Grazia R Tundo1, Diego Sbardella2, Pedro M Lacal3, Grazia Graziani4, Stefano Marini3. 1. Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy, grazia.tundo@libero.it. 2. Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy. 3. Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy. 4. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Abstract
BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.
BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.
Authors: G R Tundo; D Sbardella; A M Santoro; A Coletta; F Oddone; G Grasso; D Milardi; P M Lacal; S Marini; R Purrello; G Graziani; M Coletta Journal: Pharmacol Ther Date: 2020-05-19 Impact factor: 12.310
Authors: Chris Y Chiu; Judy J Chang; Ashanti I Dantanarayana; Ajantha Solomon; Vanessa A Evans; Rachel Pascoe; Céline Gubser; Lydie Trautman; Rémi Fromentin; Nicolas Chomont; James H McMahon; Paul U Cameron; Thomas A Rasmussen; Sharon R Lewin Journal: J Immunol Date: 2021-12-01 Impact factor: 5.422
Authors: Vera Petrova; Ihor Arkhypov; Rebekka Weber; Christopher Groth; Peter Altevogt; Jochen Utikal; Viktor Umansky Journal: Int J Mol Sci Date: 2020-03-30 Impact factor: 5.923