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Selective BRAF Inhibitors Induce Marked T-cell Infiltration Into Human Metastatic Melanoma

J. Wilmott, G. Long, J. Howle, L. Haydu, R. Sharma, J. Thompson, R. Kefford, P. Hersey, R. Scolyer
Published 2011 · Medicine

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Purpose: To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment. Experimental Design: Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B. Results: Tumor infiltration by CD4+ and CD8+ lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015). There was a correlation between the degree of tumor infiltration by CD8+ and Granzyme B–expressing lymphocytes in post–BRAF inhibitor–treated biopsies (r = 0.690 and ρ = 0.013). Increased intratumoral CD8+ lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r = −0.793, ρ = 0.011; and r = 0.761, ρ = 0.004, respectively). Conclusions: The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses. Clin Cancer Res; 18(5); 1386–94. ©2011 AACR.
This paper references
Treatment combinations targeting apoptosis to improve immunotherapy of melanoma
P. Hersey (2009)
Inhibition of mutated, activated BRAF in metastatic melanoma.
K. Flaherty (2010)
Phase 1/2 study of GSK2118436, a selective inhibitor of V600 mutant (Mut) BRAF kinase: evidence of activity in melanoma brain metastases (Mets)
Gv Long (2010)
Cutaneous melanoma.
V. Lees (1993)
The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells
H. Sumimoto (2006)
Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
P. Chapman (2011)
Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression
M. Kono (2006)
New guidelines to evaluate the response to treatment in solid tumors
P. Therasse (2000)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Predictors of competing mortality in advanced head and neck cancer.
L. Mell (2010)
The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations
B. Comin-Anduix (2010)
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
E. Eisenhauer (2009)
Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.
A. Boni (2010)
Clin Cancer Res Clinical Cancer Research American Association for Cancer Research. Downloaded from Published OnlineFirst December
Cutaneous melanoma in the era of molecular profiling
J. Thompson (2009)
Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.
G. Long (2011)
Morphologic and immunohistochemical (IHC) changes in metastatic melanoma (MM) tissue and associations with clinical outcome in patients (pts) on BRAF inhibitors (BRAFi).
G. Long (2011)
Phase 1/2 study of GSK2118436, a selective inhibitor of V600 mutant (Mut) BRAF kinase: evidence of activity in melanoma brain metastases (Mets)
LongGV (2010)
Favorable outcome in clinically stage II melanoma patients is associated with the presence of activated tumor infiltrating T‐lymphocytes and preserved MHC class I antigen expression
I. S. van Houdt (2008)
Final version of 2009 AJCC melanoma staging and classification.
C. Balch (2009)
B-RAF is a therapeutic target in melanoma
M. Karasarides (2004)
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
C. Robert (2011)
Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors.
R. Kefford (2010)

This paper is referenced by
Melanoma: oncogenic drivers and the immune system.
N. Karachaliou (2015)
BreastCare Immunomodulation via Chemotherapy and Targeted Therapy : A New Paradigm in Breast Cancer Therapy ?
John Stagga Fabrice Andreb Sherene Loic (2012)
Mitigating the toxic effects of anticancer immunotherapy
Tara C. Gangadhar (2014)
ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma.
P. Brastianos (2016)
Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance
Bhargavi Pulluri (2017)
Novel Treatments in Development for Melanoma.
C. Bernatchez (2016)
Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma
A. Ribas (2019)
Consolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenib
S. Valpione (2015)
Harnessing the power of the immune system to target cancer.
G. Lizée (2013)
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4
L. Liu (2015)
The Ins and Outs of Chemokine-Mediated Immune Cell Trafficking in Skin Cancer
A. O. Yam (2019)
Emerging insights into resistance to BRAF inhibitors in melanoma.
A. Bucheit (2014)
Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial
R. Gutzmer (2020)
Regulation of MAPK signaling and implications in chronic lymphocytic leukemia
Ashima Shukla (2018)
Phase I/II RAF kinase inhibitors in cancer therapy
S. Turajlic (2013)
Immunotolerance as a Mechanism of Resistance to Targeted Therapies in Melanoma.
M. Mandala (2018)
Molecular pathology of malignant melanoma: changing the clinical practice paradigm toward a personalized approach.
Joshua R. Bradish (2014)
Controversies in the Management of Advanced Melanoma
A. Jarkowski (2014)
Anti-PD-1 therapy in melanoma.
B. Homet Moreno (2015)
Immunotherapy of melanoma: Present options and future promises
Anand Rotte (2014)
Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib–treated Patients with BRAFV600-mutated Metastatic Melanoma
Y. Yan (2019)
The immune‐related role of BRAF in melanoma
S. Tomei (2015)
Immunotherapy and Cancer Therapeutics: A Rich Partnership
G. Chen (2013)
Adoptive T-cell Transfer Therapy and Oncogene-Targeted Therapy for Melanoma: The Search for Synergy
M. L. Kwong (2013)
Targeting the PD-1 pathway: a promising future for the treatment of melanoma
A. Mamalis (2014)
Upregulation of microRNA-31 is associated with poor prognosis in patients with advanced colorectal cancer
Nobuhito Kubota (2020)
Universes collide: combining immunotherapy with targeted therapy for cancer.
J. Wargo (2014)
Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma
P. Ascierto (2019)
Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients.
D. Massi (2017)
Therapeutic vaccination immunomodulation: forming the basis of all cancer immunotherapy
B. J. Coventry (2019)
Are we entering the era of combination therapy for melanoma?
Justine V Cohen (2017)
BiomarkersforImmunostimulatoryMonoclonalAntibodiesin C ombination S trateg ies for Melanoma and O th er T umor T yp es
P. Ascierto (2013)
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