Amanda M. Nash, Samira Aghlara-Fotovat, Bertha Castillio, Andrea Hernandez, Aarthi Pugazenthi, Hyun-Sung Lee, Hee-Jin Jang, Annie Nguyen, Alexander Lu, Bryan M. Burt, Ravi K. Ghanta, Omid Veiseh; Activation of adaptive and innate immune cells via localized Interleukin-2 cytokine factories eradicates mesothelioma tumors. Clin Cancer Res 2022; https://doi.org/10.1158/1078-0432.CCR-22-1493
Purpose: Interleukin-2 (IL-2) 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 IL-2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. Experimental Design: We evaluated the therapeutic efficacy of IL-2 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. Results: IL-2 cytokine factories enabled 150x higher IL-2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after one week of monotherapy treatment, and 7/7 of animals exhibited tumor eradication without recurrence when IL-2 cytokine factories were combined with aPD1. Further, CyTOF analysis showed an increase in CD69+CD44+ and CCD69-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. Conclusion: IL-2 cytokine factories led to the eradication of aggressive mouse MM tumors, protection from tumor recurrence, and increased the therapeutic efficacy of anti-PD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL-2-based delivery system.
Supplementary Table Supplementary Figure legend 1-9
Supplemental Figure 1. Dose dependent anti-tumor effects of RPE-mIL2 administration
Supplemental Figure 2. CD8+ T cells are needed for a robust anti-tumor response in mice with MPM tumors
Supplemental Figure 3. Combination treatment did not cause significant deviations in body weight
Supplemental Figure 4. aPD-1 therapy is not effective as a single agent for MPM tumors.
Supplemental Figure 5. Combination of RPE-mIL2 and aPD1 checkpoint therapy elicit MPM tumor eradication.
Supplemental Figure 6. Gating strategies of CyTOF data.
Supplemental Figure 7. RPE-hIL2 Pharmacokinetics in immunocompetent mice
Supplemental Figure 8. Toxicological analysis of RPE-hIL2 in the rat pleura Supplemental Figure 9. Safe and local delivery of capsules to the pleural space via catheter.
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