title: BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency.
abstract: OBJECTIVE
  An intact immune system likely contributes to the outcome of treatment and may be important for clearance of drug-resistant tumor cells and for prevention of recurrence. Although pharmacologic inhibition of BRAF(V600E) in melanoma patients, which is linked to immune suppression, results in an initial response rate, these responses are typically of limited duration. Combining immunotherapeutic drugs with kinase-targeted agents is an attractive strategy to increase clinical efficacy. Evidence suggesting that mitogen-activated protein kinase pathway activation in tumor cells contributes to immune suppression suggests that the two approaches may be synergistic, provided that BRAF(V600E) inhibitors are nontoxic to immune cells.
  
  
  METHODS
  To assess effects of mutant BRAF inhibition on systemic immunity, we studied 13 patients with tumors carrying a BRAF mutation who underwent treatment with GSK2118436, a V600 mutant BRAF-specific inhibitor. We carried out peripheral blood immunomonitoring before and following one or two 28-day cycles of treatment.
  
  
  RESULTS
  GSK2118436 treatment had no detectable impact on most immune parameters tested, including serum cytokine levels, peripheral blood cell counts, leukocyte subset frequencies, and memory CD4(+) and CD8(+) T-cell recall responses. A slight increase in serum TNF-α over the course of treatment was observed. In addition, three of the four human leukocyte antigen-A2-positive patients experienced a modest increase in circulating tumor antigen-specific CD8(+) T cells following BRAF(V600) inhibitor therapy.
  
  
  CONCLUSIONS
  GSK2118436 treatment results in no detectable negative impact on existing systemic immunity or the de novo generation of tumor-specific T cells. These findings suggest that future trials combining specific BRAF(V600E) inhibition with immunotherapy should not impair immune response.
authors.affiliation: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas 77030, USA. dshong@mdanderson.org
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Luis
authors.initials: L
authors.lastname: Vence
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Radvanyi
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.forename: Vicki
authors.initials: V
authors.lastname: Goodman
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Legos
authors.forename: Sam
authors.initials: S
authors.lastname: Blackman
authors.forename: Antonio
authors.initials: A
authors.lastname: Scarmadio
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizee
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015179:Colorectal Neoplasms / Q000188:drug therapy; D016207:Cytokines / Q000097:blood; D005260:Female; D006680:HLA Antigens / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007111:Immunity, Cellular / Q000187:drug effects*; D007121:Immunocompetence; D018655:Lymphocyte Count; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D010091:Oximes / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D007093:Imidazoles; D010091:Oximes; D014409:Tumor Necrosis Factor-alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib