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Published on: February 25, 2020
Genomics- and Transcriptomics-Based Patient Selection for Cancer Treatment With Immune Checkpoint Inhibitors: A
Krijn K Dijkstra1, Paula Voabil2, Ton N Schumacher2
1Division of Molecular Oncology, Antoni van Leeuwenhoek, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Importance:
Checkpoint blockade therapy targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathways (PD-1/PD-L1) have achieved success in treating a number of malignancies. However, only a subset of patients responds to these therapies, and optimization of patient selection for treatment is imperative to avoid adverse effects without clinical benefit and keep costs manageable.
Observations:
The past few years have witnessed checkpoint inhibition becoming a first-line treatment option with US Food and Drug Administration approvals for various tumor types. Genomic analyses (whole genome, exome, and transcriptome) have been instrumental in identifying a genetic profile associated with sensitivity to checkpoint inhibitors. Therapy outcome is determined at various levels: (1) the degree of tumor "foreignness," as reflected by mutational burden and expression of viral genes, (2) the composition and activity of a preexisting immune infiltrate, and (3) mechanisms of tumor escape from immune surveillance. In addition, there are opportunities for genomic analyses of genetic polymorphisms and the gut microbiome that may be associated with clinical response to therapy.
Conclusions And Relevance:
Genomics provides powerful tools for the identification of biomarkers for response to immune checkpoint blockade, given their potential to analyze multiple parameters simultaneously in an unbiased manner. This offers the opportunity for genomics- and transcriptomics-based selection of patients for rationally designed therapy with immune checkpoint inhibitors.
Insights
Genomic analyses identify biomarkers for immune checkpoint blockade therapy response. This enables selecting patients for targeted cancer treatments, improving outcomes and managing costs.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint blockade therapies targeting CTLA-4 and PD-1/PD-L1 are successful in treating malignancies.
- However, patient response varies, necessitating improved patient selection to optimize treatment and manage costs.
Purpose of the Study:
- To explore the role of genomic analyses in identifying biomarkers for predicting response to immune checkpoint inhibitors.
- To enhance patient selection for immunotherapy.
Main Methods:
- Utilized genomic analyses, including whole genome, exome, and transcriptome sequencing.
- Investigated tumor characteristics like mutational burden and viral gene expression.
- Examined immune infiltrate composition and activity, and tumor escape mechanisms.
- Considered genetic polymorphisms and gut microbiome analyses.
Main Results:
- Genomic analyses are instrumental in identifying genetic profiles associated with sensitivity to checkpoint inhibitors.
- Therapy outcome is influenced by tumor "foreignness," immune infiltrate, and tumor escape mechanisms.
- Genetic polymorphisms and gut microbiome may correlate with clinical response.
Conclusions:
- Genomics offers powerful, unbiased tools for identifying biomarkers of response to immune checkpoint blockade.
- Genomics and transcriptomics enable rational patient selection for immunotherapy.
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