Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma

Ascierto, Paolo A.; Ferrucci, Pier Francesco; Fisher, Rosalie; Vecchio, Michele Del; Atkinson, Victoria; Schmidt, Henrik; Schachter, Jacob; Queirolo, Paola; Long, Georgina V.; Giacomo, Anna Maria Di; Svane, Inge Marie; Lotem, Michal; Bar-Sela, Gil; Couture, Félix; Mookerjee, Bijoyesh; Ghori, Razi; Ibrahim, Nageatte; Moreno, Blanca Homet; Ribas, Antoni

doi:10.1038/s41591-019-0448-9

Cited by 275 publications

(274 citation statements)

References 28 publications

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“…Due to the immunological effects reported, preclinical studies tested combinations of BRAFi and/or MEK inhibitor (MEKi) with anti‐PD‐1 checkpoint blocking antibody and observed increased ratio of CD8 + effector T cells to Tregs in tumor biopsies . Recently, performed clinical trials with the triple combination of BRAFi, MEKi and checkpoint inhibitor demonstrated promising response rates in subgroups of melanoma patients, but also reported high toxicities . A deeper understanding of the tumor microenvironmental changes during targeted therapy and how the immune system can be manipulated to potentiate responses is crucial for the development of urgently needed, alternative combinations.…”

Section: Introductionmentioning

confidence: 99%

“…20,21 Recently, performed clinical trials with the triple combination of BRAFi, MEKi and checkpoint inhibitor demonstrated promising response rates in subgroups of melanoma patients, but also reported high toxicities. [22][23][24] A deeper understanding of the tumor microenvironmental changes during targeted therapy and how the immune system can be manipulated to potentiate responses is crucial for the development of urgently needed, alternative combinations.…”

Section: Introductionmentioning

confidence: 99%

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A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

Bellmann

Cappellano

Schachtl-Rieß

et al. 2019

Intl Journal of Cancer

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Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAFV600E mutation and concomitant PTEN loss in order to characterize alterations in tumor‐infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi‐sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor‐infiltrating effector cells were activated and produced high levels of IFN‐γ, TNF‐α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor‐infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi‐sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

Bellmann

Cappellano

Schachtl-Rieß

et al. 2019

Intl Journal of Cancer

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“…Melanoma most commonly arises through activating mutations in BRAF or NRAS driving deregulated proliferation when combined with (usually solar UV irradiation-induced) genetic alterations and/or epigenetic events that promote senescence bypass (Bennett 2008;Shain and Bastian 2016). Notably, over the past 8 yr or so major advanc-es in melanoma therapy, from targeting oncogenic BRAF and MEK through to the breakthroughs in immunotherapies (Hodi et al 2010;Chapman et al 2011;Long et al 2014;Robert et al 2015a,b;Wolchok et al 2017;Ascierto et al 2019;Ribas et al 2019) have led to important lessons for cancer therapy in general and highlighted the many challenges to successful treatment strategies. Indeed, the durable response rate to any approved therapy still remains relatively low and the vast majority of patients who initially respond to treatment later develop resistance Jenkins et al 2018).…”

Section: Genetic Vs Nongenetic Intratumor Heterogeneitymentioning

confidence: 99%

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

2019

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An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.

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“…1,2 A growing body of evidence suggests that combining CB with other treatments such as small molecule inhibitors, cytotoxic agents, and radiotherapy could potentiate the response to CB, in part by augmenting tumor immunogenicity through increased surface pMHC expression. [3][4][5][6][7][8][9] While clinical trials in this space have shown promise 10,11 , the optimal combination of agents, as well as the order and timing of administration, are only beginning to be understood. In order to improve combinatorial strategies, a quantitative, molecular understanding of how different perturbations shift the immunopeptidome is required.…”

Section: Introductionmentioning

confidence: 99%

Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

Stopfer

Mesfin

Joughin

et al. 2020

Preprint

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Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire's response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking robust normalization controls. We describe a novel approach that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input.HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma to profile the immunopeptidome response to CDK4/6 inhibition and interferon gamma, known modulators of antigen presentation, we uncovered treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.

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Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma

Cited by 275 publications

References 28 publications

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

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