title: Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.
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.
authors.affiliation: Authors' Affiliations: Departments of Surgical Oncology and Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas;
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Cambridge; Department of Microbiology and Immunobiology; Harvard Medical School; Divisions of.
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Juneja
authors.affiliation: Department of Microbiology and Immunobiology; Harvard Medical School; Divisions of.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sage
authors.affiliation: Medical Oncology.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Harvard Medical School; Divisions of Dermatopathology, and.
authors.forename: Adriano
authors.initials: A
authors.lastname: Piris
authors.affiliation: Harvard Medical School; Divisions of.
authors.forename: Devarati
authors.initials: D
authors.lastname: Mitra
authors.affiliation: Harvard Medical School; Divisions of.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lo
authors.affiliation: Harvard Medical School; Divisions of Department of Medical Oncology, Dana-Farber Cancer Institute;
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Harvard Medical School; Divisions of Department of Medical Oncology, Dana-Farber Cancer Institute;
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: Helen Diller Family Comprehensive Cancer Center; and Department of Cell and Molecular Pharmacology, University of California San Francisco, San Francisco, California.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Harvard Medical School; Divisions of Medical Oncology.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Harvard Medical School; Divisions of Dermatology, Massachusetts General Hospital;
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: Department of Microbiology and Immunobiology; Harvard Medical School; Divisions of Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Authors' Affiliations: Departments of Surgical Oncology and Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas; jwargo@mdanderson.org.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007121:Immunocompetence; D007211:Indoles / Q000008:administration & dosage; D000074324:Ipilimumab; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D007211:Indoles; D000074324:Ipilimumab; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf