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Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with
Emma Titmuss1, Irene S Yu2, Erin D Pleasance3
1Department of Medical Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada.
Abstract:
Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.
Insights
Germline mutations in HLA-B27 may predispose patients to severe immune-related adverse events (irAEs) when treated with immune checkpoint inhibitors (ICIs). This genetic link highlights potential risks for specific patient populations receiving cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint inhibitors (ICIs) offer durable responses in various cancers but can cause significant immune-related adverse events (irAEs).
- Identifying patients at higher risk for irAEs is crucial for optimizing cancer immunotherapy.
- Limited data exists on the role of germline mutations in predicting irAE risk.
Purpose of the Study:
- To investigate the association between germline mutations and the incidence of irAEs in patients treated with ICIs.
- To identify specific genetic markers that may predict irAE development.
Main Methods:
- Retrospective analysis of 117 patients with metastatic solid tumors or hematologic malignancies from the Personalized OncoGenomics (POG) program.
- Genomic analysis including whole genome sequencing of tumor and matched normal specimens.
- Chart review to identify and grade irAEs in patients receiving ICIs.
Main Results:
- MHC class I alleles in the HLA-B27 family were significantly associated with grade 3 hepatitis and pneumonitis (q = 0.007).
- This association was observed in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors with IDO-1 inhibitors.
- Findings suggest a genetic predisposition to irAEs in certain patients.
Conclusions:
- Germline HLA-B27 alleles may indicate an elevated risk for severe irAEs, particularly hepatitis and pneumonitis.
- These findings highlight the potential for genetic profiling to personalize immunotherapy strategies.
- Further research is warranted to validate these genetic predictors for irAEs.
