Abstract
The success of immune checkpoint inhibitors (ICIs) in an increasing range of heavily mutated tumor types such as melanoma has culminated in their exploration in different subsets of patients with metastatic colorectal cancer (mCRC). As a result of their dramatic and durable response rates in patients with chemorefractory, mismatch repair-deficient-microsatellite instability-high (dMMR-MSI-H) mCRC, ICIs have become potential alternatives to classical systemic therapies. The anti-programmed death-1 (PD-1) agents, Pembrolizumab and Nivolumab, have been granted FDA approval for this subset of patients. Unfortunately, however, not all CRC cases with the dMMR-MSI-H phenotype respond well to ICIs, and ongoing studies are currently exploring biomarkers that can predict good response to them. Another challenge lies in developing novel treatment strategies for the subset of patients with the mismatch repair-proficient-microsatellite instability-low (pMMR-MSI-L) phenotype that comprises 95% of all mCRC cases in whom treatment with currently approved ICIs has been largely unsuccessful. Approaches aiming at overcoming the resistance of tumors in this subset of patients are being developed including combining different checkpoint inhibitors with either chemotherapy, anti-angiogenic agents, cancer vaccines, adoptive cell transfer (ACT), or bispecific T-cell (BTC) antibodies. This review describes the rationale behind using immunotherapeutics in CRC. It sheds light on the progress made in the use of immunotherapy in the treatment of patients with dMMR-MSI-H CRC. It also discusses emerging approaches and proposes potential strategies for targeting the immune microenvironment in patients with pMMR-MSI-L CRC tumors in an attempt to complement immune checkpoint inhibition.
Highlights
The observation that the anti-CCR4 antibody, Mogamulizumab, depletes CCR4 positive inhibitory T-regs in patients with cancer has paved the way for its evaluation in combination with other immune therapies for malignancies that are highly infiltrated with T-regs, including proficient MMR (pMMR)-microsatellite instability (MSI)-L Colorectal cancer (CRC) [239]
This ongoing trial aims at assessing the safety and efficacy of the combination of Regorafenib and Nivolumab in patients with previously treated, advanced gastric cancer or CRC. 25 gastric cancer and 25 CRC patients were recruited until October 2018, and they were exposed to both, Regorafenib and Nivolumab
Since not all CRC cases with the deficient MMR (dMMR)-MSI-H phenotype respond well to Immune checkpoint inhibitor IDO1 (ICI), further studies are ongoing to better understand both, the mechanisms that render some of these tumors resistant to immunotherapy and the biomarkers that provide them with positive prognostic implications
Summary
Colorectal cancer (CRC) is the third most common malignancy worldwide with about 1.4 million newly diagnosed cases per year [1, 2]. It is the third leading cause of cancer-related mortality in the United States and is responsible for around 700,000 annual deaths worldwide [2]. Preventive and screening strategies have been appropriately developed in several countries, around 25% of patients still present at late stages, and 25–50% of them present at an early stage but proceed to develop regional or distant metastasis later on [2, 3,4,5,6,7,8] Among those presenting with late stage disease, 86% die within 5 years [9]. Despite advances in systemic therapy and liver-directed treatments, the prognosis of patients with metastatic CRC (mCRC) remains poor, with a low median survival ranging between 5 months and 2 years and a low median 5-year survival of only 12.5% in the United States [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
