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The potential of BRAF-targeted therapy combined with immunotherapy in melanoma.

ABSTRACT: Introduction: Immune checkpoint inhibitor therapy and BRAF-targeted therapy have been developed for the treatment of metastatic melanoma. The optimal use of these agents, either in sequence or combination, for the 40-50% of melanoma patients whose tumors harbor a BRAFV600 mutation is unknown, but data from a number of clinical trials, including one randomized Phase II study, are emerging.Areas covered: This review describes the preclinical and clinical rationale for combined BRAF-targeted therapy with immunotherapy, including the known effects of BRAF-targeted therapy on the immune microenvironment, and the clinical trial data from a number of studies.Expert opinion: BRAF-targeted therapy is associated with high response rates in patients with metastatic melanoma but also leads to changes in the tumor microenvironment that may sensitize these tumors to immunotherapy. The early trials of BRAF-targeted therapy with immunotherapy, in particular with anti-PD-1/PD-L1 agents, are encouraging and suggest that some patients may benefit from this treatment approach. However, incorporating these combinations into routine clinical practice requires the read-out from two randomized clinical trials expected in the coming 1-2 years.

SUBMITTER: Naderi-Azad S

PROVIDER: S-EPMC7150269 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The potential of BRAF-targeted therapy combined with immunotherapy in melanoma.

Naderi-Azad Sheida S Sullivan Ryan R

Expert review of anticancer therapy 20200205 2

<b>Introduction</b>: Immune checkpoint inhibitor therapy and BRAF-targeted therapy have been developed for the treatment of metastatic melanoma. The optimal use of these agents, either in sequence or combination, for the 40-50% of melanoma patients whose tumors harbor a BRAFV600 mutation is unknown, but data from a number of clinical trials, including one randomized Phase II study, are emerging.<b>Areas covered</b>: This review describes the preclinical and clinical rationale for combined BRAF-t ...[more]

PMID: 32003263

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Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.

Dataset Information

The potential of BRAF-targeted therapy combined with immunotherapy in melanoma.

Publications

The potential of BRAF-targeted therapy combined with immunotherapy in melanoma.

Similar Datasets

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