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Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer.

ABSTRACT: Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair proficient (pMMR)/non-MSI-H mCRC. The immune resistance mechanisms in pMMR/non-MSI-H mCRC have not yet been clearly elucidated. Significant efforts are currently focused on identifying effective combination immunotherapy regimens for the treatment of patients with pMMR/non-MSI-H mCRC. The combination of atezolizumab with cobimetinib had shown promising clinical activity in an early-phase clinical trial. Unfortunately, the IMblaze 370 (COTEZO) phase III trial of atezolizumab/cobimetinib combination in patients with mCRC failed to show significant improvement in overall survival in patients treated with the atezolizumab/combimetinib combination in comparison with regorafenib alone. This review summarizes the recent major advances in the clinical development of immunotherapy regimens for patients with pMMR/non-MSI-H mCRC.

SUBMITTER: Lee JJ

PROVIDER: S-EPMC6612427 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer.

Lee James J JJ Chu Edward E

Clinical colorectal cancer 20180621 4

Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair ...[more]

PMID: 30072278

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Project description:BackgroundMismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.MethodsWe confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.ResultsWe identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.ConclusionsWe demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.

Project description:The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population-based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5-year disease-free survival (DFS) rates were 59, 68, 78, 83 and 94% (p < 0.001); 5-year disease-specific survival (DSS) rates were 47, 55, 75, 80, and 89% (p < 0.001); and 5-year overall survival (OS) rates were 40, 44, 66, 61, and 76% (p < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite-stable (MSS) and microsatellite-instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and BRAF mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.

Dataset Information

Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer.

Publications

Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer.

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