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C. Bernatchez



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    OA 13 - Immuno-Biology (ID 677)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 13.05 - Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues (ID 8766)

      11:45 - 11:55  |  Author(s): C. Bernatchez

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.

      Method:
      We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.

      Result:
      Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.

      Conclusion:
      These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-062 - PIVOT-02: Phase 1/2 Study of NKTR‐214 and Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumor Malignancies (ID 9130)

      09:30 - 09:30  |  Author(s): C. Bernatchez

      • Abstract
      • Slides

      Background:
      Abundance and functional quality of tumor infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors. NKTR-214 is a CD122-biased agonist that targets the IL2 pathway and is designed to provide sustained signaling through the heterodimeric IL2 receptor pathway (IL2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells within the tumor microenvironment. NKTR‐214 is administered on an outpatient basis as a 15-minute IV infusion and has been administered to 28 patients with advanced solid tumors. Single-agent NKTR-214 demonstrates a substantial increase in both CD8+ T and NK cells within the tumor microenvironment in those patients with prior immune checkpoint therapy (Bernatchez et al, SITC poster 2016). Given the favorable safety profile and strong biomarker data, a trial combining NKTR‐214 and nivolumab was initiated.

      Method:
      PIVOT‐02 is a phase 1/2 open‐label trial in patients with locally advanced or metastatic melanoma (MM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple‐negative breast cancer (TNBC). Approximately 250 patients will be enrolled across 5 tumor types and 8 indications, with 26-38 patients per indication. Patients who are immunotherapy naïve will be studied for all 5 tumor types. MM, RCC, or NSCLC patients who are relapse/refractory on one prior anti-PD-1/PD-L1 containing regimen will be studied separately. The primary objectives are to evaluate safety and tolerability, determine the recommended phase 2 dose (RP2D), and assess tumor response by RECIST 1.1. The dose-escalation portion of the trial has enrolled 23 patients (MM= 8, RCC= 11, NSCLC=4), in 5 different cohorts including NKTR-214 at 0.003 (q2w), 0.006 (q2w or q3w), or 0.009 (q3w) mg/kg in combination with a flat dose of nivolumab at 240 (q2w) or 360 (q3w) mg. Extensive blood and tumor tissue samples are being collected in both escalation and expansion phase to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T-cell clonality and gene expression analyses. Based on safety/tolerability, PK/PD and early biomarker data, the recommended phase 2 dose of NKTR-214 is 0.006 mg/kg q3w with nivolumab 360 mg q3w. The expansion phase of the study is now open for accrual.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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