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Andrew Leader



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-15 - NSCLC Response Determinants to Chemoimmunotherapy: Deep Profiling of Tumors Following Neoadjuvant Cemiplimab and Chemotherapy (Now Available) (ID 1021)

      08:00 - 18:00  |  Author(s): Andrew Leader

      • Abstract
      • Slides

      Background

      Clinical trials have demonstrated synergistic effects of combination chemoimmunotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC), however, our understanding is limited as to why and for whom PD-1 blockade with or without chemotherapy is effective, as is our understanding of the mechanism of synergy between these therapies.

      While most patients with resectable NSCLC receive neoadjuvant or adjuvant chemotherapy, this intervention only changes the natural course of disease for ~5% of patients. Early studies have demonstrated major pathologic responses to neoadjuvant immunotherapy ± chemotherapy.

      Method

      To investigate the immunodynamic effect of PD-1 blockade and chemotherapy, and identify potentially more effective immune modifying targets or combinations, we will use novel immunophenotyping platforms to characterize the effect of this combination on the tumor. This trial will enroll 52 patients with Stage Ib-IIIa NSCLC into three cohorts receiving 2 cycles of 1) platinum-doublet chemotherapy, 2) the PD-1 antibody cemiplimab, or 3) combination chemoimmunotherapy. Following surgery, patients will receive additional adjuvant chemoimmunotherapy; in total all patients will receive 4 cycles of standard platinum-doublet chemotherapy and 8 cycles of cemiplimab. All patients will undergo pre-treatment biopsies of their tumor, and blood will be collected at 6 time-points before and after surgery.

      The primary endpoint for this clinical trial is major pathologic response, defined as ≤10% viable tumor within resection. Secondary endpoints include: delay of surgery, disease-free survival, overall response rate, overall survival, measurement of adverse events, and change in CD8 T-cell infiltration.

      Exploratory endpoints include in-depth analysis of the pre-treatment tumor biopsies and post-treatment surgical specimens, and paired blood. We will characterize proteomic and transcriptomic changes in the stromal and immune compartment of tumors at the histologic level using a multiplexed ion-beam imaging (MIBI)—a novel multiplex immunohistochemistry platform capable of analyzing >50 markers on a single section of tissue—and at the single-cell level using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), a novel platform combining the proteomic data-potential of mass cytometry (CyTOF) and the transcriptomic data-potential of single cell RNA sequencing including TCR sequencing. Feasibility of this multi-pronged approach has been demonstrated on untreated NSCLC (unpublished data, submitted as abstract to WCLC by our group).

      To probe for biomarkers correlating with response or resistance to therapy, we will perform unbiased analysis of peripheral blood lymphoid and myeloid populations by CyTOF, and measure nearly 100 soluble factors in serum using Olink.

      Result

      This trial opened to accrual April 2019.

      Conclusion

      Section not applicable.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-04 - CITEseq Characterization in Early Stage NSCLC Patients Identifies Distinct Patterns of Immune Infiltrate (ID 2305)

      10:15 - 18:15  |  Author(s): Andrew Leader

      • Abstract

      Background

      The success of immunotherapy in late-stage lung cancer patients, together with the need for novel therapies for early-stage disease, mandates an increased understanding of the immune infiltrate in early-stage lesions. Recent advances in sequencing-based single-cell technologies have enabled an unprecedented degree of resolution in the phenotypic characterization of patient tissues.

      Method

      Tumor and non-involved lung resection specimens were acquired from 23 early-stage NSCLC patients. Immune cells were isolated and analyzed by single-cell RNAseq (scRNAseq) using the 10X Chromium platform. Resulting expression signatures were clustered using an in-house pipeline. To validate populations and elucidate surface marker staining patterns for transcriptionally-defined cell clusters, we used cellular indexing of transcriptomes and epitopes by sequencing (CITEseq)—using oligonucleotide-conjugated antibodies to simultaneously measure expression of over 50 surface proteins along with transcriptomes of single cells—to analyze tumors from 8 additional patients. To identify T cell phenotypes that were differentially present and clonally expanded within tumor compared to non-involved lung, we paired scRNAseq with T cell receptor repertoire profiling in 3 patients. Finally, to validate the transcriptional phenotypes we detected and to extend our dataset, we incorporated 8 patients from a public dataset, totaling 39 patients included in the study. Immune signatures were correlated with presence of actionable mutations, smoking history, stage, and histology.

      Result

      Using these single cell analyses, all major immune cell lineages were identified within tumors, including multiple distinct myeloid and lymphoid subsets, which notably were phenotypically distinct from those isolated from uninvolved lung tissue. Existing databases of ligand-receptor pairs were leveraged to construct an interactome, implicating specific axes of cell-cell communication in driving changes common to tumors. As we hypothesized, correlative analyses across tumor samples revealed a cellular module marked by exhausted T cells, plasma cells, mature dendritic cells, and monocyte-derived macrophages that was enriched in patients with significant smoking histories and EGFRWT disease.

      Conclusion

      These findings indicate that strong immune differences exist between treatment-naïve lesions, and that these differences stratify with smoking history and smoking-related driver mutations. Given existing literature indicating that positive smoking history confers improved response to immune checkpoint blockade, our data suggests that this disparity may be mediated by set differences in treatment-naïve immune microenvironments. We will now apply this analysis pipeline to tumors treated in the neoadjuvant setting in an ongoing trial (submitted to WCLC in abstract form).