Patients with non-small lung cancer with CTLA-4 variant may respond better to immunotherapy
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Patients with non-small cell lung cancer and an exceptionally high anti-PD-1 therapy response more frequently had a variant of the CTLA-4 gene, which may be used to identify those who may benefit from such treatment.
Data presented at American Association for Cancer Research Annual Meeting showed patients with the CTLA-4 variant, which is associated with autoimmune disease, experienced more optimal responses compared with a cohort of patients with lung cancer and healthy individuals.
“As there remains considerable interindividual variability in response to checkpoint inhibitors, there is an increasing need for better predictive biomarkers of response to current available treatments,” India A. Allen, BSc, research assistant at Garvan Institute of Medical Research in Australia, told Healio.
Methodology
The analysis included 35 patients with NSCLC exhibiting exceptional response and high toxicity to anti-PD-1 therapy, which researchers defined as PFS of at least 2 years and one or more immune-related adverse events of grade 2 or higher.
Allen and colleagues performed whole-genome sequencing on germline DNA from the patients prospectively recruited from a treatment pool of more than 700. Researchers analyzed the frequency of a curated list of single nucleotide polymorphisms located within a 200-kilobase region encompassing CTLA-4 and compared it with that of patients with lung cancer within the Pan-Cancer Analysis of Whole Genomes, as well as with cancer- and dementia-free elderly individuals in the Medical Genome Reference Bank.
Key findings
Allen and colleagues identified several noncoding SNPs enriched within the exceptional responders compared with control populations and reported the presence of one SNP in 15.7% of exceptional responders — twice the frequency of comparable cases in Pan-Cancer Analysis of Whole Genomes and almost four times more than among individuals in the Medical Genome Reference Bank.
Additionally, they noted that the noncoding SNPs’ enrichment within the exceptional responders suggested altered CTLA-4 function may cooperate with PD-1 blockade to confer higher immune response. They also reported that the common variant may provide a biomarker for single-agent anti-PD-1 treatment or a potential therapeutic target.
“The enrichment of this SNP within our exceptional responders’ cohort could signify a potential biomarker of high response to anti-PD-1/PD-L1 therapy and, as such, could be utilized as a predictive tool for patient selection for this line of treatment,” Allen said.
Implications
Through genomic sequencing, the identification of this genetic variant could be used alongside existing biomarkers to help select patients with NSCLC who may experience better response to anti-PD-1/PD-L1 checkpoint therapy and those at risk for more severe autoimmune adverse events, according to researchers.
Next steps in research include expanding the search for genetic response biomarkers to other autoimmune-linked genes, including neighboring genes of CTLA-4, such as CD28 and inducible T-cell co-stimulator.
“Further investigation into the mechanism behind this SNP that could be driving increased response to therapy is underway,” Allen said.
Perspective
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Erminia Massarelli, MD, PhD, MS
Immune checkpoint blockade has become the standard of care in patients with advanced/metastatic NSCLC, demonstrating superior OS and PFS in several trials. Although immune checkpoint inhibitors have demonstrated durable clinical efficacy in a subset of patients with NSCLC, many have primary resistance to immune checkpoint inhibitors. As such, several clinical trials have begun to investigate novel immunotherapeutic combination strategies, including double immune checkpoint blockade or targeting other checkpoints such as CTLA-4. Moreover, although several predictive biomarkers of immunotherapy response exist, such as high PD-L1 expression and high tumor mutational burden, more research is warranted to investigate more reliable biomarkers that can better predict response to immunotherapy.
In this abstract, Allen and colleagues further examine SNPs in the CTLA-4 gene that are already seen in various autoimmune diseases, such as rheumatoid arthritis and type 1 diabetes, which demonstrate similar symptoms to immune-related adverse events observed in patients with NSCLC undergoing immune checkpoint inhibitor therapy. Thus, they hypothesized that a subgroup of patients with NSCLC with prolonged and durable response to anti-PD-1 monoclonal antibodies (> 2 years PFS) and immune-related adverse events of grade 2 or higher would also exhibit SNPs that affect CTLA-4 function.
Unfortunately, not many patients would meet the inclusion criteria of this study, resulting in a small cohort of prospective patients. They observed one noncoding SNP within CTLA-4 in 15.7% of their cohort, suggesting it could potentially act as a predictive biomarker for immune checkpoint inhibitors. This is a very interesting finding that will need to be confirmed within a larger subset of patients, and a comparison analysis would be helpful to validate whether this variant in CTLA-4 could truly predict immunotherapy response.
Ultimately, the future of immunotherapy and improving patient response lies in investigating novel biomarkers, as well as novel combination immunotherapeutic treatment strategies. An effective predictive biomarker would have to be easy to test, especially in liquid biopsies, considering that tumor tissue is sometimes difficult to retrieve in advanced NSCLC.
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Allen IA, et al. Abstract 665. Presented at American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
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