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Martin Henry Norman Tattersall



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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-11 - Exploring the Germ-Line Contribution to Exceptional Response to PD-1/PD-L1 Inhibition in Patients with NSCLC by Whole Genome Sequencing (ID 12646)

      16:45 - 18:00  |  Author(s): Martin Henry Norman Tattersall

      • Abstract
      • Slides

      Background

      Responses to immune checkpoint inhibitors (CPI) may vary between individuals because of somatic mutation differences 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 (NSCLC) treated with single agent PD-1 or PD-L1 inhibitors recruited from a treatment pool of 420 patients (total) / 137 (active since 1 August 2017).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Rare and common germ-line DNA variants are analysed in exceptional responders and non-responders by whole genome sequencing (WGS) (Illumina HiSeqX Ten). Exceptional responders are defined as patients with complete or partial response of more than 12 months or stable disease of more than 24 months (per RECIST), and a concurrent immune-related adverse event of any grade. Non-responders are defined as patients with best response of progressive disease, having received at least 4 cycles or 2 months of treatment.

      In these individuals, the burden of rare and common variants in immune tolerance genes is analysed and compared to the Medical Genome Reference Bank (MGRB), comprising WGS of 1144 well-elderly individuals. Comparisons are made with Fisher Exact test. Genetic risk scores for auto-immune conditions are calculated for these cohorts, MGRB and NSCLC patients included in The Cancer Genome Atlas. Scores are calculated using curated risk alleles and OR weightings derived from the NHGRI-EBI GWAS catalogue.

      4c3880bb027f159e801041b1021e88e8 Result

      Recurrent rare variants (Exome Aggregation Consortium (ExAC) frequency < 1%) were found within responders sequenced to date (n=20), including variant A, a frameshift mutation in a protein kinase not present in ExAC, with allelic frequency (AF) of 1.27% in MGRB and 17.5% of our cohort (p<0.0001). Multiple common variants (ExAC ≥1%) were more frequent within the cohort compared with population standard. Among these, three functional variants within gene B, encoding a protein involved in modulating immune-responsiveness, (variant B.1, B.2 and B.3, ExAC AF: 1.3%, 0.99% and 2.3%), were found seven times (total) across six individuals (one compound heterozygous B.2/B.3). The exceptional responders cohort was enriched for subjects with higher genetic risk for Disease A, psoriasis and psoriatic arthritis compared with control groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Preliminary findings suggest individuals harbouring functional variants in genes promoting immune tolerance may be more responsive to PD-1/PD-L1 inhibitors. This may be due to higher basal immune activation, 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.

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