Immune Checkpoint Blockade in Cancer Therapy

Abstract

Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have demonstrated promise in a variety of malignancies. Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade are being investigated to determine whether they enhance the efficacy of either approach alone. Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation.

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

“…Because some cancers, including MPM, engage immune checkpoints to escape antitumour immune responses, checkpoint molecule blockade has been pursued as a therapeutic anticancer strategy 3, 4, 5. Immunotherapy targeting the immune checkpoint programmed death‐1 (PD‐1)/PD‐ligand (L) 1 axis has been used to treat various cancers including non‐small‐cell lung cancer, melanoma, renal cell carcinoma and Hodgkin lymphoma 6, 7, 8, 9, 10.…”

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…Whilst strategies employed by the tumour to avoid immune-mediated clearance are complex and multifaceted, some therapeutic approaches to promote anti-tumour immunity are emerging. Antibody-mediated blockade of immune-checkpoint receptors is now clinically approved across a range of indications, 1 however such treatments lack sustained efficacy in the majority of patients. 2 Thus, a deeper understanding of therapeutic interventions represents an area of unmet clinical need.…”

Le vaccin ARN, une approche prometteuse pour la réactivation du système immunitaire dans la lutte contre le cancer

“…Ainsi, on observe, d'une part, un défaut d'activation des LT par les cellules dendritiques (DC) dans les ganglions, cellules dendritiques qui sont elles-mêmes inhibées par le contexte tumoral [1] ; d'autre part, une « paralysie » des LT activés ayant infiltré les tumeurs (ou tumor-infiltrating lymphocyte -TIL), ce qui les empêche d'éliminer les cellules tumorales [1] ( Figure 1). Les points de contrôles immunitaires sont des récepteurs de régulation négative présents à la surface des LT, tels que CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) et PD-1 (programmed death 1), dont l'engagement par leurs ligands exprimés par les cellules tumorales ou des cellules immunosuppressives du microenvironnement 1 bloque la fonction des LT [2]. Il est donc apparu logique de tenter de lutter contre le cancer en réac-tivant le système immunitaire, et les LT en particulier, d'une part, en bloquant la nanoparticule (Figure 2).…”

“…Cependant, dans un grand nombre de cancers, le système immunitaire est dérégulé par la tumeur afin qu'il ne puisse plus protéger l'organisme du développement tumoral (Figure 1). [2], ou sur la suppression des LT régulateurs immunosuppresseurs [1]. La seconde approche repose sur des stratégies visant à stimuler les propriétés des cellules dendritiques.…”