Correlation between a CTLA-4 single nucleotide polymorphism and high response to anti-PD1/PDL1 immunotherapy in advanced non small cell lung cancer

Abstract Blockade of the immune checkpoint protein Programmed Cell Death Protein-1 or its ligand (PD-1 and PD-L1, respectively) allows durable cancer control in a proportion of patients with non-small cell lung cancer (NSCLC). However, a substantial proportion of patients have suboptimal outcomes and variability in response remains incompletely understood. Immune-related adverse events (irAEs) correlate with survival for single agent anti-PD1/PD-L1 therapy in NSCLC, suggesting benefits of systemic immune activation. Similarly, combined pharmacological blockade of a second checkpoint, such as Cytotoxic T-lymphocyte Antigen-4 (CTLA-4), with PD-1 gives heightened immune activation, resulting in both improved cancer outcomes and more irAEs. Inherited heterozygosity for single nucleotide polymorphisms (SNPs) within and surrounding CTLA-4 is associated with autoimmune disease, including autoimmune thyroid disease, rheumatoid arthritis (RA) and Type 1 diabetes (T1D). Many of these autoimmune diseases are clinically and pathologically indistinguishable from anti-CTLA4-induced irAEs, suggesting equivalence of pharmacological and genetic blockade of the gene. We hypothesised that SNPs impacting CTLA-4 function would be enriched in a cohort of NSCLC patients exhibiting exceptional response to single-agent anti-PD1. For the purposes of this analysis, exceptional response was defined as progression free survival of at least 2 years and one or more irAE of CTCAE grade 2 or higher. We performed whole genome sequencing (Illumina HiSeq X Ten) on germline DNA from 35 prospectively recruited patients meeting these criteria from a treatment pool of over 700 patients. In these individuals, frequency of a curated list of SNPs located within a 200 kilobase region encompassing CTLA-4 was analysed and compared to patients with lung cancer within the Pan-Cancer Analysis of Whole Genomes (PCAWG) and to cancer- and dementia-free elderly individuals in the Medical Genome Reference Bank (MGRB). Using linear regression analysis, we identified several non-coding SNPs enriched within the exceptional responders compared with control populations. One SNP was present in 15.7% of exceptional responders; twice the frequency of comparable cases within PCAWG and almost four times more than MGRB, remaining statistically significant following rigorous adjustment. This non-coding SNP is reported to exhibit differential enhancer activity and has been associated with RA and T1D. Its enrichment within the exceptional responders suggests that the altered CTLA-4 function may cooperate with blockade of PD-1 to confer higher immune response. This common variant may provide a biomarker for single agent anti-PD1 treatment or a potential therapeutic target. Pre-clinical analyses and validation within an independent cohort are underway. Citation Format: India A. Allen, Amanda Russell, Katherine J. Jackson, Timothy Peters, Greg Gibson, Anthony M. Joshua, Christopher C. Goodnow, Deborah L. Burnett, Megan B. Barnet. Correlation between a CTLA-4 single nucleotide polymorphism and high response to anti-PD1/PDL1 immunotherapy in advanced non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 665.