Abstract LB-121: Exploring the germ-line contribution to exceptional response to PD-1/PD-L1 inhibition in patients with metastatic non-small-cell lung cancer by whole genome sequencing
Authors: Barnet Megan B. , Jackson Katherine J. , Gao Bo , Nagrial Adnan M. , Boyer Michael J. , Cooper Wendy A. , Hui Rina , Linton Anthony , Tattersall Martin H. , Gibson Greg , Cebon Jonathan , Long Georgina V. , Menzies Alexander M. , Scolyer Richard A. , Lacaze Paul , Brink Robert , Peters Timothy , Cowley Mark , Gayevskiy Velimir , Thomas David M. , Pinese Mark , Blinman Prunella , Kao Steven , Goodnow Christopher C. 
Published: August 2018

Abstract
Responses to immune checkpoint inhibitors (CPI) may vary between individuals because of differences in somatic mutations in the tumour and/or germ-line differences in immunological tolerance. To explore the latter, this ongoing study evaluates patients with metastatic non-small cell lung cancer treated with single agent PD-1 or PD-L1 inhibitors from an active treatment pool of over 200 patients. Rare and common germ-line DNA variants are analysed in exceptional responders and non-responders by whole genome sequencing (Illumina HiSeq X Ten). Exceptional responders are defined as individuals with sustained partial (&gt;6 months) or complete response per RECIST criteria with concurrent autoimmune toxicity, implying systemic immune activation. In these individuals, the cumulative burden of rare and common variants in a curated list of immune tolerance genes is analysed and compared to the Medical Genome Reference Bank, comprising whole genome sequences of 1146 well-elderly individuals. Comparisons are made with Fisher Exact test.
Recurrent rare variants (Exome Aggregation Consortium (ExAC) frequency &lt;1%) were found within responders sequenced to date (n=10), including variant A, a frameshift mutation in a protein associated with autoimmunity, not present in ExAC with Genome Aggregation Database (GnomAD) frequency 0.0002% (P &lt; 0.0001). Multiple common variants (ExAC &gt;2%) are more frequent within this cohort compared with population standard, for example variant B, a missense mutation within a DNA-repair protein that has ExAC allelic frequency of 2.5% and is present in 30% of our cohort (P = .013). Polygenic risk scores for diseases of impaired immune tolerance within exceptional responders are distinct from control groups. Further analyses of immune-related variants within anti-PD-1/PD-L1 responders and control groups will be presented.
Preliminary findings suggest individuals harbouring damaging variants in genes promoting immune tolerance are more responsive to PD-1/PD-L1 inhibitors because basal immune activation is higher, requiring greater reliance on inhibitory checkpoints to maintain homeostasis. Ordinarily, this would be clinically undetectable, however the addition of a pharmacological CPI may more effectively break immune tolerance in this primed environment.
Citation Format: Megan B. Barnet, Katherine J. Jackson, Bo Gao, Adnan M. Nagrial, Michael J. Boyer, Wendy A. Cooper, Rina Hui, Anthony Linton, Martin H. Tattersall, Greg Gibson, Jonathan Cebon, Georgina V. Long, Alexander M. Menzies, Richard A. Scolyer, Paul Lacaze, Robert Brink, Timothy Peters, Mark Cowley, Velimir Gayevskiy, David M. Thomas, Mark Pinese, Prunella Blinman, Steven Kao, Christopher C. Goodnow. Exploring the germ-line contribution to exceptional response to PD-1/PD-L1 inhibition in patients with metastatic non-small-cell lung cancer by whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-121.