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RNA Cancer Immunotherapy Shown Feasible in Preclinical Test

Lung cancer illustration

(NIH.gov)

7 Oct. 2022. Tests with lab animals show synthetic viral RNA particles, encased in natural oils, can safely invoke an immune response to attack solid tumors. Results of preclinical tests conducted by the biotechnology company Oncorus Inc. in Andover, Massachusetts, appear in today’s issue of the journal Nature Communications.

Oncorus is a seven year-old enterprise developing cancer therapies with synthetic viruses engineered with RNA to generate an immune response against solid tumor cancers. Up to now, says the company, most cancer immunotherapies are designed to invoke a response from T-cells in the immune system, with mixed results. Some cancer patients, says Oncorus, don’t respond to these therapies, while others who may respond initially, later relapse. The company says much of the problem can be traced to neutralizing antibodies also generated by the immune system, which limit the effects of therapy and prevent subsequent treatments.

The technology designed by Oncorus aims to address these issues. Oncorus engineers natural viruses, such as herpes simplex or Seneca Valley virus, with tumor-specific RNA. These synthetic viral RNA strands are designed to generate responses from multiple immune system cells to attack tumors and degrade the tumor’s protective environment, while sparing healthy cells and tissue. The company says this approach invokes both the innate or general immune system, as well as the adaptive immune system that responds to specific threats.

Infectious viral particles that replicate and spread within tumors

In addition, Oncorus says it delivers its synthetic viral RNA therapies as nanoscale particles packaged in lipids or natural oils. This lipid packaging, says the company, hides synthetic viruses from the immune system long enough for delivery to targeted tumors, to prevent generation of neutralizing antibodies that would otherwise damage the viral therapies. As a result, says Oncorus, its therapies retain their efficacy, making possible multiple treatments for patients.

The Nature Communications paper presents findings from tests of the company’s self-amplifying viral RNA therapies in lab cultures, then given intravenously to mice and monkeys induced with solid tumor cancers. The tests show engineered Seneca Valley virus and Coxsackievirus treatments in lipid nanoparticles or LNPs produce infectious viral particles that replicate and spread within tumors. The researchers tested these engineered viruses with RNA therapies in lab mice grafted with non-small cell lung cancer and melanoma, showing the tumors regress after receiving treatments.

Moreover, the tests show the mice tolerate the treatments, at doses above levels needed to regress tumors, with little body weight change, and minimal effects on their organs. Similar tests with macaque monkeys, infused three times every two weeks with engineered Seneca Valley virus therapies, show delivery of lipid-encased viral nanoparticles to tissues and organs in their bodies, with few adverse effects on those organs. Plus, when challenged with additional neutralizing antibodies, the lipid-encased engineered Seneca Valley virus therapies remain effective in test animals.

Oncorus believes the findings advance the company’s first cancer treatment with this specific technology, code-named ONCR-021. “As demonstrated in animal models outlined here,” says Oncorus vice-president for research Matthew Kennedy and lead author on the paper in a company statement, “we’ve established a way to simultaneously cause direct tumor cell killing in addition to broad immune stimulation in multiple tumors through an IV-administered self-amplifying RNA encapsulated within an LNP. We look forward to progressing our first candidate from this platform, ONCR-021, in patients with non-small cell lung cancer, renal cell carcinoma, melanoma, and hepatocellular carcinoma.”

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