Intravenous immunotherapy
Synthetic oncolytic viruses can be injected intravenously
Yulia Panchenko, PCR.news
Oncolytic viruses selectively kill cancer cells and cause inflammation in the tumor microenvironment, which makes them attractive candidates for therapy. So far, the successful use of such viruses has been demonstrated only when they are injected directly into the tumor. Intravenous administration of oncolytic viruses can increase the effectiveness of therapy, as it will cover all tumor sites, including metastases. However, after intravenous administration, neutralizing antibodies against the virus are quickly formed.
Researchers from the American company Oncorus, Inc. have developed a platform for delivering viral RNA using lipid nanoparticles. It allows you to re-administer intravenous viral immunotherapy. The authors called the platform a synthetic RNA virus (Synthetic RNA virus). Scientists used two picornaviruses — Seneca Valley Virus (SVV) and Coxsackie virus A21 (CVA21). Their oncolytic activity and safety are well studied.
Lipid nanoparticles and viral RNA enter tumor cells, after which the RNA is replicated. The affected cell releases many infectious virions that spread locally, killing nearby tumor cells and attracting immune cells to the tumor microenvironment. The authors optimized lipid nanoparticles so that they had small dimensions (85 nm), were monodisperse and effectively encapsulated viral RNA.
The researchers injected synthetic viruses with SVV RNA into mice with xenografts of small cell lung cancer. The therapy significantly inhibited the growth of tumors; the size of even very large tumors decreased, while the body weight did not decrease. The authors confirmed that the viruses replicated in tumor cells and selected the optimal dosage. The effectiveness of CVA21 was confirmed in a mouse model of melanoma.
Synthetic viruses with SVV RNA did not cause significant side effects in mice with neuroblastomas. Weight, clinical signs and results of histopathology did not change. 30 minutes after injection, lipid nanoparticles were detected in all the studied tissues, but after 24 hours they ceased to be detected. Clinical chemistry, including liver function, did not change. Immediately after the introduction of therapy, the levels of pro-inflammatory cytokines temporarily increased, but the complement system was not activated. In naive mice, the authors demonstrated minimal and temporary viral replication in the lungs, spleen and liver.
The effectiveness of a synthetic virus carrying CVA21 RNA was tested on transgenic mice that expressed the human ICAM1 gene (sensitive to CVA21 infection). No adverse clinical signs were detected, when checking histopathology, small changes in the liver were detected, which, according to the authors, were caused by lipid nanoparticles. A low level of viral replication was detected in the spleen, liver, lungs, heart and kidneys two days after injection, but ceased to be detected after seven days.
Crab-eating macaques also tolerated the injection of synthetic virus with SVV RNA in a dosage exceeding that required for therapeutic effect. In these experiments, scientists also investigated the pharmacokinetics of the drug. They detected temporary changes in parameters reflecting the state of the liver and increased levels of cytokines.
In experiments on immunodeficient mice, the authors showed that the presence of antibodies to SVV did not interfere with the antitumor effect of the synthetic virus. The administration of the drug to model mice with orthotopic tumors led to an increase in their survival rate by almost two times. The effectiveness of therapy has also been demonstrated on mice carrying xenografts obtained from patient tumor samples, as well as on genetically modified mice. Also, the antitumor effect can be enhanced with anti-PD-1 therapy.
Thus, synthetic RNA viruses have shown good results in preclinical trials even in the presence of neutralizing antibodies. The authors say that their results allow them to plan clinical trials.
Article by Kennedy et al. The development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer is published in the journal Nature Communications.
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