Browsing by Author "Lu, Alexander"

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    Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors
    (AACR, 2022) Nash, Amanda M.; Aghlara-Fotovat, Samira; Castillio, Bertha; Hernandez, Andrea; Pugazenthi, Aarthi; Lee, Hyun-Sung; Jang, Hee-Jin; Nguyen, Annie; Lu, Alexander; Burt, Bryan M.; Ghanta, Ravi K.; Veiseh, Omid
    IL2 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
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    mplantable Cell Based Therapy for Treatment of Inflammatory Heart and Lung Conditions
    (2022-04-22) Lu, Alexander; Veiseh, Omid
    In this work, we explore utilizing encapsulated engineered cells for targeted release of anti-inflammatory cytokines. A plasmid encoding the cytokine hIL-10 and suicide system iCasp9 was created and inserted into ARPE-19 cells. After integration, cells were assayed for hIL-10 production and response to an iCasp9 activating molecule. To better understand clinical translatability of a capsule based delivery system, two surgical approaches to delivery of capsules were tested on cadaveric porcine hearts and cadaveric mice. hIL-10 cells showed variable hIL-10 production over 24 hours, ranging from 0.3 - 5.2 pg/cell/24hr. Cells exposed to 1nM of AP1903, 10% of previously reported doses, demonstrated significant cell death over 24 hours. Existing surgical methods involving placement of capsules ultimately proved unsuitable for clinical use. This work serves as an initial proof of concept for treating inflammatory conditions using biologically and physically targeted therapies.