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Charles M Rudin



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    MS14 - Molecular Subsets and Novel Targeted Approaches to Small Cell and Neuroendocrine Cancers (ID 77)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      MS14.04 - Targeting DNA Damage and Repair (Now Available) (ID 3522)

      11:30 - 13:00  |  Presenting Author(s): Charles M Rudin

      • Abstract
      • Presentation
      • Slides

      Abstract

      Genomic profiling of small cell lung cancer has revealed nearly universal inactivation of the key tumor suppressor genes TP53 and RB1. Loss of these critical regulators of cell cycle entry and DNA damage response together results in selective sensitivity to DNA damaging agents, inhibitors of DNA damage repair, and inhibitors of the remaining late phase cell cycle checkpoints. Multiple preclinical studies and recent clinical data nominate these pathways as potential synthetic lethal vulnerabilities in small cell lung cancer. Recent study has also demonstrated that targeting DNA damage response can activate the anti-tumor immunity and potentiate the response of immune checkpoint blockade antibodies. This talk will review these recent studies, focusing on opportunities and future directions in investigational therapy for patients with small cell lung cancer.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-26 - EMT-Associated Response and Resistance to MEK Inhibitor and Immune Checkpoint Blockade Combinations in KRAS-Mutant NSCLC (ID 1129)

      09:45 - 18:00  |  Author(s): Charles M Rudin

      • Abstract
      • Slides

      Background

      Current work by our group using mutant KRAS and TP53 (KP) mouse models of NSCLC have shown that rationally designed therapies combining PD-L1 immune checkpoint blockade (ICB) with MEK inhibitors (MEKi) significantly decreases tumor growth and metastases compared to either monotherapies in syngeneic KP mice tumors. Despite these encouraging results, therapeutic resistance still occurs. Analyses from these tumors showed an increase in Tregs and CTLA-4 immune checkpoint expression. As anti-CTLA-4 ICB is particularly effective in increasing the CD8 / Treg ratio, we hypothesized that the addition of this agent may improve the outcome.

      Method

      Using in vivo KP syngeneic mouse models, we compared tumor size, tumor weight and lung metastatic nodules between two treatment regimens: the triple combination of selumetinib (MEKi) and anti-PD-L1 with either: 1) anti-CTLA-4 or; 2) IgG2b isotype control. FACS-based immunoprofiling was conducted at the time of response (5 weeks following treatment initiation) and resistance (maximal tumor volume). Whole tumors at the time of response and resistance, as well as ex vivo resistant cell lines, were also characterized by qPCR and Western Blotting (WB). Moreover, whole tumors from multiple treatment combinations and KP models were processed for custom codeset Nanostring mRNA analyses.

      Result

      The addition of anti-CTLA-4 to anti-PD-L1 and MEKi improved survival in the epithelial 393P KP mouse model (HR=3.517; p=0.03). Because FACS immunoprofiling of cytotoxic CD8+ T cells subtypes, NK cells and Tregs did not reveal statistically significant changes (p>0.05), we investigated potential tumor-intrinsic mechanisms. All resistant 393P cell lines displayed a mesenchymal morphology. Furthermore, whole tumors from the anti-CTLA-4 group demonstrated significantly less expression of Zeb1 (WB; p=0.05) at the time of response. Nanostring analyses comparing anti-PD-1 + anti-CTLA-4 vs anti-PD-L1 monotherapy in 344SQ KP mesenchymal tumors also showed statistically significant downregulation of epithelial-to-mesenchymal (EMT) markers (p=0.001). Finally, in vivo experiments using resistant 393P (MEKi + ICB) and mesenchymal 344SQ cells, demonstrated abrogation of the survival benefit initially observed with sensitive epithelial 393P cells upon treatment with combination therapies.

      Conclusion

      The combination of a MEKi, anti-PD-L1 and anti-CTLA-4 improves survival in epithelial syngeneic KP pre-clinical models of NSCLC, and this benefit is associated with downregulation of EMT markers. Therefore, further in-depth studies are required to understand the effect of ICB on EMT. In an upcoming single center, Phase I / II clinical trial, two combination schedules of selumetinib, tremelimumab and durvalumab will be compared with historical controls in patients with previously treated, metastatic NSCLC.

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