Article Text
PDF
Abstract
Background Lung carcinoma is one of the most common cancers and has one of the lowest survival rates in the world. Cytokines such as interleukin-12 (IL-12) have demonstrated considerable potential as robust tumour suppressors. However, their applications are limited due to off-target toxicity.
Methods In this study, we develop inhalable extracellular vesicles loaded with IL-12 mRNA to address lung cancer and bolster systemic immunity in lung tumor-bearing mouse models. IL-12 mRNA is loaded into human embryonic kidney cell-derived exosomes (HEK-Exo) through electroporation, yielding IL-12 mRNA-loaded exosomes (IL-12-Exo). The local gene translation, immune response, tumor rechallenge, and synergistic application have been explored. Additionally, the preliminary long-term toxicity is assessed on non-human primates and mice.
Results Inhalation and preferential uptake by cancer cells results in targeted delivery and fewer systemic side effects. The IL-12 messenger RNA generates interferon-γ production in both innate and adaptive immune-cell populations. This activation consequently incites an intense activation state in the tumor microenvironment and augments its immunogenicity. The increased immune response results in the expansion of tumor cytotoxic immune effector cells, the formation of immune memory, improved antigen presentation and tumor-specific T cell priming. The strategy is demonstrated against primary neoplastic lesions and provides profound protection against subsequent tumor rechallenge. Therapeutic benefits in combination with the checkpoint inhibitor and the long-term safety indicate the translational potential of IL12-Exo therapy.
Conclusions This novel therapy shows the potential for locally delivered cytokine-based immunotherapies to address orthotopic and metastatic lung tumors (figure 1). For future clinical study, this therapy may be suited well to patients with refractory non-small cell lung cancer and those with cancers from other organs metastatic to the lung.
Abstract image. Schematic of IL12-Exo in initiating immune responses against lung cancer
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.