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Review
. 2021 Mar;51(3):544-556.
doi: 10.1002/eji.202048747. Epub 2021 Feb 23.

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action

Zena N Willsmore  1 , Ben G T Coumbe  1 , Silvia Crescioli  1 , Sara Reci  1 , Ayushi Gupta  1 , Robert J Harris  1 , Alicia Chenoweth  1   2 , Jitesh Chauhan  1 , Heather J Bax  1   3 , Alexa McCraw  1 , Anthony Cheung  1   2 , Gabriel Osborn  1 , Ricarda M Hoffmann  1 , Mano Nakamura  1 , Roman Laddach  1   4 , Jenny L C Geh  5 , Alastair MacKenzie-Ross  5 , Ciaran Healy  5 , Sophia Tsoka  4 , James F Spicer  3 , Debra H Josephs  1   3 , Sophie Papa  6   7 , Katie E Lacy  1 , Sophia N Karagiannis  1   2
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Free article
Review

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action

Zena N Willsmore et al. Eur J Immunol. 2021 Mar.
Free article

Abstract

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.

Keywords: CTLA-4; Cancer; Immunotherapy; Melanoma; PD-1.

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