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The Emergence of Immune-checkpoint Inhibitors in Colorectal Cancer Therapy

[ Vol. 22 , Issue. 9 ]

Author(s):

Michele Ghidini*, Nicola Fusco, Massimiliano Salati, Shelize Khakoo, Gianluca Tomasello, Fausto Petrelli, Dario Trapani and Angelica Petrillo   Pages 1021 - 1033 ( 13 )

Abstract:


Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients’ progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines.

Keywords:

Colorectal cancer, immunotherapy, immune-checkpoint inhibitors, microsatellite stable, adoptive cell therapies, cancer vaccines.

Affiliation:

Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Department of Oncology and Hemato-Oncology, University of Milan, PhD Program, Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Department of Medicine, The Royal Marsden Hospital NHS Foundation Trust, London and Surrey, Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Medical Oncology Unit, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio, Bergamo, Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Medical Oncology Unit, Ospedale del Mare, Naples

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