Abstract
Immunotherapy has considerably increased the number of anticancer agents in many tumor types including metastatic colorectal cancer (mCRC). Anti-PD-1 (programmed death 1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint inhibitors (ICI) have been shown to benefit the mCRC patients with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). However, ICI is not effective in mismatch repair proficient (pMMR) colorectal tumors, which constitute a large population of patients. Several clinical trials evaluating the efficacy of immunotherapy combined with chemotherapy, radiation therapy, or other agents are currently ongoing to extend the benefit of immunotherapy to pMMR mCRC cases. In dMMR patients, MSI testing through immunohistochemistry and/or polymerase chain reaction can be used to identify patients that will benefit from immunotherapy. Next-generation sequencing has the ability to detect MSI-H using a low amount of nucleic acids and its application in clinical practice is currently being explored. Preliminary data suggest that radiomics is capable of discriminating MSI from microsatellite stable mCRC and may play a role as an imaging biomarker in the future. Tumor mutational burden, neoantigen burden, tumor-infiltrating lymphocytes, immunoscore, and gastrointestinal microbiome are promising biomarkers that require further investigation and validation.
Highlights
Colorectal cancer (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer [1,2]
In that study (Checkmate 142), 82 dMMR or microsatellite instability (MSI)-H patients were treated with a combination of ipilimumab and nivolumab, followed by nivolumab monotherapy and had an objective response rate (ORR) of 46%
There has been an accumulation of evidence that the two PD1-blocking antibodies, namely pembrolizumab and nivolumab, and one anti-CTLA4 antibody, i.e., ipilimumab, can considerably improve survival in many metastatic CRC (mCRC) patients with MSI-H or dMMR
Summary
Colorectal cancer (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer [1,2]. Many of these studies evaluating the efficacy of immunotherapy are currently ongoing in mCRC, either combined with or compared to chemotherapy. Gray indicates countries without clinical trials registered in ClinicalTrials.gov database. This map was created using an interactive map obtained from mapchart.net. Mutational burden related to MSI-H CRC results in tumors that express a plethora of neoantigens, studies them have shown respond chemotherapy [10]. The main aim of this review is to examine the various immunotherapy approaches in metastatic CRC and discuss biomarkers for the prediction of therapeutic effectiveness
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