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F. Hilberg



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    OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA11.06 - Role of Fibroblasts in the Subtype-Specific Therapeutic Effects of Nintedanib in Non-Small Cell Lung Cancer (NSCLC) (ID 5029)

      11:00 - 12:30  |  Author(s): F. Hilberg

      • Abstract
      • Presentation
      • Slides

      Background:
      There is growing evidence that tumor-associated fibroblasts (TAFs) play a major role in critical steps of tumor progression in solid tumors including NSCLC. However the role of TAFs in regulating the response to targeted therapies is poorly understood. One of such targeted therapies is nintedanib (NTD), a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients. Although the therapeutic effects of NTD in lung cancer have been associated with its anti-angiogenic functions, NTD has also been shown to exhibit anti-fibrotic effects in patients with idiopathic pulmonary fibrosis. Since lung fibrosis is largely driven by activated fibroblasts/myofibroblasts, and TAFs are positive for myofibroblasts markers, it is conceivable that NTD anti-tumor effects may be additionally driven through its direct action on lung TAFs. The main goal of this study was to analyze the latter hypothesis.

      Methods:
      Patient derived lung TAFs from ADC and SCC patients as well as paired control fibroblasts from non-malignant pulmonary tissue were exposed to increasing concentrations of NTD and analyzed for growth and activation upon stimulation with growth factors and TGF- β1, respectively. Activation markers included alpha-smooth muscle actin and collagen-I.

      Results:
      We found that NTD exhibited a dual inhibitory role in TAFs in terms of growth and TGF-β1-induced activation in a subtype-specific fashion. Specifically, NTD-mediated growth inhibition was larger in SCC-TAFs than in ADC-TAFs, which correlated with the larger Erk signaling previously reported by our group in SCC-TAFs in the absence of mitogenic stimuli. Conversely, inhibition by NTD of TGF-β1-mediated activation was larger in ADC-TAFs than SCC-TAFs. Likewise, NTD inhibited the growth and invasive advantages of ADC cancer cells in vitro elicited by the conditioned medium of ADC-TAFs treated with TGF-β1 compared to those advantages elicited in the absence of NTD. These results reveal for the first time that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.

      Conclusion:
      TAFs in vivo are largely activated and quiescent, and TGF-β1 is a potent fibroblast activator that is frequently upregulated in lung cancer and associated with poor prognosis. Based on these previous observations, we argue that our new findings strongly suggest that the selective therapeutic advantage observed for NTD in ADC patients may be in part related to its selective inhibition of TGF-β1-dependent activation of ADC-TAFs. These findings provide novel mechanistic insights on the subtype-specific therapeutic effects of NTD in NSCLC.

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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
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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 - 15:45  |  Author(s): F. Hilberg

      • 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.