title: The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy.
abstract: Colorectal cancers (CRCs) have been identified as potential targets for immunotherapy with programmed cell death (PD)-1 inhibitors. English-language publications from MedLine and Embase that evaluated PD-1/PD ligand 1 (PD-L1) in the CRC tumor microenvironment and clinical trials that assessed PD-1 inhibitors were included. Sixteen abstracts were screened. Fifteen met the inclusion criteria. After review of the full texts, this resulted in a final reference list of 8 studies eligible for review. Five studies that assessed PD-1/PD-L1 in CRC and 3 trials that assessed PD-1 inhibitors were included. PD-1-positive (PD-1+) tumor-infiltrating lymphocytes and PD-L1+cancer cells featured more prominently in high-level microsatellite instability (MSI-H) CRCs compared with microsatellite stable (MSS) CRCs, except in 1 study in which PD-L1 expression was higher in MSS CRCs. In the 3 trials that assessed PD-1 inhibitor, all 3 studies recruited patients with metastatic CRC (mCRC). One study also included patients with recurrent CRC. The objective response according to the Response Evaluation Criteria in Solid Tumors criteria was 0% (19 CRC patients with unknown microsatellite instability status) in the nivolumab study. In the pembrolizumab study, the objective response to PD-1 inhibitor was 40% and 0% in patients with MSI-H and MSS mCRC, respectively (10 patients in the MSI-H group, 18 patients in the MSS group). Seventy-eight percent of the patients in the MSI-H mCRC group compared with 11% in the MSS mCRC group (P < .005) showed no further disease progression at 12 weeks. In the nivolumab with or without ipilimumab study, objective partial response at 12 weeks to PD-1 inhibitor with or without cytotoxic T-lymphocyte-associated protein 4 inhibitor was 25.5% to 33.3% and 5% in the MSI-H and MSS groups, respectively (100 patients in the MSI-H group, 20 patients in the MSS group). Clinical trials that assessed PD-1 inhibitor immunotherapy in patients with CRC have recruited only small cohorts of patients with mCRC. Studies on the tumor microenvironment have been on the basis of archival specimens with different antibody PD-1 and PD-L1 preparations for immunohistochemistry, independent from immunotherapy trials. Immunotherapy with PD-1 therapy has potential benefit for immunogenic MSI-H CRCs whereas there is no evidence to date to suggest immunotherapy benefit in MSS CRCs. The available data are limited, and there is no information on non-mCRCs. Future trials are under way to determine its benefits.
authors.affiliation: Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Discipline of Surgery, Sydney Medical School, The University of Sydney, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Colorectal Surgery, Westmead Hospital, Westmead, New South Wales, Australia. Electronic address: james.toh@unsw.edu.au.
authors.forename: James W T
authors.initials: JWT
authors.lastname: Toh
authors.affiliation: Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: de Souza
authors.affiliation: Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Lim
authors.affiliation: Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.
authors.forename: Puneet
authors.initials: P
authors.lastname: Singh
authors.affiliation: Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Chua
authors.affiliation: Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia; Department of Medical Oncology, Liverpool Hospital, Liverpool, New South Wales, Australia.
authors.forename: Weng
authors.initials: W
authors.lastname: Ng
authors.affiliation: Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia; Liverpool Clinical School, Western Sydney University, Liverpool, New South Wales, Australia; South West Clinical School, Faculty of Medicine, The University of New South Wales, Liverpool, New South Wales, Australia; Centre for Oncology Education and Research Translation (CONCERT), Liverpool, New South Wales, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Spring
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000074324:Ipilimumab; D053842:Microsatellite Instability; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab
keywords: Microsatellite instability; Nivolumab; PD-L1; Pembrolizumab; TILs