BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res 2012 Apr 15;18(8):2326-35
Date
02/23/2012Pubmed ID
22355009DOI
10.1158/1078-0432.CCR-11-2515Scopus ID
2-s2.0-84859807701 (requires institutional sign-in at Scopus site) 95 CitationsAbstract
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.
Author List
Hong DS, Vence L, Falchook G, Radvanyi LG, Liu C, Goodman V, Legos JJ, Blackman S, Scarmadio A, Kurzrock R, Lizee G, Hwu PAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CD4-Positive T-LymphocytesCD8-Positive T-Lymphocytes
Colorectal Neoplasms
Cytokines
Female
HLA Antigens
Humans
Imidazoles
Immunity, Cellular
Immunocompetence
Lymphocyte Count
Male
Melanoma
Molecular Targeted Therapy
Neoplasms
Oximes
Proto-Oncogene Proteins B-raf
Thyroid Neoplasms
Tumor Necrosis Factor-alpha
