Division of Health Sciences and Technology, Cambridge; Department of Microbiology and Immunobiology; Harvard Medical School; Divisions of.
3
Department of Microbiology and Immunobiology; Harvard Medical School; Divisions of.
4
Medical Oncology.
5
Harvard Medical School; Divisions of Dermatopathology, and.
6
Harvard Medical School; Divisions of.
7
Harvard Medical School; Divisions of Department of Medical Oncology, Dana-Farber Cancer Institute;
8
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut;
9
Helen Diller Family Comprehensive Cancer Center; and Department of Cell and Molecular Pharmacology, University of California San Francisco, San Francisco, California.
10
Harvard Medical School; Divisions of Medical Oncology.
11
Harvard Medical School; Divisions of Dermatology, Massachusetts General Hospital;
12
Department of Microbiology and Immunobiology; Harvard Medical School; Divisions of Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
13
Authors' Affiliations: Departments of Surgical Oncology and Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas; jwargo@mdanderson.org.

Abstract

BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.

PMID:
24903021
PMCID:
PMC4097121
DOI:
10.1158/2326-6066.CIR-13-0215
[Indexed for MEDLINE]
Free PMC Article

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