Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer

Meder, Lydia; Schuldt, Philipp; Thelen, Martin; Schmitt, Anna; Dietlein, Felix; Klein, Sebastian; Borchmann, Sven; Wennhold, Kerstin; Vlašić, Ignacija; Oberbeck, Sebastian; Riedel, Richard; Florin, Alexandra; Golfmann, Kristina; Schlößer, Hans; Odenthal, Margarete; Buettner, Reinhard; Wolf, Juergen; Hallek, Michael; Herling, Marco; Bergwelt‐Baildon, Michael von; Reinhardt, Hans Christian; Ullrich, Roland T.

doi:10.1158/0008-5472.can-17-2176

Cited by 139 publications

(117 citation statements)

References 51 publications

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“…5,6 Agents targeting VEGF or VEGFR have demonstrated efficacy in solid tumors, including non-SCLC (NSCLC); 5,6 however, their role in SCLC remains controversial. [7][8][9][10][11] A previous study indicated that the addition of bevacizumab to cisplatin and etoposide in patients with extensive SCLC improved progression-free survival (PFS) and overall survival, 10 but a subsequent report suggested that the addition of bevacizumab to paclitaxel did not improve outcomes in patients with relapsed chemosensitive SCLC. 11 Evidence for the use of anti-angiogenesis drugs for SCLC thus remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Low-dose apatinib monotherapy in advanced chemotherapy-refractory small cell lung cancer: a case series and literature review

et al. 2019

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The therapeutic regimen for small cell lung cancer (SCLC) has changed little in the past several decades. Apatinib is a small molecule inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase. Apatinib has demonstrated efficacy against advanced gastric cancer and breast cancer, and recent studies have also reported its successful use in non-SCLC; however, its efficacy in SCLC remains unclear. In this study, we used apatinib as salvage therapy for chemotherapy-refractory SCLC. Five male patients with advanced SCLC were administered oral apatinib (250 mg/day) as 2nd- to 4th-line treatment. One patient showed a partial response to apatinib, one showed stable disease, and three patients showed progressive disease. The progression-free survival durations in the patients with stable disease and partial response were 1.5 and 3 months, respectively. Only three patients showed adverse effects, including mild hypertension, vomiting, and hand–foot syndrome, respectively, all of which were manageable. Apatinib might thus be a salvage option in patients with advanced SCLC after chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Low-dose apatinib monotherapy in advanced chemotherapy-refractory small cell lung cancer: a case series and literature review

et al. 2019

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“…These results suggest that the FGF signaling pathway contributes to resistance to anti-VEGF therapy; however, it is largely unknown how the FGF signaling pathway becomes activated when tumors acquire resistance to anti-VEGF therapy. Recently, the role of the VEGF signaling pathway in cancer immunity has received increased attention because of the promising combination antitumor activity of anti-VEGF therapy with immune checkpoint inhibitors in pre-clinical models 16,17 and clinical trials 18,19 . Therefore, it has become more important to understand the mechanism for acquired resistance to anti-VEGF therapy.Here, we developed novel tumor models for acquired resistance to anti-VEGF therapy by expressing a fusion protein of the mouse VEGFR2 extracellular domain and human IgG4 fragment crystallizable (Fc) region (VEGFR2-Fc) in Renca mouse renal cell carcinoma and B16F10 mouse melanoma cell lines.…”

mentioning

confidence: 99%

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Ichikawa

Miyano

Minoshima

et al. 2020

Sci Rep

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Anti-vascular endothelial growth factor (VEGF) therapy shows antitumor activity against various types of solid cancers. Several resistance mechanisms against anti-VEGF therapy have been elucidated; however, little is known about the mechanisms by which the acquired resistance arises. Here, we developed new anti-VEGF therapy-resistant models driven by chronic expression of the mouse VEGFR2 extracellular domain fused with the human IgG4 fragment crystallizable (Fc) region (VEGFR2-Fc). In the VEGFR2-Fc-expressing resistant tumors, we demonstrated that the FGFR2 signaling pathway was activated, and pericytes expressing high levels of FGF2 were co-localized with endothelial cells. Lenvatinib, a multiple tyrosine kinase inhibitor including VEGFR and FGFR inhibition, showed marked antitumor activity against VEGFR2-Fc-expressing resistant tumors accompanied with a decrease in the area of tumor vessels and suppression of phospho-FGFR2 in tumors. Our findings reveal the key role that intercellular FGF2 signaling between pericytes and endothelial cells plays in maintaining the tumor vasculature in anti-VEGF therapy-resistant tumors.Anti-vascular endothelial growth factor (VEGF) therapy, such as anti-VEGF antibody (Ab), anti-VEGFR2 Ab, and multiple tyrosine kinase inhibitors (TKIs) targeting VEGFR2, has been used to treat various types of solid cancers for over a decade. Despite massive efforts, the mechanisms of acquired resistance to anti-VEGF therapy are still not completely understood 1,2 .Other angiogenic factors such as fibroblast growth factors (FGFs) 3,4 , angiopoietins 5,6 , and platelet-derived growth factors (PDGFs) 7-9 have been reported to induce tumor angiogenesis as a single factor or in crosstalk with VEGF 10 . Upregulation of FGFs by chronic anti-VEGF therapy has been reported in the RIP1-Tag2 mouse (a pancreatic neuroendocrine tumor model) treated by DC101 (an anti-VEGFR2 Ab) 11 , and in a human head and neck squamous cell carcinoma xenograft tumor model treated by bevacizumab (an anti-VEGFA Ab) 12 . In a study of MCaIV syngeneic tumor models, cancer-associated fibroblasts and adipocytes expressed FGF2 and mediated resistance to anti-mouse VEGF Ab B20 13 . In addition, in the Y-MESO-14 (human malignant pleural mesothelioma cell line) xenograft tumor model, fibrocyte-like cells mediated the resistance to bevacizumab by producing FGF2 14 . In contrast, concurrent inhibition of VEGFR and FGFR by a chimeric dual decoy receptor enhanced antitumor activity in A549 (human lung cancer cell line) and Caki-1 (human renal cancer cell line) xenograft tumor models 15 . These results suggest that the FGF signaling pathway contributes to resistance to anti-VEGF therapy; however, it is largely unknown how the FGF signaling pathway becomes activated when tumors acquire resistance to anti-VEGF therapy. Recently, the role of the VEGF signaling pathway in cancer immunity has received increased attention because of the promising combination antitumor activity of anti-VEGF therapy with immune checkpoint inhibitors in pre-clinica...

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“…The study also suggests that miR-210 can serve as a prognostic marker for breast tumors. Together, the interplay between angiogenesis and cancer immune evasion has been investigated in many preclinical studies, which highlight the synergistic effect of immune checkpoint blockade in combination with antiangiogenic agents [111,112]. Conversely, miR-519c, miR-20b, and miR-107 have been reported to suppress vascular endothelial growth factor (VEGF) and HIF-1a expression under hypoxia and thus negatively regulate angiogenesis.…”

Section: The Role Of Mirnas In Modulating Angiogenesismentioning

confidence: 99%

“…2) [110]. Together, the interplay between angiogenesis and cancer immune evasion has been investigated in many preclinical studies, which highlight the synergistic effect of immune checkpoint blockade in combination with antiangiogenic agents [111,112]. Inspired by promising animal studies, many clinical trials are underway to explore the combination of different compounds that target immune checkpoints and angiogenesis (NCT03024437, NCT02659384, NCT02873962, NCT02017717).…”

Section: The Role Of Mirnas In Modulating Angiogenesismentioning

confidence: 99%

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

et al. 2019

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Cancer immunotherapy represents a promising new era in cancer management due to the relatively high safety margins and selectivity, compared to the classical cancer chemotherapeutic agents. However, there is an imperative need to overcome tumor resistance in order to improve clinical outcomes and maximize the benefits of cancer immunotherapy. The interaction between the programmed cell death‐1 (PD‐1) receptor and its ligand PD‐L1 is a vital immune checkpoint that is often adopted by cancer cells to undergo immune evasion. PD‐1/PD‐L1 signaling is regulated at multiple levels through the crosstalk with other immune targets or relevant signaling partners involved in the cancer progression. Among the significant epigenetic players that are implicated in modulating the immune system are microRNAs (miRNAs). A complex system of these noncoding RNAs regulates the gene expression at the post‐transcriptional level and plays a significant role in the modulation of both innate and the adaptive immune systems. The expression profile of immune‐modulatory miRNAs might be useful as a predictive biomarker for the response and clinical outcomes in cancer immunotherapy. Therefore, in the current review, we highlighted the role of miRNAs in cancer immune evasion through a critical discussion of their impact on key immune checkpoints as well as the role of miRNAs in cancer progression and resistance.

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Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer

Cited by 139 publications

References 51 publications

Low-dose apatinib monotherapy in advanced chemotherapy-refractory small cell lung cancer: a case series and literature review

Low-dose apatinib monotherapy in advanced chemotherapy-refractory small cell lung cancer: a case series and literature review

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

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