Advances in Immuno-oncology for the Treatment of Colorectal and Anal Cancers

2021 ◽  
Author(s):  
Nataliya V. Uboha ◽  
Patrick T. Grogan ◽  
Dustin A. Deming
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Anal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gastrointestinal Cancers ◽  
Colorectal Tumors ◽  
Ongoing Research

AbstractImmune checkpoint inhibitors changed treatment paradigms across several malignancies. With the exception of tumors with microsatellite instability (MSI-H), gastrointestinal cancers have been largely resistant to these agents. Herein, we review the data supporting the use of immunotherapy for patients with (MSI-H) colorectal tumors. We discuss ongoing research and answered questions regarding resistance and sequence of use of these agents for this disease. We discuss ongoing research efforts to augment activity of these agents in microsatellite stable colorectal cancer. We also provide an overview of the data and ongoing studies immune checkpoint inhibitors in the treatment of anal cancer.

scholarly journals Gastrointestinal cancer treatment with immune checkpoint inhibitors

2021 ◽  
Vol 64 (5) ◽  
pp. 342-348
Author(s):  
Jin Won Kim
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Gastrointestinal Cancers ◽  
First Line ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
First Line Treatment

Immuno-oncological treatment approaches, particularly with the use of immune checkpoint inhibitors such as antiprogrammed death 1 (PD-1)/programmed death ligand 1 antibody or anti-cytotoxic T-lymphocyte associated protein 4 antibody, have become the standard treatment for gastrointestinal cancers. However, gastrointestinal cancers show an overall modest tumor response to immune checkpoint inhibitors. Nevertheless, subgroups such as tumors that are DNA mismatch repair-deficient or have high microsatellite instability particularly benefit from immune checkpoint inhibitors. Even in the first-line setting for colorectal cancer, the clinical efficacy of pembrolizumab, an anti–PD-1 antibody, was superior to that of chemotherapy. Recently, a combination of atezolizumab, an anti-programmed death ligand 1 antibody, and bevacizumab was approved as the first-line treatment for hepatocellular carcinoma, and was reported as superior to sorafenib. Nivolumab, an anti–PD-1 antibody that is added to chemotherapy as the first-line treatment for gastric cancer, resulted in longer survival compared with chemotherapy alone. Further studies are ongoing to investigate additional immune checkpoint inhibitors for other gastrointestinal cancers. This review aims to provide an overview of the results of clinical trials for immune checkpoint inhibitors in gastrointestinal cancers, including colorectal cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, and biliary tract cancer.

scholarly journals Current status and perspectives of immune checkpoint inhibitors for colorectal cancer

2020 ◽  
Vol 51 (1) ◽  
pp. 10-19
Author(s):  
Hidekazu Hirano ◽  
Atsuo Takashima ◽  
Tetsuya Hamaguchi ◽  
Dai Shida ◽  
Yukihide Kanemitsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
High Level ◽  
Deficient Mismatch Repair

Abstract Immunotherapy, especially immune checkpoint inhibitors, has revolutionized the standard-of-care of multiple types of tumors. For colorectal cancer, the clinical development of immune checkpoint inhibitors is mainly separated according to the status of microsatellite instability or mismatch repair in a tumor. High-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer generally has a tumor microenvironment with infiltration of T cells, associated with a favorable response to immune checkpoint inhibitors. Immune checkpoint inhibitors, including pembrolizumab (anti-PD-1 inhibitor) and nivolumab (anti-PD-1 inhibitor) with or without ipilimumab (anti-CTLA-4 inhibitor), have been integrated into the standard-of-care for high-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer. Conversely, limited T-cell infiltration in the tumor microenvironment of microsatellite stable/proficient mismatch repair metastatic colorectal cancer, which constitutes the majority of metastatic colorectal cancer, is assumed to be a major resistant mechanism to immune checkpoint inhibitors. Currently, clinical trials to improve the clinical activity of immune checkpoint inhibitors by immunomodulation are ongoing for metastatic colorectal cancer. Furthermore, immune checkpoint inhibitors are under development in neoadjuvant and/or adjuvant setting. Here, we review the existing clinical data with ongoing trials and discuss the future perspectives with a focus on the immunotherapy of colorectal cancer.

scholarly journals Rnf43 Mutation As A Biomarker For Immune Checkpoint Inhibitor Efficacy In Colorectal Cancer

2021 ◽  
Author(s):  
Nan Zhang ◽  
XinPeng Shi ◽  
WenCui Ju ◽  
YunFeng Lou ◽  
XiaoYong Luo
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Gene Mutation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Data Set ◽  
Cancer Data ◽  
Low Efficiency

Abstract Background: Immune checkpoint inhibitors can prolong the survival of patients with advanced colorectal cancer and have been approved for the treatment of metastatic colorectal cancer patients with mismatch repair defects and high microsatellite instability (dMMR-MSI-H). However, there are still many deficiencies in their clinical application, such as their benefit in a limited population, low efficiency, and lack of accurate markers. Therefore, finding accurate biomarkers has become an urgent problem in the immunotherapy of colorectal cancer. Our research aimed to find biomarkers that can accurately predict the population with potential benefit.Methods: We analysed data from a colon cancer immunotherapy cohort (n = 110, ICI cohort), including mutation data and clinical data, to identify the mutated gene closely related to Immune Checkpoint Inhibitors (ICIs). Next, we further verified the relationship between gene mutation and clinical features, such as Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI) status in the TCGA colorectal cancer data set (non-ICI cohort). Then, CIBERSORT was used to analyse the relationships between gene mutation and both immune cell infiltration and immune genes, and GSEA was used to analyse the effect of gene mutation on pathway activation levels. In addition, we analysed the Whole-exome Sequencing (WES) and drug sensitivity data of colorectal cancer cell lines in the GDSC database.Conclusions: Our results show that Rnf43 mut can be used as a biomarker to predict the efficacy of ICI for colorectal cancer, and it can be used for clinical screening of patients who benefit from ICI for colorectal cancer.

Microsatellite instability status in metastatic colorectal cancer and effect of immune checkpoint inhibitors on survival in MSI-high metastatic colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15106-e15106 ◽  
Author(s):  
Wataru Okamoto ◽  
Yoshiaki Nakamura ◽  
Manabu Shiozawa ◽  
Yoshito Komatsu ◽  
Tadamichi Denda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Large Scale ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Gene Mutations ◽  
Poorly Differentiated

e15106 Background: Tumor mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI. Methods: mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumors exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS. Results: From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 51.0 vs. 43.8, p=0.31; right-sided primary (%) 70.6 vs. 25.0, p<0.001; and poorly differentiated histology (%) 33.3 vs. 8.9, p<0.001. Of the 864 pts who received parallel NGS testing, median tumor mutation burdens (TMB) in MSI-H and MSI-L/MSS were 32.8 and 12.6 mt/Mb, p<0.001. High TMB, defined as >20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p<0.001; PIK3CA 48.3 vs. 13.2, p<0.001; BRAF 34.5 vs. 7.5, p<0.001; MSH2 17.2 vs. 0, p<0.001; CTNNB1 17.2 vs. 0.6, p<0.001; and ERBB2 10.3 vs. 1.4, p<0.001. ERBB2 amplification was detected only in MSI-L/MSS pts (2.3%). Two-year survival rates from first-line systemic therapy in 389 pts with MSI-L/MSS, 5 pts with MSI-H treated with ICI in any-line, and 5 pts with MSI-H not treated with ICI, were 77.7, 100, and 33.3%, respectively. Conclusions: MSI-H mCRC tumors were more frequent in right-sided colon primaries and with poorly differentiated histology. Median TMB was significantly greater in MSI-H pts, and a very high burden was frequently seen. Survival in MSI-H mCRC was poor before ICIs; these agents may improve outcomes for MSI-H pts. Clinical trial #UMIN000020437.

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