scholarly journals Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance

2021 ◽  
Vol 19 (2) ◽  
pp. 130-133
Author(s):  
Agata A. Bielska ◽  
Walid K. Chatila ◽  
Henry Walch ◽  
Nikolaus Schultz ◽  
Zsofia K. Stadler ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Syndrome ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.

scholarly journals Integrating Circulating Biomarkers in the Immune Checkpoint Inhibitor Treatment in Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3625
Author(s):  
Boris Duchemann ◽  
Jordi Remon ◽  
Marie Naigeon ◽  
Laura Mezquita ◽  
Roberto Ferrara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Circulating Biomarkers ◽  
Liquid Biopsies ◽  
Technical Requirements ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host’s immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers.

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.

Tumor mutational burden assessed by a targeted NGS assay to predict clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14266-e14266 ◽  
Author(s):  
Sacha Rothschild ◽  
Ilaria Alborelli ◽  
Katharina Leonards ◽  
Laura P Leuenberger ◽  
Spasenija Savic Prince ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Predictive Power ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Nsclc Patients

e14266 Background: In non-small cell lung cancer (NSCLC) immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here we evaluated the predictive power of TMB measured through / by the Oncomine Tumor Mutational Load (TML - Thermo Fisher Scientific) targeted sequencing assay in 71 NSCLC patients treated with ICIs. Methods: TMB was assessed retrospectively in 71 metastatic NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were characterized as either having durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. Results: TMB was significantly higher in patients with DCB compared to patients with NDB (median TMB = 9.2 versus 5.3 mutations/Mb, Mann-Whitney p = 0.014). 70% of patients with high TMB (cutoff = 3rd tertile, TMB ≥ 9.2) were responders (DCB) compared to 29% of patients with low TMB (cutoff = 1st tertile, TMB ≤ 4.5). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log rank test, p = .0030 for PFS and 0 .0375 for OS, respectively). Combining PD-L1 expression and TMB value increased the predictive power of TMB. Conclusions: Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. We believe that a combination of biomarkers will maximize the precision of patient selection.

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