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Yuting Liu



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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-86 - Highly Immunogenic Neoantigens Enhance Tumor Response to Immune Checkpoint Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 771)

      10:15 - 18:15  |  Author(s): Yuting Liu

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors have revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC) as significantly extending survival in patients relative to chemotherapy. However evidence to support the role of immune checkpoint inhibitors in EGFR-mutant lung cancers remains conflicting. In recent years, neoantigens become promising targets for cancer immunotherapy. Immunogenic neoantigens generated by somatic mutations can be recognized by the host immune system and then tumor clones presenting such neoantigens will be eliminated.

      Method

      We report two advanced NSCLC patients with EGFR mutations who have both exhibited durable response to PD-1 blockade. We comprehensively analyzed predictive biomarkers and experimentally validated immunogenicity of peptides generated by driver mutations.

      Result

      Patient 1 is a 34-year-old male diagnosed with lung adenocarcinoma (IV, cT4N2M1b). EGFR exon 19 deletion and TP53 point mutation (A161T) were identified by next generation sequencing in February 2017 and first line treatment was initiated with Icotinib. He obtained PD within 5 months. After 5 cycles of chemotherapy, brain metastasis was confirmed and EGFR T790M mutation was identified by lung biopsy in June 2018. The patient was enrolled in a phase III clinical trial of Nivolumab in July 2018. Patient 2 is a 61-year-old female diagnosed with stage IV lung adenocarcinoma harboring EGFR exon 19 deletion identified by next generation sequencing in March 2018. After multilines treatment including TKI therapy, chemotherapy and anti-angiogenic therapy, Nivolumab was given alone to the patient from November 2018. Both patients achieved partial response (PR) to Nivolumab based on imRECIST criteria. The PD-L1 expression level was > 50% and 5%, respectively in Patient 1 and Patient 2. We performed a target region sequencing which covered 811 cancer genes to determine tumor mutation burden (TMB) and tumor neoantigen burden (TNB). Both patients had moderate level of TMB and TNB. TMB was 6.00 muts/Mb and 4.69 muts/Mb while TNB was 2.67 neos/Mb and 2.68 neos/Mb, respectively in Patient 1 and Patient 2. In order to evaluate the immunogenicity of neoantigens, peptides representing top 7 putative neoantigens were synthesized and tested against PBMC in an IFNγ ELISpot assay. The results revealed tumor-specific T cell immunity targeting neoantigens derived from EGFR exon 19 deletion and TP53 point mutation and the latter exhibited the highest immunogenicity. Strikingly, the patient harboring these mutations achieved partial response for more than 9 months. Additionally, the dynamic changes of TCR profiling during Nivolumab treatment were examined to assess T cell immunity responses. Data shown the maintenance of a majority of high-frequency clonotypes, suggesting the preexisting high-avidity T cells may contribute to antitumor immune response.

      Conclusion

      Our study suggests that EGFR-mutant NSCLC may still respond to PD-1 blockade. This is the first report on experimentally verifying the highly immunogenic neoantigens derived from EGFR driver mutation in patients receiving immunotherapy, which supports potential value of such neoantigens as therapeutic agents. Our study also shows the dynamic monitoring of TCR profiling could help predict T cell immune response.

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