Article Text
PDF
Abstract
Background High-dose interleukin-2 (IL-2) immunotherapy has previously demonstrated effective tumor lysis via activation of effector immune cells;1 however, clinical utility is limited due to pharmacokinetic challenges and life-threatening toxicities experienced by patients.2 To overcome these challenges, we developed a safe and clinically translatable localized IL-2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.3
Methods We evaluated the therapeutic efficacy of hydrogel encapsulated, cell-based IL-2 cytokine factories in a mouse model of malignant mesothelioma. An effective and well tolerated dose was determined by tracking tumor burden in response to increasing doses of our cytokine factories. Therapeutic efficacy of the optimal dose was subsequently evaluated in combination with anti-PD1 checkpoint inhibitor. Changes in immune populations across groups were analyzed using time-of-flight mass cytometry (CyTOF). Finally, safety and translatability of the platform were evaluated following pleural implant in rats, 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 systemic circulation. Additionally, AB1 tumor burden was reduced by 80% after one week of monotherapy treatment, and 7/7 animals exhibited tumor eradication when IL-2 cytokine factories were combined with aPD1 therapy (figure 1A). Resultantly, IL-2+aPD1 combination therapy led to significant improvements in tumor-free survival compared to controls (figure 1B). Further, CyTOF analysis showed an increase in CD69+CD44+ and CD69-CD44+CD62L- T cells (figure 1C-F), reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages (figure 1G and H) and MHC II+ dendritic cells after treatment. Finally, healthy blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.
Conclusions IL-2 cytokine factories led to eradication of aggressive mouse malignant mesothelioma tumors, protection from tumor recurrence, and increased the therapeutic efficacy of anti-PD1 checkpoint therapy. The results of this study provide support for clinical evaluation of our IL-2-based delivery system.
References
Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, Rodríguez-Ruiz ME, Ponz-Sarvise M, Castañón E, Melero I. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019; 120:6-15.
Sivakumar PV, Garcia R, Waggie KS, Anderson-Haley M, Nelson A, Hughes SD. Comparison of vascular leak syndrome in mice treated with IL21 or IL2. Comp Med. 2013; 63:13-21.
Nash AM, Jarvis MI, Aghlara-Fotovat S, Mukherjee S, Hernandez A, Hecht AD, Rios PD, Ghani S, Joshi I, Isa D, Cui Y, Nouraein S, Lee JZ, Xu C, Zhang DY, Sheth RA, Peng W, Oberholzer J, Igoshin OA, Jazaeri AA, Veiseh O. Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors. Sci Adv. 2022; 8:eabm1032.
IL-2 Cytokine factories eradicate MM tumors.(A) Luminescent images tracking tumor burden over time. (B) Survival curves plotted as percent survival over time beginning after tumor injection (n=7-8). C-F) Comparison of activated, and effector memory CD4+ and CD8+ T cells across treatment groups. G & H) Comparison of M1-like and M2-like macrophages across treatment groups.