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1. Supplementary Figure S5 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S5 shows the immunohistochemical evaluation of hypoxia in NCI-H1703 subcutaneous tumor model

Published
2023
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2. Supplementary Materials and Methods SM1 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

supplementary materials & methods

Published
2023
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3. Supplementary Figure S8 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S8 shows that EVT801 doesn’t modify blood pressure in rat while sorafenib increases it

Published
2023
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4. Supplementary Figure S9 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S9 provides an overview of the mechanisms by which EVT801 exerts its anti-tumor effects

Published
2023
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5. Supplementary Table TS2 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Table S2 shows EVT801 metabolite potency and selectivity profile

Published
2023
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6. Supplementary Figure S4 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S4 shows the evaluation of EVT801’s pharmacokinetics and pharmacodynamics

Published
2023
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7. Supplementary Table TS1 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Table S1 shows EVT801 potency and selectivity profile

Published
2023
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8. Supplementary Figure S2 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S2 shows that EVT801 inhibits tubule formation

Published
2023
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9. Supplementary Figure S7 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S7 shows that EVT801 decreases immunosuppressive cell infiltration in VEGFR3-positive BNL hepatoma tumors

Published
2023
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10. Supplementary Figure S6 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S6 shows that EVT801 inhibits growth of VEGFR3-positive BNL hepatoma tumors, while decreasing vasculature and hypoxia

Published
2023
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11. Supplementary Table TS3 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Table S3 shows pharmacokinetic parameters of EVT801 in mice and rats

Published
2023
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12. Supplementary Figure S1 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S1 shows that EVT801 metabolite is a selective VEGFR-3 inhibitor

Published
2023
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13. Supplementary Figure S3 from Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy

Author

Pierre Fons, Mark Whittaker, Ian Hunneyball, Antoine Alam, Isabelle Blanc, Françoise Bono, Frédérique Dol-Gleizes, Jean-Pierre Delord, Céleste Lebbé, Maxime Battistella, Philippe Rochaix, Janik Selves, Anne Gomez-Brouchet, Valérie Martin, Jérôme Meneyrol, Dennis Özcelik, Eric Erdociain, David Sibrac, Pierre-Benoit Ancey, Anne Briaux, Gaelle Badet, Pauline Barron, Florence Gaujarengues, Geneviève Gueguen-Dorbes, Virgile Visentin, Mélanie Pichery, Céline Poussereau-Pomié, Florie A. Bertrand, Michael Esquerré, and Michael R. Paillasse

Abstract

Supplementary Figure S3 shows the expression of VEGFR3 altogether with vascular and lymphatic markers in primary kidney tumors

Published
2023
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14. Supplementary Figure 3 from SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Author

Françoise Bono, Pierre Savi, Paul Schaeffer, Jean-Pascal Hérault, Frédérique Dol, Florence Gaujarengues, Gaelle Morin, Marie-Claude Laplace, Pauline Barron, Jacques Bonnin, Olivier Duclos, Geneviève Gueguen-Dorbes, Isabelle Blanc, and Antoine Alam

Abstract

PDF file - 269K, This file shows immunohistological illustrations for blood and lymphatic vessels, for lymph nodes osteopontin and for macrophages

Published
2023
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16. Supplementary Table 2 from SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Author

Françoise Bono, Pierre Savi, Paul Schaeffer, Jean-Pascal Hérault, Frédérique Dol, Florence Gaujarengues, Gaelle Morin, Marie-Claude Laplace, Pauline Barron, Jacques Bonnin, Olivier Duclos, Geneviève Gueguen-Dorbes, Isabelle Blanc, and Antoine Alam

Abstract

PDF file - 93K, This file shows the effect of SAR131675 on a number of non-kinase enzymes, receptors and on ion channels

Published
2023
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17. Supplementary Figure 2 from SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Author

Françoise Bono, Pierre Savi, Paul Schaeffer, Jean-Pascal Hérault, Frédérique Dol, Florence Gaujarengues, Gaelle Morin, Marie-Claude Laplace, Pauline Barron, Jacques Bonnin, Olivier Duclos, Geneviève Gueguen-Dorbes, Isabelle Blanc, and Antoine Alam

Abstract

PDF file - 76K, This file shows the pharmacokinetic parameters of SAR131675 and its effect on blood pressure

Published
2023
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18. Supplementary Table 3 from SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Author

Françoise Bono, Pierre Savi, Paul Schaeffer, Jean-Pascal Hérault, Frédérique Dol, Florence Gaujarengues, Gaelle Morin, Marie-Claude Laplace, Pauline Barron, Jacques Bonnin, Olivier Duclos, Geneviève Gueguen-Dorbes, Isabelle Blanc, and Antoine Alam

Abstract

PDF file - 55K, This file shows the results obtained with SAR131675 on the in vitro proliferation of a panel of tumor cell lines and on normal human dermal fibroblasts and PBLs

Published
2023
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19. Supplementary Figure 1 from SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Author

Françoise Bono, Pierre Savi, Paul Schaeffer, Jean-Pascal Hérault, Frédérique Dol, Florence Gaujarengues, Gaelle Morin, Marie-Claude Laplace, Pauline Barron, Jacques Bonnin, Olivier Duclos, Geneviève Gueguen-Dorbes, Isabelle Blanc, and Antoine Alam

Abstract

PDF file - 194K, This files shows the effect of SAR131675 different variants of human VEGFR-3 and on murin VEGFR-3. It also shows example of results obtained with sunitinib on VEGFRs and on lymphatic cells proliferation

Published
2023
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20. Supplementary Table 1 from SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Author

Françoise Bono, Pierre Savi, Paul Schaeffer, Jean-Pascal Hérault, Frédérique Dol, Florence Gaujarengues, Gaelle Morin, Marie-Claude Laplace, Pauline Barron, Jacques Bonnin, Olivier Duclos, Geneviève Gueguen-Dorbes, Isabelle Blanc, and Antoine Alam

Abstract

PDF file - 76K, This file shows the effect of SAR131675 on a number of recombinant kinases

Published
2023
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21. Abstract 2634: EVT801: Standalone cancer immunotherapy in VEGFR3+ tumors and combination with immune checkpoint therapies in VEGFR3- tumors

Author

Jérémy Kagan, Joanna Lisztwan, Florence Gaujarengues, Gaelle Badet, Jerome Meneyrol, Antoine Alam, Mark Whittaker, Pierre Fons, Michael Esquerre, Isabelle Blanc, Roselyne Broussy, Françoise Bono, Pauline Barron, and Michael R. Paillasse

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Tumor microenvironment, business.industry, Angiogenesis, medicine.medical_treatment, T cell, Cancer, medicine.disease, Immune checkpoint, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Cancer immunotherapy, 030220 oncology & carcinogenesis, Internal medicine, medicine, Myeloid-derived Suppressor Cell, business, CD8
Abstract

In collaboration with Sanofi, we previously showed that inhibition of the VEGFR3 pathway by SAR131675 leads to reduction of tumor growth by acting on the tumor microenvironment. We have identified a new drug candidate, EVT801, and evaluated its activity on tumor models expressing VEGFR3. For proof-of-concept, we transfected the mouse BNL hepatoma cell line with VEGFR3. EVT801 displayed a strong therapeutic activity by acting on both VEGFR3+ tumor cells and on the Tumor Microenvironment (TME). By deciphering the mechanism of action of the compounds we showed that EVT801 strongly decreased tumor-associated immunosuppression by decreasing MDSCs (Myeloid Derived Suppressor cells) and CD4+ regulatory T cells and by increasing macrophages with a M1 phenotype inside the tumor. As a consequence the T-cell:MDSC ratios were increased in the TME and also in peripheral blood. In addition to its immunomodulatory properties, EVT801 decreased angiogenesis without increasing hypoxia. We have evaluated EVT801 therapeutic activity in syngeneic tumor mouse models which are not expressing VEGFR3 such as 4T1 mammary carcinoma and CT26 colon carcinoma models. As expected, we observed an intermediate therapeutic activity of the compound on both tumor models. Positive modulation of the TME was equivalent to what we observed with the VEGFR3+ tumor model. With this unique mechanism of action of EVT801 on the TME, we evaluated its ability to increase therapeutic activity of standard Immune Checkpoint Therapies (ICT) such as anti-CTLA-4 and anti-PD-1 mAbs. Strong additive therapeutic activities were observed with EVT801 in combination with these ICT as illustrated by the development of long-term tumor-specific memory CD8+ T cell responses. Toxicological data show that EVT801 has a favorable pharmacological profile consistent with its entry into pre-clinical development. Taken together, these results indicate that EVT801 represents an innovative drug for cancer Immunotherapy which provide a favorable microenvironment to promote tumor regression. In addition, EVT801 may improve the frequency of response to ICT. Citation Format: Michael Esquerré, Pierre Fons, Gaëlle Badet, Pauline Barron, Jérémy Kagan, Antoine Alam, Jérôme Meneyrol, Isabelle Blanc, Roselyne Broussy, Florence Gaujarengues, Joanna Lisztwan, Michael Paillasse, Mark Whittaker, Françoise Bono. EVT801: Standalone cancer immunotherapy in VEGFR3+ tumors and combination with immune checkpoint therapies in VEGFR3- tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2634. doi:10.1158/1538-7445.AM2017-2634

Published
2017
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22. SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities

Author

Gaelle Morin, Frédérique Dol, Jacques Bonnin, Geneviève Gueguen-Dorbes, Isabelle Blanc, Pauline Barron, Françoise Bono, Pierre Savi, Jean-Pascal Herault, Marie-Claude Laplace, Antoine Alam, Olivier Duclos, Florence Gaujarengues, and Paul J. Schaeffer

Subjects
Cancer Research, Cell Survival, Neovascularization, Physiologic, Angiogenesis Inhibitors, Antineoplastic Agents, Mice, Transgenic, Biology, Pharmacology, Metastasis, Mice, In vivo, Cell Movement, medicine, Animals, Humans, Lymphocytes, Lymphangiogenesis, Naphthyridines, Neoplasm Metastasis, Protein Kinase Inhibitors, Zebrafish, Vascular Endothelial Growth Factor Receptor-1, Kinase, Macrophages, Autophosphorylation, Mammary Neoplasms, Experimental, medicine.disease, Vascular Endothelial Growth Factor Receptor-3, Vascular Endothelial Growth Factor Receptor-2, Xenograft Model Antitumor Assays, Tumor Burden, Enzyme Activation, Cell Transformation, Neoplastic, Oncology, Vascular endothelial growth factor C, Syngenic, Female, Tyrosine kinase
Abstract

SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC50 values of 20 and 45 nmol/L, respectively. SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC50 of about 20 nmol/L. SAR131675 was found to be highly selective for VEGFR-3 versus 107 receptors, enzymes, ion channels, and 65 kinases. However, it was moderately active on VEGFR-2 with a VEGFR-3/VEGFR-2 ratio of about 10. SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells, further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models, including mammary 4T1 carcinoma and RIP1.Tag2 tumors. Interestingly, it significantly reduced lymph node invasion and lung metastasis, showing its antilymphangiogenic activity in vivo. Moreover, treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis. Tumor-associated macrophages (TAM) play an important role in tumor growth and metastasis. The expression of VEGFR-3 on TAMs has been recently described. F4/80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors. Taken together, SAR131675 is the first highly specific VEGFR-3-TK inhibitor described to date, displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion. Mol Cancer Ther; 11(8); 1637–49. ©2012 AACR.

Published
2012

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