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Immune checkpoint inhibitors in luminal gastrointestinal malignancies: going beyond MSI-H/dMMR, TMB and PD-L1
Daniel S Lefler1, Adam E Snook2,3, Babar Bashir1,2
1Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA.
Abstract:
In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review is to characterize luminal gastrointestinal tumors' responses to ICIs considering known predictive biomarkers and discuss emerging therapeutic approaches using ICIs.
Insights
Immune checkpoint inhibitors (ICIs) show promise in luminal gastrointestinal tumors, guided by biomarkers like PD-L1 and dMMR. Further research into the tumor microenvironment can refine ICI therapy and improve patient outcomes.
Area of Science:
- Oncology
- Immunology
- Gastroenterology
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 are explored for luminal gastrointestinal tumors.
- Therapeutic indications rely on biomarkers such as PD-L1 expression, tumor mutational burden, and mismatch repair deficiency (dMMR).
Purpose of the Study:
- To review luminal gastrointestinal tumor responses to ICIs based on predictive biomarkers.
- To discuss emerging therapeutic strategies involving ICIs in this context.
Main Methods:
- Literature review of studies investigating ICIs in luminal gastrointestinal cancers.
- Analysis of predictive biomarkers and their clinical utility.
- Exploration of the tumor microenvironment's role.
Main Results:
- Biomarkers like PD-L1, tumor mutational burden, and dMMR/microsatellite instability status are crucial for ICI efficacy.
- Variability exists in biomarker measurement and therapeutic application.
- Understanding the tumor microenvironment is key to optimizing ICI use.
Conclusions:
- ICIs represent a significant therapeutic avenue for luminal gastrointestinal tumors.
- Personalized treatment strategies incorporating biomarkers and tumor microenvironment insights are essential for maximizing ICI benefits.
- Further research is needed to refine ICI applications and explore novel therapeutic combinations.
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