Review
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2024; 30(13): 1815-1835
Published online Apr 7, 2024. doi: 10.3748/wjg.v30.i13.1815
Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions
Samantha Sharma, Naresh Singh, Anita Ahmed Turk, Isabella Wan, Akshay Guttikonda, Julia Lily Dong, Xinna Zhang, Mateusz Opyrchal
Samantha Sharma, Naresh Singh, Isabella Wan, Akshay Guttikonda, Julia Lily Dong, Xinna Zhang, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Anita Ahmed Turk, Mateusz Opyrchal, Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Xinna Zhang, Mateusz Opyrchal, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Co-first authors: Samantha Sharma and Naresh Singh.
Author contributions: Sharma S and Singh N contributed equally to the study's conception, design, and wrote the manuscript as co-first authors; Turk AA offered insights into the current clinical aspects of colorectal cancer patients; Wan I, Guttikonda A, and Dong JL assisted in drafting the manuscript; Zhang X and Opyrchal M supervised the review framework as senior authors, offered valuable feedback, and contributed to the writing of the manuscript.
Supported by IU Simon Comprehensive Cancer Center grant, No. 5P30CA082709-24.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Samantha Sharma, PhD, Assistant Professor, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 980 W Walnut St, R3.C260, Indianapolis, IN 46202, United States. samshar@iu.edu
Received: December 5, 2023
Peer-review started: December 5, 2023
First decision: January 27, 2024
Revised: February 22, 2024
Accepted: March 13, 2024
Article in press: March 13, 2024
Published online: April 7, 2024
Processing time: 120 Days and 3.5 Hours
Abstract

Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Keywords: Colorectal cancer; Immune checkpoint inhibitors; Clinical trials; Immunotherapy; Microsatellite instability; Microsatellite stability; DNA mismatch repair

Core Tip: Colorectal cancer (CRC) often eludes early detection, limiting the efficacy of existing chemotherapy and targeted therapies. This article delves into the realm of immune checkpoint inhibitors in CRC, dissecting their mechanisms and outcomes through a comprehensive review of clinical trials. It sheds light on the underlying rationale, challenges faced, and potential strategies to improve prognosis and trial success in this critical domain. Notably, while microsatellite instability-high CRC exhibits heightened responsiveness to checkpoint inhibitors, the article underscores potential breakthroughs in treating microsatellite stable CRC-the predominant cases-providing insights into bettering prognosis and trial outcomes in CRC treatment.