Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein
Background The administration of recombinant interleukin 2 (IL-2) in oncology is frequently hampered by dose-limiting toxicities, including potentially lethal vascular leak syndrome. Antibody-IL-2 fusion proteins capable of preferential tumor localization have shown encouraging signs of activity in...
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BMJ Publishing Group
2025-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/5/e010831.full |
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| author | Francesco Prisco Dario Neri Emanuele Puca Eleonora Prodi Cornelia Halin Giulia Rotta Ettore Gilardoni Frauke Seehusen Matilde Bocci Claudia Comacchio Sheila Dakhel Plaza |
| author_facet | Francesco Prisco Dario Neri Emanuele Puca Eleonora Prodi Cornelia Halin Giulia Rotta Ettore Gilardoni Frauke Seehusen Matilde Bocci Claudia Comacchio Sheila Dakhel Plaza |
| author_sort | Francesco Prisco |
| collection | DOAJ |
| description | Background The administration of recombinant interleukin 2 (IL-2) in oncology is frequently hampered by dose-limiting toxicities, including potentially lethal vascular leak syndrome. Antibody-IL-2 fusion proteins capable of preferential tumor localization have shown encouraging signs of activity in clinical trials; however, they typically cause side effects shortly after intravenous administration, which may limit escalation to curative doses. There is an urgent need to engineer IL-2 products with “activity-on-demand” able to mask on-target off-tumor IL-2 activity without compromising therapeutic efficacy.Methods To design IL-2 biopharmaceuticals with “activity-on-demand”, which would be non-toxic on administration but regain activity at the tumor site, we explored the therapeutic potential of the co-administration of signaling inhibitors with matched pharmacokinetic properties. In this work, we used the tumor-homing F8-IL2 fusion protein, specific to a splice variant of fibronectin, and masked off-tumor toxicity by co-administration of upadacitinib, which rapidly clears from circulation. Vascular leak syndrome was monitored by histopathological analysis, the extent of peripheral edema, and cytokine levels. Immune profiling of the tumors and secondary lymphoid organs was performed by flow cytometry.Results In immunocompetent tumor-bearing mice, the combinatorial treatment significantly improved tolerability without any detectable loss of therapeutic activity, protecting the mice from body weight loss, uncontrolled systemic cytokine release, and severe vascular leak syndrome manifestations, including peripheral edema. F8-IL2 efficiently controlled tumor growth and retained its immunological activity within the neoplastic mass, as evidenced by the massive natural killer and cytotoxic T-cell infiltrates.Conclusions This study suggests that combinatorial treatments enable the administration of potentially curative doses of targeted IL-2 products while sparing healthy organs from life-threatening toxicities. |
| format | Article |
| id | doaj-art-e24f8db03db344669c98d996bfb078e0 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e24f8db03db344669c98d996bfb078e02025-08-20T03:09:39ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-05-0113510.1136/jitc-2024-010831Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion proteinFrancesco Prisco0Dario Neri1Emanuele Puca2Eleonora Prodi3Cornelia Halin4Giulia Rotta5Ettore Gilardoni6Frauke Seehusen7Matilde Bocci8Claudia Comacchio9Sheila Dakhel Plaza103 Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland1 Philochem AG, Otelfingen, Switzerland1 Philochem AG, Otelfingen, Switzerland1 Philochem AG, Otelfingen, Switzerland6 Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland2 Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy1 Philochem AG, Otelfingen, Switzerland3 Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland1 Philochem AG, Otelfingen, Switzerland1 Philochem AG, Otelfingen, Switzerland1 Philochem AG, Otelfingen, SwitzerlandBackground The administration of recombinant interleukin 2 (IL-2) in oncology is frequently hampered by dose-limiting toxicities, including potentially lethal vascular leak syndrome. Antibody-IL-2 fusion proteins capable of preferential tumor localization have shown encouraging signs of activity in clinical trials; however, they typically cause side effects shortly after intravenous administration, which may limit escalation to curative doses. There is an urgent need to engineer IL-2 products with “activity-on-demand” able to mask on-target off-tumor IL-2 activity without compromising therapeutic efficacy.Methods To design IL-2 biopharmaceuticals with “activity-on-demand”, which would be non-toxic on administration but regain activity at the tumor site, we explored the therapeutic potential of the co-administration of signaling inhibitors with matched pharmacokinetic properties. In this work, we used the tumor-homing F8-IL2 fusion protein, specific to a splice variant of fibronectin, and masked off-tumor toxicity by co-administration of upadacitinib, which rapidly clears from circulation. Vascular leak syndrome was monitored by histopathological analysis, the extent of peripheral edema, and cytokine levels. Immune profiling of the tumors and secondary lymphoid organs was performed by flow cytometry.Results In immunocompetent tumor-bearing mice, the combinatorial treatment significantly improved tolerability without any detectable loss of therapeutic activity, protecting the mice from body weight loss, uncontrolled systemic cytokine release, and severe vascular leak syndrome manifestations, including peripheral edema. F8-IL2 efficiently controlled tumor growth and retained its immunological activity within the neoplastic mass, as evidenced by the massive natural killer and cytotoxic T-cell infiltrates.Conclusions This study suggests that combinatorial treatments enable the administration of potentially curative doses of targeted IL-2 products while sparing healthy organs from life-threatening toxicities.https://jitc.bmj.com/content/13/5/e010831.full |
| spellingShingle | Francesco Prisco Dario Neri Emanuele Puca Eleonora Prodi Cornelia Halin Giulia Rotta Ettore Gilardoni Frauke Seehusen Matilde Bocci Claudia Comacchio Sheila Dakhel Plaza Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein Journal for ImmunoTherapy of Cancer |
| title | Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein |
| title_full | Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein |
| title_fullStr | Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein |
| title_full_unstemmed | Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein |
| title_short | Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein |
| title_sort | combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor targeted il 2 fusion protein |
| url | https://jitc.bmj.com/content/13/5/e010831.full |
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