What are Immune Checkpoint Inhibitors?
Heralded as one of the greatest recent advancements in cancer therapy, immune checkpoint inhibitors (ICIs) are a class of treatments that help the immune system target cancer cells more effectively. Cancer cells can “hide” themselves from the immune system by expressing certain surface proteins that interact favorably with immune cells. ICIs are monoclonal antibodies against these proteins, blocking the favorable interactions between cancer cells and immune cells and thus making cancer visible to the immune system once more.
Some of the most common ICIs are anti-CTLA-4 (ipilimumab/Yervoy) and anti-PD-1 (pembrolizumab/Keytruda). The results and profits of these drugs speak for themselves: in a 2022 phase 3 clinical trial of non-small cell lung carcinoma, patients with a positive indication for pembrolizumab therapy had a five-year survival rate twice as high as patients treated with chemotherapy. Merck, the maker of pembrolizumab, reported $5.4 billion in sales of the drug in the third quarter of 2022 alone.
Pros and Cons of ICI Therapy
The improved efficacy of ICI therapy over traditional approaches is exciting without a doubt but can come at a cost. These drugs are highly specific to their targets, so have little-to-no effect on cancers that don’t express these key proteins, leaving many patients without any benefit from these revolutionary therapies.
In patients that do respond to ICIs, anywhere from 10-55% of patients develop off-target immune effects which can be severe and even lethal. Collectively called immune-related adverse events (irAEs), the causes of these undesirable side effects are not fully understood. The ability to predict a patient’s predisposition to irAEs and the severity of any such effects would allow physicians to maximize the benefits of ICI therapies while minimizing their risks.
Predicting Patient Response Using Genetic Variation
Trying to uncover genetic and transcriptomic biomarkers related to ICIs isn’t new. Several studies have attempted to determine both single-protein and multi-omics-based biomarker profiles to predict whether a patient’s tumor will respond to ICI therapy.
However, a recent review in npj Genomic Medicine focused on genetic indications of immune-related adverse events from ICIs instead. The authors synthesized dozens of studies to draw three interesting conclusions. The first is that, perhaps unsurprisingly, many of the genes identified in association with irAEs are involved in the cancer immunity cycle, a step-wise cycle of the immune system to target and eliminate cancerous cells.
There was a significant overlap between the genetic indicators of treatment success previously mentioned and genetic indicators of immune-related toxicity. This makes sense as these pathways are inextricably linked, but presents a challenge for clinicians to balance the odds of success with the toxic side effects.
The authors concluded that the existing studies attempting to determine these predictive variants suffer from small sample sizes and require additional independent validation. They propose conducting genome-wide association studies in irAE cohorts to more robustly identify the exact SNPs and other genetic variants associated with patient responses.
Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help
Interrogating the genome for answers to research questions like these is a major bioinformatic undertaking. As experts across data types from cutting-edge sequencing platforms, we can help you tackle the challenging computational tasks of storing, analyzing, and interpreting genomic and transcriptomic data. Bridge Informatics’ bioinformaticians are trained bench biologists, so they understand the biological questions driving your computational analysis. Click here to schedule a free introductory call with a member of our team.
Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].