Interleukin Factory
Implantable "cytokine factories" reduce tumor size in mice
Alyona Kharlamova, PCR.news
Malignant mesothelioma is a tumor that develops from the mesothelium lining the serous membranes of the body cavities (peritoneum, pleura, pericardium, etc.). It is very aggressive and difficult to treat. One of the new methods of tumor therapy is inhibitors of immune response checkpoints, however, they have many undesirable side effects, and their effectiveness is not as high as we would like.
Interleukin-2 (IL-2) is a pro—inflammatory cytokine that is necessary for the activation, differentiation and survival of T cells and natural killers, as well as for attracting immune cells into the tumor microenvironment. The use of IL-2 in therapy is associated with a number of difficulties: when it spreads throughout the body, hyperactivation of T-lymphocytes occurs, which leads to a cytokine storm. However, topical administration can be safe and effective, which is why IL-2 is approved by the FDA as a drug for the treatment of certain malignant tumors.
Researchers from Rice University and Baylor College of Medicine (USA) have developed a new platform for cytokine delivery using immunostimulating microparticles — the "cytokine factory". The source of cytokine (IL-2) is human retinal pigment epithelial cells encapsulated in biocompatible alginate microparticles. The factories are implanted next to the tumor, in this case the local concentration of IL-2 reaches sufficiently large values, and the concentration in the blood remains low.
In previous studies, the same scientific group has shown the effectiveness of microparticles for the treatment of ovarian cancer and colorectal cancer in mice; the development was approved for phase 1 clinical trials. In the new work, scientists used a mouse model of malignant mesothelioma to test the therapeutic effect of the cytokine factory.
The authors of the work demonstrated that microparticles effectively reduced the size of the tumor in this mouse model. At the same time, the tumor reduction was proportional to the number of cells implanted in mice. Also, scientists have determined the optimal dose.
To analyze changes in immune cell populations, the authors used time-of-flight cytometry. As a result, they showed an increase in the populations of cells responsible for the anti-inflammatory and antitumor response: activated T-lymphocytes (CD69+CD44+ and CD69-CD44+CD62L-T cells), as well as CD86+PDL1+ M1-like macrophages and MHC II+ dendritic cells. In addition, there was a decrease in the number of anti-inflammatory CD86-PD-L1- M2-like macrophages, as well as naive CD4+ and CD8+ T cells. All this indicates effective stimulation of both innate and acquired immunity.
The combined use of the cytokine factory together with the inhibitor of immune control points significantly increased the effectiveness of the latter. In all mice undergoing combination therapy, the tumor disappeared completely without relapses, which may indicate the formation of immune memory.
Pharmacokinetics and safety were tested on the pleural cavity of Sprag-Doly rats. The microparticles in the factories were not destroyed and were biocompatible. Further biochemical blood tests indicated minimal cytokine ingress into the bloodstream of mice and the absence of toxic effects of the factory on the body.
Thus, scientists have confirmed the effectiveness of the use of cytokine factories with IL-2 for the treatment of malignant mesotheliomas and described their advantages over other therapies. Now the researchers hope to get permission to conduct clinical trials in humans.
Article by Nash et al. Activation of adaptive and innate immune cells via localized Interleukin-2 cytokine factories eradicates mesothelioma tumors is published in the journal Clinical Cancer Research.
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