Author of

• 17398

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  P2.01 - Poster Session with Presenters Present (ID 461)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17443

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    P2.01-045 - Nintedanib Improves Anti-Tumor Efficacy in Combination with Anti PD-1 in Syngeneic Tumor Models Sensitive and Refractory to IO Inhibition (ID 4190)

    14:30 - 14:30  |  Author(s): M.H. Hofmann
    • Abstract

    Background:
    Nintedanib, an oral triple-angiokinase inhibitor, has received regulatory approval in combination with docetaxel based on the demonstrated efficacy as a 2[nd] line treatment for NSCLC patients. Two recently approved immune checkpoint PD1 antagonists have shaken up the established lines of NSCLC therapy. In order to explore the combination potential of Nintedanib with PD1 antagonists, we performed in vivo combination experiments in two syngeneic murine tumor models.
    
    Methods:
    The murine tumor cell lines CT-26 and 4T1 were injected subcutaneously into female BALB/c mice. Established tumors around of 50-100mm³ were randomized into the different treatment groups and treated with vehicle, RMP1-14 (murine anti PD-1, 10mg/kg, i.p., q3or4d), Nintedanib (50mg/kg, p.o., qd) and RMP1-14 plus Nintedanib. Anti tumor efficacy was determined after 3 weeks of treatment. In a separate pharmacodynamic approach larger tumors of~300mm³ were treated for 10 days followed by FACS analyses of the dissociated tumors for various myeloid cell subsets including monocytes/macrophages and granulocytes (Markers: CD11c, CD11b, Ly6C, Ly6G, PD-L1, F4/80), T cells/activation (Markers: CD3, CD4, CD8, CD25, FoxP3, IFN-gamma, PD-1) and NK cells (Markers: CD335/Nkp46).
    
    Results:
    Single agent treatment of CT-26 subcutaneous tumors with RMP1-14 and Nintedanib resulted in anti-tumor effect with T/C values of 45% and 63%, respectively. The combination treatment group after 24 days showed a T/C value of 34%. In the RMP1-14 refractory tumor model 4T1 neither anti-PD1 treatment nor nintedanib showed benefit (T/C=88% and 82%). The combination treatment after 26 days resulted in a T/C value of 38%. The particular immune cell infiltrate composition and activation state in the different treatment groups will be reported.
    
    Conclusion:
    The combination of angiogenic and immune checkpoint inhibition is an attractive opportunity to improve overall response rates and efficacy based on the dual roles of angiogenic factors in blood vessel formation and immune regulation. In the CT-26 model improved additive efficacy could be demonstrated by combining Nintedanib with anti PD-1. More interestingly, the addition of Nintedanib in the anti PD-1 refractory model 4T1 showed a synergistic combinatorial anti-tumor effect. These data fit well with the hypothesis that interfering with tumor angiogenesis in combination with immune checkpoint inhibition will result in additive and synergistic effects by positively regulating immune cell function and infiltration.