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

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dc.citation.firstpage5121
dc.citation.issueNumber23
dc.citation.journalTitleClinical Cancer Research
dc.citation.lastpage5135
dc.citation.volumeNumber28
dc.contributor.authorNash, Amanda M.
dc.contributor.authorAghlara-Fotovat, Samira
dc.contributor.authorCastillio, Bertha
dc.contributor.authorHernandez, Andrea
dc.contributor.authorPugazenthi, Aarthi
dc.contributor.authorLee, Hyun-Sung
dc.contributor.authorJang, Hee-Jin
dc.contributor.authorNguyen, Annie
dc.contributor.authorLu, Alexander
dc.contributor.authorBurt, Bryan M.
dc.contributor.authorGhanta, Ravi K.
dc.contributor.authorVeiseh, Omid
dc.date.accessioned2023-01-27T14:47:14Z
dc.date.available2023-01-27T14:47:14Z
dc.date.issued2022
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. 5010
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.
dc.identifier.digital5121
dc.identifier.doihttps://doi.org/10.1158/1078-0432.CCR-22-1493
dc.identifier.urihttps://hdl.handle.net/1911/114257
dc.language.isoeng
dc.publisherAACR
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleActivation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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