Scientists have discovered a way to use inhalable exosomes to deliver interleukin-12 (IL-12) mRNA to the lungs for cancer therapy. The technology provides a means of achieving sufficiently concentrated IL-12 levels in the lungs and bypassing some of the off-target side effects of IL-12 therapy delivered systemically through other delivery mechanisms, including tumor injections or via the blood stream. Their work is published in Nature Nanotechnology.
Cytokines such as interleukin-12 (IL-12) have long offered promise as tumor suppressors. Despite the immune response of these proteins’ monotherapy or the combination with other immunotherapies systemic cytokine administration can induce severe side effects.
To develop localized tumor microenvironment (TME) delivery strategies, researchers at Columbia University have found that extracellular vesicles, or exosomes, deliver IL-12 mRNA to the TME while minimizing systemic exposure. While scientists have previously used liposomes or lipid nanoparticles to deliver mRNA, this method has several problems, including a lack of tissue homing, where the particles do not go to the target organs, and concerns about the potential toxicity after long-term exposure.
This research is the latest from the laboratory of Ke Cheng who has been studying exosomes as drug carriers for over 15 years.
“Exosomes are usually injected systemically into the bloodstream,” said Cheng. “In this new study, we show that inhaled exosomes can efficiently reach the lung and deliver an anti-lung cancer cargo, IL-12 mRNA.”
This work builds on the wider recognition that extracellular vehicles, especially exosomes, are increasingly harnessed as natural mRNA delivery systems. “Delivery through inhalation presents an effective, non-invasive local administration route, as we demonstrated previously for treating pulmonary fibrosis and COVID-19,” the authors write.
In this study, Cheng’s team found that inhaled exosome-encased IL-12 mRNA could not only deliver locally concentrated IL-12 into the lungs of mice but also could better fight the cancer with minimal side effects. The treated mice demonstrated lung tumor suppression as well as heightened resistance against tumor rechallenges.
The researchers observed that inhaling the IL-12 mRNA exosomes incites an intense antitumor activation state in the tumor to augment its immunogenicity. The IL-12 messenger RNA generates interferon-γ production in both innate and adaptive immune-cell populations. “These results underscored IL-12-exosome’s proficiency in bolstering localized IL-12 expression in the TME, thereby evading off-target toxicity and improving systemic cytokine tolerability,” the authors write. The tumor’s response results in expanding tumor cytotoxic immune effector cells, forming immune memory, improving antigen presentation and specific T cell priming. Specifically, after 3 days of IL-12 administration, immune stimulation within the lung TME revealed enhanced influx of CD8+ T cells, accompanied by increased recruitment of CD4+ T cells, natural killer (NK) cells and monocytes.
In addition, IL-12 helps train these immune cells to remember the unique features of tumor cells. As a result, these immune cells can quickly recognize and eliminate newly invading cancer cells. The researchers also observed that these activated immune cells train neighboring immune cells to do the same against tumor rechallenge.
“Local delivery, as we use, curtails the ‘cytokine storm’ while preserving antitumor efficacy,” say the authors. “This shows the potential for locally delivered cytokine-based immunotherapies to address orthotopic and metastatic lung tumors,” opening the door to development of new inhalable drug strategies for lung cancer.
The team is now working with their Columbia oncologist colleagues to translate their discoveries into potential treatments for lung cancer patients.
