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World J Gastroenterol. Aug 7, 2019; 25(29): 3920-3928
Published online Aug 7, 2019. doi: 10.3748/wjg.v25.i29.3920
Immunotherapy in colorectal cancer: Available clinical evidence, challenges and novel approaches
Joseph Tintelnot, Alexander Stein
Joseph Tintelnot, Alexander Stein, Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
Author contributions: Tintelnot J and Stein A performed literature research; Tintelnot J drafted the manuscript and performed the revision; Stein A designed the outline, coordinated and corrected the writing of the paper.
Conflict-of-interest statement: Dr. Stein reports institutional research grants from Merck, BMS, Roche, Sanofi, and Servier, personal fees from BMS, MSD, Merck, Roche, and Amgen during the conduct of the study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Alexander Stein, MD, Assistant Professor, Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany. a.stein@uke.de
Telephone: +49-40-741056882 Fax: +49-40-741053563
Received: March 18, 2019
Peer-review started: March 19, 2019
First decision: May 9, 2019
Revised: May 21, 2019
Accepted: July 2, 2019
Article in press: July 3, 2019
Published online: August 7, 2019
Processing time: 143 Days and 11.3 Hours
Abstract

In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.

Keywords: Immunotherapy; Combination; Colorectal cancer; Metastatic; Adjuvant

Core tip: Colorectal cancer is not responsive to single agent programmed death 1/ligand 1 or cytotoxic T lymphocyte-associated antigen-4 inhibitors. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses are currently being evaluated to enhance immunogenicity of mismatch repair proficient colorectal cancers. Here we review current clinical evidence, challenges and novel approaches in ongoing clinical programs.