Document Detail


BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency.
MedLine Citation:
PMID:  22355009     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: 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:
David S Hong; Luis Vence; Gerald Falchook; Laszlo G Radvanyi; Chengwen Liu; Vicki Goodman; Jeffery J Legos; Sam Blackman; Antonio Scarmadio; Razelle Kurzrock; Gregory Lizee; Patrick Hwu
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-21
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-17     Completed Date:  2012-08-31     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2326-35     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
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MeSH Terms
Descriptor/Qualifier:
CD4-Positive T-Lymphocytes / drug effects,  immunology
CD8-Positive T-Lymphocytes / drug effects,  immunology
Colorectal Neoplasms / drug therapy
Cytokines / blood
Female
HLA Antigens / blood
Humans
Imidazoles / therapeutic use*
Immunity, Cellular / drug effects*
Immunocompetence
Lymphocyte Count
Male
Melanoma / drug therapy
Molecular Targeted Therapy
Neoplasms / drug therapy*,  immunology*
Oximes / therapeutic use*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*,  genetics
Thyroid Neoplasms / drug therapy
Tumor Necrosis Factor-alpha / blood
Chemical
Reg. No./Substance:
0/Cytokines; 0/HLA Antigens; 0/Imidazoles; 0/Oximes; 0/Tumor Necrosis Factor-alpha; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; QGP4HA4G1B/dabrafenib
Comments/Corrections
Erratum In:
Clin Cancer Res. 2012 Jul 1;18(13):3715

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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