scholarly journals Mismatch Repair ( MMR ) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR‐Deficient Colorectal Cancer

2021 ◽  
Author(s):  
Ibrahim Halil Sahin ◽  
Subir Goyal ◽  
Yoanna Pumpalova ◽  
Mohamad B. Sonbol ◽  
Satya Das ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Gene Alteration

scholarly journals Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2317 ◽  
Author(s):  
Federica Marmorino ◽  
Alessandra Boccaccino ◽  
Marco Maria Germani ◽  
Alfredo Falcone ◽  
Chiara Cremolini
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Dna Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Favorable Effect ◽  
Mutational Load ◽  
Dna Mismatch

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

scholarly journals Current Treatments of Metastatic Colorectal Cancer with Immune Checkpoint Inhibitors—2020 Update

2020 ◽  
Vol 9 (11) ◽  
pp. 3520
Author(s):  
Gerhard Jung ◽  
Daniel Benítez-Ribas ◽  
Ariadna Sánchez ◽  
Francesc Balaguer
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Host Immune System ◽  
Systemic Treatments

During the last 20 years, chemotherapy has improved survival rates of colorectal cancer (CRC). However, the majority of metastatic cases do not respond to or progress after first line conventional chemotherapy and contribute to the fatalities of patients with CRC. Insights into the immune contexture of the tumor microenvironment (TME) have enabled the development of new systemic treatments that boost the host immune system against the tumor—the immune checkpoint inhibitors (ICI). These promising drugs have already shown astonishing efficacies in other cancer types and have raised new hope for the treatment of metastatic CRC (mCRC). In this review, we will summarize the results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration (FDA) in 2017, as well as all relevant recent studies conducted since then—some of which are not published yet. We will focus on therapeutic efficacy, but also discuss the available data for drug safety and security, changes in quality of life indicators and predictive biomarkers for treatment response. The burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned. For each trial, we have made a preliminary assessment of the quality of clinical trial design and of the “European Society of Medical Oncology (ESMO) magnitude of clinical benefit” (ESMO-MCBS) in order to provide the first evidence-based recommendation to the reader.

Programmed death (PD)-ligand 1 (L1) expression and mismatch repair (MMR) deficiency across tumor types: Candidates for checkpoint inhibitor based immunotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14622-e14622
Author(s):  
Seung Tae Kim ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
Young Suk Park ◽  
Ho Yeong Lim ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
The Status ◽  
Mmr Deficiency ◽  
Tumor Types

e14622 Background: The identification of biomarkers associated with response to therapeutic agents has changed the paradigm of cancer treatment into the precision medicine by identification of right targets across cancer types. PD-L1 expression and mutational or neoatigen burden (Mismatch repair (MMR) deficiency) have been actively studied as the predictive biomarkers for the response to immune checkpoint inhibitors. Methods: We have conducted the PD-L1 and hMLH1/MSH2 expression (MMR deficiency) as part of a clinical practice for 430 patients with advanced gastrointestinal (GI) cancer, genitourinary (GU) cancer or rare cancers between June 2012 and March 2016. Herein, we evaluated potential candidates who could be targeted to further immune checkpoint inhibitors. Results: In 430 patients, 414 (96.2%) patients were available to evaluate the status of PD-L1 expression by immunohistochemistry (IHC). Irrespective of tumor-types, overall 26.8% (111 of 414) exhibited expression of PD-L1 in tumor tissues. The PD-L1 expression was examined as follows; 33.5% in HCC, 31.0% in CRC, 27.3% in GC, 25.5% in melanoma, 18.8% in BTC, 16.7% in pancreatic cancer, 15.8% in sarcoma and 13.0% in GU cancer. Among the 394 patients available for MLH1/MSH2 expression, only 18 patients (4.5%) had the MMR-deficient tumors with complete loss of MLH1/MSH2 expression. The MMR-deficiency was observed as follows; 7.9% in GC, 6.7% in HCC, 4.0% in CRC, and 2.7% in sarcoma. On 382 patients evaluable for the status of both PD-L1 and MLH1/MSH2 expression, there was no the significant association between the PD-L1 expression and MLH1/MSH2 loss (p = 0.267) Conclusions: These data may provide useful information and background for future research for immune checkpoint inhibitor across tumor-types. As a single selection biomarker for immune checkpoint inhibitor in various tumor-types, neither the PD-L1 expression nor the MMR deficiency is optimal application in clinical trials.

Immune checkpoint inhibitors for patients with colorectal cancer: mismatch repair deficiency and perspectives

2017 ◽  
Vol 6 (1) ◽  
pp. 23-31
Author(s):  
Romain Cohen ◽  
Magali Svrcek ◽  
Alex Duval ◽  
Yann Parc ◽  
Pia P Österlund ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency

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.

Sign in / Sign up

Export Citation Format

Share Document