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David S. Ettinger, MD, FACP, FCCP


Polymorphisms in Immune Checkpoint Proteins and Response to Immunotherapy

By: Gavin Calabretta, BS
Posted: Thursday, May 5, 2022

Many patients with non–small cell lung cancer (NSCLC) respond poorly to anti–PD-1 therapy, and this diminished response is incompletely understood. In addition, it has been observed that single nucleotide polymorphisms (SNPs) throughout and surrounding the CTLA-4 gene are associated with various autoimmune diseases. Accordingly, Megan B. Barnet, MBBS, FRACP, of the Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia, and colleagues hypothesized that these SNPs would be enriched in individuals who responded better to single-agent anti–PD-1; thus, they compared the SNP frequencies of those who achieved exceptional responses with those of other patients with lung cancer and cancer-free individuals.

At the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 665), Dr. Barnet and colleagues explained that the blockade of PD-1 and other immune checkpoint proteins like CTLA-4 not only often results in better treatment responses, but also in more immune-related adverse events. “This suggests a shared mechanism behind the predisposition that drives autoimmunity and better response to cancer immunotherapy,” said India Allen, BSc, also of Garvan Institute of Medical Research, in an AACR press release.

The investigators sequenced the genomes of 35 patients with NSCLC who achieved progression-free survival of at least 2 years and experienced one or more immune-related adverse events of grade 2 or higher. They compared SNP frequencies present in the genetic region encompassing CTLA-4 with those from other patients with NSCLC in the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort and dementia-free elderly individuals within the Medical Genome Reference Bank (MGRB).

Several SNPs were observed more frequently within the exceptional responders compared with the other cohorts. Notably, one SNP associated with rheumatoid arthritis and type 1 diabetes was present in 15.7% of exceptional responders—twice the frequency shown in the PCAWG cohort and almost four times the frequency in the MGRB cohort.

Disclosure: The study authors reported no conflicts of interest.

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