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K. Knutson



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    MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 05.01 - Integrating INDEL Mutations into Neoantigen Prediction in Lung Cancer: Developing Personalized Cancer Vaccines  (ID 10150)

      15:45 - 17:30  |  Author(s): K. Knutson

      • Abstract
      • Presentation
      • Slides

      Background:
      Mutant neoantigens generated from genetic alterations that are exclusively present in tumors represent highly promising cancer vaccine targets. However, publically available neoantigen prediction algorithms only identify and utilize single nucleotide mutations (SNVs) but not short insertion and deletions (INDELs). Short INDELs can lead to the generation of novel junctional or frameshift neoantigens which may be more immunogenic than neoantigens that result from single nucleotide missense mutations.

      Method:
      We developed a bioinformatics pipeline for neoantigen prediction using paired normal tissue and tumor exome sequencing, RNA sequencing and HLA binding prediction. 536 lung adenocarcinoma (LUAD) and 466 lung squamous cell carcinoma (LUSC) cases were analyzed using our bioinformatics pipeline. The non-synonymous somatic SNVs and short INDELs mutations were identified to generate a list of mutation neoantigen-derived and, when possible, their corresponding wild-type epitopes. Binding affinities of the paired wild-type and mutant peptides to HLA class I were then predicted and compared.

      Result:
      On average, 8.65 (range1-158) mutant neoantigen peptides per sample were identified in 395 out of 536 (73.6%) LUAD samples. Among them, 63.7% were SNVs and 36.3% were INDELs. On average, 8.54 (range 1-504) mutant neoantigen peptides per sample were identified in 360 out of 466 LUSC samples. Among those, 67% were SNVs and 33% were INDELs. Most neoantigen peptides are private in both LUAD and LUSC. The mutant neoantigen peptides identified from INDELs were predicted to have 3.9 (p = 2.42E-74) and 1.14 (p = 5.44E-67) fold higher HLA class I binding affinity than wild type peptide compared to those from SNVs in LUAD and LUSC respectively.

      Conclusion:
      Tumor INDELs may be a rich source of neoantigens with a higher predicted high HLA binding affinity in lung cancers that warrant consideration in development of a personalized cancer vaccine.

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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-039 - Blood Biomarkers Correlate with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 9050)

      09:30 - 16:00  |  Author(s): K. Knutson

      • Abstract

      Background:
      Anti-PD-1 antibodies have demonstrated improved overall survival (OS) and progression free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). Currently, no blood biomarkers in NSCLC predict clinical outcome to anti-PD-1 antibodies.

      Method:
      A retrospective analysis of locally advanced or metastatic NSCLC patients treated with anti-PD-1 antibodies at Mayo Clinic was performed. White blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute neutrophil to lymphocyte count ratio (ANC/ALC), absolute eosinophil count (AEC), platelet counts and myeloid to lymphoid ratio (M:L) at baseline and throughout treatment were assessed. Kaplan–Meier and Cox regression analysis were performed.

      Result:
      157 patients were treated with nivolumab or pembrolizumab between 1/2015 and 4/2017. At median follow-up of 20 months, median OS and PFS were 13.4 and 2.6 months respectively. Higher baseline ANC, AMC, ANC/ALC ratio and M:L ratio significantly correlated with worse clinical outcomes. A baseline ANC/ALC ratio ≥ 5.9 had a significantly increased risk of death [hazard ratio (HR) = 1.65; 95% CI 1.06–2.56, p 0.027] and disease progression [HR = 1.65; 95% CI 1.17–2.34, p 0.005] compared with patients with ANC/ALC ratio <5.9. A baseline M:L ratio ≥ 11.3 had significantly increased risk of death [HR = 2.13; 95% CI 1.32–3.44, p 0.002] even after a multivariate analysis [HR = 1.89, p 0.015] compared to those with lower ratio. An increase from baseline values at 8 weeks for ANC [HR 1.10, p 0.006] and WBC [HR 1.11, p 0.004] was significantly associated with worse OS. Figure 1



      Conclusion:
      Increased baseline ANC/ALC ratio and M:L ratio were associated with poor PFS and OS in NSCLC patients treated with anti-PD-1 antibodies. The potential predictive value of these biomarkers might help with risk stratification, treatment strategies and warrant further investigation in a larger, prospective study.