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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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      P1.04-14 - HLA B44 Supertype Associated with Less Favorable Neoantigen Binding in Non-Small Cell Lung Cancer Treated with Immunotherapy (ID 12285)

      16:45 - 18:00  |  Author(s): Benjamin Jones

      • Abstract
      • Slides

      Background

      Human leukocyte antigen (HLA) supertypes may influence immunotherapy efficacy, particularly HLA class 1 B44 supertype (B44), which is found in 35-55% of the population irrespective of race (Sidney, BMC Immunol). In melanoma patients treated with immune checkpoint inhibitors, presence of B44 correlated with improved survival (Chowell, Science), but in a cohort of 58 non-small cell lung cancer (NSCLC) patients treated with single-agent pembrolizumab, B44 was associated with poorer outcomes (Lu, ASCO 2018). Given B44’s small electropositive binding pocket, it was hypothesized that the transversions that predominate in NSCLC result in more positive tumor variant amino acids (vAAs) and that these neoantigens would have decreased binding affinity and/or HLA B44:peptide stability.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      58 advanced NSCLC patients treated with pembrolizumab had germline and tumor multiplexed paired-end Illumina WES performed. HLA typing used BWA-ALN and Athlates software; supertype was determined by 2008 criteria (Sidney, BMC Immunol). Six subjects with at least one strong HLA B44 supertype allele had nonsynonymous coding mutations identified with Genome Toolkit Analysis (GATK) best practices utilizing the Hg38 genome reference. PvacSeq software used NetMHC algorithms to identify tumor neoantigens 9 base pairs in length matched to their corresponding HLA B44 allele (B44-specific neoantigens, BSNs). Missense BSNs were classified by transition (Ti) transversion (Tv) ratios and vAA charge change. TiTv was compared with matched pairs analysis. Predicted NetMHC IC50 binding affinities were compared with student’s t-tests. All statistical analyses were performed with SAS JMP, Version 13.0 (Cary, NC).

      4c3880bb027f159e801041b1021e88e8 Result

      Among the 6 subjects, 3073 BSNs were identified; 1090 were unique. There were no common BSNs among subjects. Subject tumor TiTv median was 1.58 (95% CI 1.09-1.94), mean difference compared to germline was -0.62 (95% CI -1.11 to -0.12, p=0.02). BSNs with vAAs that changed charge represented 13.5% of all BSNs. Positive vAA charge changes were as expected based on theoretical distribution (12.5% Tv vs 6.3% Ti, p=0.02). In aggregate, there were 205 BSNs with negative charge change (-BSN) and 204 with positive charge change (+BSN). The anticipated HLA B44 binding affinity was lower for +BSN, with median NetMHC IC50 binding 176.2 (95% CI 178.0-217.9) vs 258.6 (95% CI 216.9-257.7) for -BSN, p<0.01.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A potential mechanism for decreased survival in B44 NSCLC subjects treated with immunotherapy is unfavorable neoantigen binding related to increased transversions leading to tumor vAAs with positive charge changes and poorer HLA B44 binding. All subjects from this cohort will be evaluated for BSNs 8-12 base-pairs long to confirm these findings.

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