title: Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma.
abstract: BACKGROUND
  Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system.
  
  
  METHODS
  Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays.
  
  
  RESULTS
  Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples.
  
  
  CONCLUSIONS
  While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK). Electronic address: bastian.schilling@uk-essen.de.
authors: B
authors: B
authors: Schilling
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: W
authors: W
authors: Sondermann
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: F
authors: F
authors: Zhao
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: K G
authors: KG
authors: Griewank
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: E
authors: E
authors: Livingstone
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: A
authors: A
authors: Sucker
authors: University Medical Center, University of Tübingen, Tübingen.
authors: H
authors: H
authors: Zelba
authors: German Cancer Consortium (DKTK); University Medical Center, University of Tübingen, Tübingen.
authors: B
authors: B
authors: Weide
authors: German Cancer Consortium (DKTK); Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin.
authors: U
authors: U
authors: Trefzer
authors: German Cancer Consortium (DKTK); Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin.
authors: T
authors: T
authors: Wilhelm
authors: German Cancer Consortium (DKTK); Department of Dermatology, University of Mainz, Mainz.
authors: C
authors: C
authors: Loquai
authors: German Cancer Consortium (DKTK); Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich.
authors: C
authors: C
authors: Berking
authors: German Cancer Consortium (DKTK); Department of Dermatology, Heidelberg University Hospital, Heidelberg.
authors: J
authors: J
authors: Hassel
authors: Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Campus Kiel.
authors: K C
authors: KC
authors: Kähler
authors: German Cancer Consortium (DKTK); Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg; Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim.
authors: J
authors: J
authors: Utikal
authors: Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
authors: P
authors: P
authors: Al Ghazal
authors: Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
authors: R
authors: R
authors: Gutzmer
authors: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors: S M
authors: SM
authors: Goldinger
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: L
authors: L
authors: Zimmer
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: A
authors: A
authors: Paschen
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: U
authors: U
authors: Hillen
authors: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
authors: D
authors: D
authors: Schadendorf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D016906:Interleukin-9 / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000097:blood; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D054400:Receptors, CCR7 / Q000096:biosynthesis; D012189:Retrospective Studies; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C515370:CCR7 protein, human; D016207:Cytokines; C508607:IL9 protein, human; D007093:Imidazoles; D007211:Indoles; D016906:Interleukin-9; D010091:Oximes; D047428:Protein Kinase Inhibitors; D054400:Receptors, CCR7; D013449:Sulfonamides; D000077484:Vemurafenib; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D017493:Leukocyte Common Antigens; C561627:dabrafenib
keywords: T cells; dabrafenib; lymphocytes; melanoma; treatment; vemurafenib