Exploring immunotherapy in colorectal cancer

Abstract

Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability—high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

“…Furthermore, recent research has also described a significant interaction between the PD-1/PD-L1 axis and the EGFR pathway [ 28 ]. These mechanisms ultimately help the tumor to escape anti-tumor immunity [ 3 , 4 , 5 , 28 , 29 , 30 , 31 ]. Therefore, monoclonal antibodies have been developed to antagonize this inhibitory signaling, and in the last decade, several randomized clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 drugs [ 29 , 30 , 31 , 32 , 33 , 34 ].…”

“…These mechanisms ultimately help the tumor to escape anti-tumor immunity [ 3 , 4 , 5 , 28 , 29 , 30 , 31 ]. Therefore, monoclonal antibodies have been developed to antagonize this inhibitory signaling, and in the last decade, several randomized clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 drugs [ 29 , 30 , 31 , 32 , 33 , 34 ]. The most immunological response is expected in those (metastatic) CRC patients who have tumors with deficient mismatch-repair and/or high levels of microsatellite instability [ 29 , 35 , 36 ].…”

Tipping the scales: Immunotherapeutic strategies that disrupt immunosuppression and promote immune activation

“…Although the percentage of patients eligible for ICI therapy has increased from 1.54% in 2011 to 43.63% in 2018 ( 4 ), the portion of patients that benefits from these therapies remains limited ( 8 – 11 ). For example, in metastatic colorectal cancer (mCRC) in which the 5-year survival is 15%, only 3.5%-6.5% of mCRC patients respond to ICB ( 9 – 11 ).…”

“…Although the percentage of patients eligible for ICI therapy has increased from 1.54% in 2011 to 43.63% in 2018 ( 4 ), the portion of patients that benefits from these therapies remains limited ( 8 – 11 ). For example, in metastatic colorectal cancer (mCRC) in which the 5-year survival is 15%, only 3.5%-6.5% of mCRC patients respond to ICB ( 9 – 11 ). In advanced cancers, such as head and neck squamous cell carcinoma (HNSCC) and advanced melanoma, only 15%-20% and 33%-44% of the patients, respectively, benefit with pembrolizumab or nivolumab (anti-PD-1) treatment ( 4 , 8 , 12 – 15 ).…”

Prognostic role of indoleamine 2,3-dioxygenase 1 expression in solid tumors: A systematic review and meta-analysis

“…It is reported that high mutational burden and PD-L1 expression of urothelial carcinoma made it more sensitive to immunotherapy (2,3), and several ICs had been approved to treat it (4). Similarly, ICIs had also shown good clinical efficacy in prostatic cancer (5), penile cancer (6), testicular cancer (7), colorectal cancer (8), and esophagus cancer (9). Additionally, nivolumab, pembrolizumab, camrelizumab, and tislelizumab had been approved to treat Hodgkin lymphoma (HL) (10).…”