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Janis M Taube



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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.10 - Peripheral T Cell Repertoire Evolution in Resectable NSCLC Treated with Neoadjuvant PD-1 Blockade (Now Available) (ID 1999)

      14:00 - 15:30  |  Author(s): Janis M Taube

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-02 - The AEGEAN Phase 3 Trial of Neoadjuvant/Adjuvant Durvalumab in Patients with Resectable Stage II/III NSCLC (ID 1375)

      09:45 - 18:00  |  Author(s): Janis M Taube

      • Abstract

      Background

      For patients (pts) with early stage non-small cell lung cancer (NSCLC) (Stages I–IIIA) surgery is the primary treatment. Adjuvant and neo-adjuvant chemotherapy (CTx) are both accepted approaches for resectable NSCLC, and result in modest but clinically meaningful improvements in overall survival (OS) compared with surgery alone; nevertheless, recurrence rates remain high and improved therapies are needed. Checkpoint inhibitors that block programmed death 1 (PD-1)/PD ligand 1 (PD-L1) have shown benefit as monotherapy and in combination with CTx in NSCLC. Durvalumab (durva), a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, significantly improved progression-free survival and OS in pts with unresectable Stage III NSCLC who did not progress following chemoradiotherapy (Antonia et al, NEJM 2017; 2018). The AEGEAN study (NCT03800134) will assess the activity and long-term clinical outcomes of durva plus CTx prior to surgery, as well as further administration of durva post-surgery, in pts with resectable Stages II and III NSCLC.

      Method

      The AEGEAN trial is a Phase 3, double-blind, placebo-controlled, multi-center study. Approximately 300 pts with resectable Stage II and III NSCLC will be randomized 1:1 to receive either durva (1500 mg intravenously) or placebo every 3 weeks (wks) alongside platinum-based CTx (4 cycles) prior to surgery, followed by either durva or placebo alone every 4 wks for an additional 12 cycles post-surgery. Pts will be stratified by disease stage and PD-L1 expression levels (<1% vs ≥1%); the number of pts with EGFR/ALK mutations will be capped at 20%. Tumor size (according to RECIST v1.1 criteria) will be evaluated at completion of neo-adjuvant CTx prior to surgery, every 12 wks for the first year; every 24 wks for 2–4 years; then yearly thereafter. The primary endpoint is major pathological response (≤10% residual viable tumor in the resected primary lung tumor after neoadjuvant treatment) in the full analysis set (FAS). Secondary endpoints include safety assessments, a range of efficacy measures including complete pathological response (FAS and PD-L1-TC ≥1%) and OS, pt-reported outcomes, durva pharmacokinetics and immunogenicity. This trial is currently recruiting.

      Result

      Section not applicable

      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
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-24 - Transcriptional Profiling of Neoantigen Specific T Cells in Resectable NSCLC Treated with Neoadjuvant Anti-PD-1 (Now Available) (ID 2357)

      10:15 - 18:15  |  Author(s): Janis M Taube

      • Abstract
      • Slides

      Background

      Neoadjuvant nivolumab has a manageable safety profile and can be effective in patients with resectable non-small cell lung cancer (NSCLC). To characterize the immune response in these patients, we sought to evaluate the existence and dynamics of neoantigen specific tumor-infiltrating T cells and identify their molecular phenotype including co-inhibitory checkpoint expression.

      Method

      We evaluated peripheral blood and tumor infiltrating lymphocytes from seven patients treated with nivolumab. To identify neoantigen-specific T cell responses, we used MANAFEST (Mutation Associated Neoantigen Functional Expansion of Specific T cells), an assay we developed that links antigen specificity with unique CD8+ TCR Vβ CDR3 identities. We then carried out single cell TCRseq/RNAseq of tumor infiltrating T lymphocytes (TIL) to enumerate the genome wide digital gene expression and T cell clonotypic identity of each single cell (VDJ+DGE analysis), and particularly those with Vβ CDR3 regions identical to those identified as neoantigen-specific by MANAFEST.

      Result

      Neoantigen-specific TCRs were detected in peripheral blood in all 3 patients with major pathologic response (MPR) and in 3 of 4 patients without MPR. Several of these clonotypes were found in the resected tumor and underwent peripheral expansions upon PD-1 blockade. In one notable patient, MD043-011, MANAFEST detected a T cell clonotype specific for a CARM1 R208W mutation, despite this patient having no evidence of pathologic response. This neoantigen-specific clonotype represented 3.4% of TIL. Two years later, this patient recurred with a solitary brain metastasis. Single cell analyses of TIL in the primary lung lesion and brain metastasis revealed the same neoantigen-specific T cell clonotype was detected in the metastatic lesion. Strikingly, this clonotype exhibited a differential expression profile in the primary and recurrent lesion, with the clonotype in the primary tumor having an enrichment and upregulation of heat shock proteins indicating molecular stress and the clone in the metastatic lesion having an upregulation of checkpoint molecules, including CTLA4, TIM3, and LAG3. T cell cloning and validation experiments, as well as identification of transcriptional programs associated with MPR, are ongoing.

      Conclusion

      The coupling of MANAFEST with single cell VDJ+ DGE analysis enabled us to characterize antigen specific clonotypes after differential expansion using the TCR as a molecular barcode. The presence of alternate co-inhibitory immune checkpoints on neoantigen-specific TIL from non-responding tumors suggests a potential driver of resistance to anti-PD-1 in early stage NSCLC. Ultimately, this integrative approach may provide key insights in predicting and understanding clinical response to neoadjuvant PD-1 blockade in NSCLC.

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