Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors

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dc.citation.firstpage5121en_US
dc.citation.issueNumber23en_US
dc.citation.journalTitleClinical Cancer Researchen_US
dc.citation.lastpage5135en_US
dc.citation.volumeNumber28en_US
dc.contributor.authorNash, Amanda M.en_US
dc.contributor.authorAghlara-Fotovat, Samiraen_US
dc.contributor.authorCastillio, Berthaen_US
dc.contributor.authorHernandez, Andreaen_US
dc.contributor.authorPugazenthi, Aarthien_US
dc.contributor.authorLee, Hyun-Sungen_US
dc.contributor.authorJang, Hee-Jinen_US
dc.contributor.authorNguyen, Annieen_US
dc.contributor.authorLu, Alexanderen_US
dc.contributor.authorBurt, Bryan M.en_US
dc.contributor.authorGhanta, Ravi K.en_US
dc.contributor.authorVeiseh, Omiden_US
dc.date.accessioned2023-01-27T14:47:14Zen_US
dc.date.available2023-01-27T14:47:14Zen_US
dc.date.issued2022en_US
dc.description.abstractIL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system.See related commentary by Palanki et al., p. 5010en_US
dc.identifier.citationNash, Amanda M., Aghlara-Fotovat, Samira, Castillio, Bertha, et al.. "Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors." <i>Clinical Cancer Research,</i> 28, no. 23 (2022) AACR: 5121-5135. https://doi.org/10.1158/1078-0432.CCR-22-1493.en_US
dc.identifier.digital5121en_US
dc.identifier.doihttps://doi.org/10.1158/1078-0432.CCR-22-1493en_US
dc.identifier.urihttps://hdl.handle.net/1911/114257en_US
dc.language.isoengen_US
dc.publisherAACRen_US
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licenseen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleActivation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumorsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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