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Denise Aberle



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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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      EP1.04-20 - Phase I Trial of in Situ Vaccination with Autologous CCL21-Modified Dendritic Cells (CCL21-DC) Combined with Pembrolizumab for Advanced NSCLC (Now Available) (ID 1888)

      08:00 - 18:00  |  Author(s): Denise Aberle

      • Abstract
      • Slides

      Background

      Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those that are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment promoting both local and systemic T cell activation. The chemokine CCL21 promotes co-localization of naive T cells and dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in effective T cell responses and systemic antitumor immunity. However, increased PD-L1 expression was observed in some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC that are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy.

      Method

      This is a phase I, single institution, non-randomized, dose-escalating, multi-cohort trial followed by dose expansion. A maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC (5x106, 1x107, 3x107) when combined with pembrolizumab. Primary objective of dose expansion is objective response rate (ORR) of CCL21-DC at MTD combined with pembrolizumab. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P1.11 - Screening and Early Detection (ID 177)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.11-14 - SGLT2 Is a Diagnostic and Therapeutic Target for Early-Stage Lung Adenocarcinoma (ID 2854)

      09:45 - 18:00  |  Author(s): Denise Aberle

      • Abstract
      • Slides

      Background

      Early diagnosis of lung adenocarcinoma (LUAD) is crucial. The National Lung Screening Trial showed a 20% reduction in lung cancer mortality in high risk individuals using low-dose helical computed tomography (CT). CT is highly sensitive for detecting lung nodules, but is limited by low specificity, especially for LUAD. On CT, LUAD may appear as solid or subsolid nodules. Most subsolid nodules are not cancer, and many will remain stable or resolve; however, subsolid lesions can represent premalignancy or adenocarcinoma in situ. These lesions in the early spectrum of LUAD may persist for months to years before transforming into invasive disease. As a result, current standard of care is to follow these patients with CT imaging to monitor these indeterminate lesions for radiologic signs of malignant progression. The identification of novel biomarkers to predict the malignant potential of these nodules at their initial identification is of paramount importance.

      Method

      We have recently discovered that premalignant ad early invasive lesions of the LUAD spectrum rely on sodium-glucose transporter 2 (SGLT2) for glucose uptake, whereas advanced carcinomas up-regulate transporters of the GLUT family. This is consistent with the observation that positron emission tomography (PET) with 2-[18F] fluorodeoxyglucose (FDG), which detects GLUT but not SGLT activity, is a standard tool for staging advanced disease, but has low sensitivity for early-stage LUAD. We measured SGLT2 activity in vivo with the PET tracer methyl-4-[18F] fluorodeoxyglucose (Me4FDG).

      Result

      Me4FDG detects early-stage, FDG-negative LUAD in mouse models and in patients. Importantly, Me4FDG uptake correlates with tumor growth rate in patient-derived LUAD xenografts (fig. 1). Targeting SGLT2 with FDA-approved inhibitors significantly reduces tumor growth and prolongs survival in genetic and patient-derived murine models, confirming an important role of SGLT2 in early-stage LUAD.

      Fig. 1. Me4FDG PET detects early lung adenocarcinoma and predicts growth rate. A) Time course of Me4FDG and FDG imaging in genetically engineered mice with LUAD. The early time point was taken when tumor nodules reached an average diameter of 7 mm (left panels), and the advanced time point was performed on the same mice 1 month later (right panels). B) Representative image of Me4FDG PET/CT imaging in mice carrying patient-derived LUAD xenografts. C) Correlation between Me4FDG uptake in the patient-derived xenografts and the fold increase in volume in a 1-month period following the PET/CT scan.fig.1.jpg

      Conclusion

      SGLT2 is a promising biomarker not only to diagnose early-stage tumors by PET imaging, but also to predict response to SGLT2 inhibitors.

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