BRAF inhibitors and their immunological effects in malignant melanoma

Rebecca Adams; Jack E M Coumbe; Ben G T Coumbe; Jennifer Thomas; Zena Willsmore; Marija Dimitrievska; Monica Yasuzawa-Parker; Maximilian Hoyle; Suhaylah Ingar; Jenny Geh; Alastair MacKenzie Ross; Ciaran Healy; Sophie Papa; Katie E Lacy; Sophia N Karagiannis

doi:10.1080/1744666X.2022.2044796

BRAF inhibitors and their immunological effects in malignant melanoma

Rebecca Adams, Jack E M Coumbe, Ben G T Coumbe, Jennifer Thomas, Zena Willsmore, Marija Dimitrievska, Monica Yasuzawa-Parker, Maximilian Hoyle, Suhaylah Ingar, Jenny Geh, Alastair MacKenzie Ross, Ciaran Healy, Sophie Papa, Katie E Lacy, Sophia N Karagiannis

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Abstract

Introduction: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. Areas covered: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. Expert opinion: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing ‘old friends’ in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

Original language	English
Pages (from-to)	347-362
Number of pages	16
Journal	Expert Review Of Clinical Immunology
Volume	18
Issue number	4
Early online date	23 Feb 2022
DOIs	https://doi.org/10.1080/1744666X.2022.2044796
Publication status	E-pub ahead of print - 23 Feb 2022

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10.1080/1744666X.2022.2044796

Adams Coumbe Coumbe et al_BRAF_inhibitors_and_their_immunological_effects_in_malignant_melanoma__BRAFi_Accepted 180222aAccepted author manuscript, 842 KBLicence: CC BY

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Adams, R., Coumbe, J. E. M., Coumbe, B. G. T., Thomas, J., Willsmore, Z., Dimitrievska, M., Yasuzawa-Parker, M., Hoyle, M., Ingar, S., Geh, J., MacKenzie Ross, A., Healy, C., Papa, S., Lacy, K. E., & Karagiannis, S. N. (2022). BRAF inhibitors and their immunological effects in malignant melanoma. Expert Review Of Clinical Immunology, 18(4), 347-362. Advance online publication. https://doi.org/10.1080/1744666X.2022.2044796

@article{a76ad56478ad47eabd29cd710fdaf44e,

title = "BRAF inhibitors and their immunological effects in malignant melanoma",

abstract = "Introduction: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. Areas covered: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. Expert opinion: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing {\textquoteleft}old friends{\textquoteright} in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.",

author = "Rebecca Adams and Coumbe, {Jack E M} and Coumbe, {Ben G T} and Jennifer Thomas and Zena Willsmore and Marija Dimitrievska and Monica Yasuzawa-Parker and Maximilian Hoyle and Suhaylah Ingar and Jenny Geh and {MacKenzie Ross}, Alastair and Ciaran Healy and Sophie Papa and Lacy, {Katie E} and Karagiannis, {Sophia N}",

note = "Funding Information: The authors acknowledge support by the Medical Research Council (MR/ L023091/1; MR/V049445/1); Cancer Research UK King?s Health Partners Centre at King?s College London (C604/A25135); CR UK//NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); Breast Cancer Now (147; KCL-BCN-Q3); the Guy?s and St Thomas? Foundation Trust Charity, Melanoma Special Fund (SPF573); Cancer Research UK (C30122/A11527; C30122/A15774). The research was supported by the National Institute for Health Research Biomedical Research Centre based at Guy?s and St Thomas? NHS Foundation Trust and King?s College London (IS-BRC-1215-20006). The authors are solely responsible for study design, data collection, analysis, decision to publish, and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.",

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doi = "10.1080/1744666X.2022.2044796",

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Adams, R, Coumbe, JEM, Coumbe, BGT, Thomas, J, Willsmore, Z , Dimitrievska, M, Yasuzawa-Parker, M, Hoyle, M, Ingar, S, Geh, J, MacKenzie Ross, A, Healy, C, Papa, S, Lacy, KE & Karagiannis, SN 2022, 'BRAF inhibitors and their immunological effects in malignant melanoma', Expert Review Of Clinical Immunology, vol. 18, no. 4, pp. 347-362. https://doi.org/10.1080/1744666X.2022.2044796

TY - JOUR

T1 - BRAF inhibitors and their immunological effects in malignant melanoma

AU - Adams, Rebecca

AU - Coumbe, Jack E M

AU - Coumbe, Ben G T

AU - Thomas, Jennifer

AU - Willsmore, Zena

AU - Dimitrievska, Marija

AU - Yasuzawa-Parker, Monica

AU - Hoyle, Maximilian

AU - Ingar, Suhaylah

AU - Geh, Jenny

AU - MacKenzie Ross, Alastair

AU - Healy, Ciaran

AU - Papa, Sophie

AU - Lacy, Katie E

AU - Karagiannis, Sophia N

N1 - Funding Information: The authors acknowledge support by the Medical Research Council (MR/ L023091/1; MR/V049445/1); Cancer Research UK King?s Health Partners Centre at King?s College London (C604/A25135); CR UK//NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587); Breast Cancer Now (147; KCL-BCN-Q3); the Guy?s and St Thomas? Foundation Trust Charity, Melanoma Special Fund (SPF573); Cancer Research UK (C30122/A11527; C30122/A15774). The research was supported by the National Institute for Health Research Biomedical Research Centre based at Guy?s and St Thomas? NHS Foundation Trust and King?s College London (IS-BRC-1215-20006). The authors are solely responsible for study design, data collection, analysis, decision to publish, and preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

PY - 2022/2/23

Y1 - 2022/2/23

N2 - Introduction: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. Areas covered: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. Expert opinion: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing ‘old friends’ in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

AB - Introduction: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. Areas covered: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. Expert opinion: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing ‘old friends’ in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

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U2 - 10.1080/1744666X.2022.2044796

DO - 10.1080/1744666X.2022.2044796

M3 - Article

C2 - 35195495

SN - 1744-666X

VL - 18

SP - 347

EP - 362

JO - Expert Review Of Clinical Immunology

JF - Expert Review Of Clinical Immunology

IS - 4

ER -

BRAF inhibitors and their immunological effects in malignant melanoma

Abstract

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