“Any new oncolytic virus [that is] created has to go through the entire clinical trials process, which takes about 10 years from discovery to final approval. With the flu shot, these are not live viruses and they are already FDA-approved drugs; they have many years of use, in millions of patients, so the safety profile is good and we know they are effective,” said Dr Zloza.

Although the availability, price and safety profile of the flu vaccine is understandably appealing if these results should be repeated in human clinical trials, how does the vaccine compare to other similar viral-based therapies?

“This is not as impressive as a number of oncoviruses out there, but it’s fine and it has antitumor effects in the models they looked at,” said Hardev Pandha, MD, PhD, consultant oncologist and director and the Surrey Cancer Research Institute at the University of Surrey in the U.K. “However, it’s similar to a number of oncolytic viruses already out there (eg, coxsackie viruses); they are all quite impressive … but they always are in the mice,” he added.

“An advantage of this approach is that its readily available and you can just take what’s available for flu season and try it on the patient’s tumor, but I don’t see anything particularly special for this approach over [the use of intratumoral injection of] other viruses,” said Siwen Hu-Lieskovan, MD, PhD, a medical oncologist from the Huntsman Cancer Institute at the University of Utah, Salt Lake City. But, she added, “I would assume the vaccine against different strains of the virus may have different immunogenicity; some are stronger than others. Are you going to have variable efficacies towards the tumor? This should probably be looked into.” 


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One of the most intriguing and perhaps unexpected findings of the study was that squalene, a commonly used vaccine adjuvant, actually seemed to reduce the antitumor effects of the flu vaccine when injected into tumors in mice — although it maintained its ability to induce flu resistance.

“We would expect an immune modulator would increase responses to the flu shot, so we would have expected the adjuvant to help amplify this,” said Dr Zloza.

The authors showed that the presence of the adjuvant squalene maintains the presence of regulatory B cells in the tumor, preventing the antitumoral response. Removing the adjuvant, depleting B cells, or blocking the IL-10 produced by regulatory B cells, recovered the antitumor effect.

The study did not test other common adjuvants, but it does raise questions about whether using adjuvants in combination with viruses for immune priming might not be the best strategy.

“Normally, with viral therapies, we actually add the adjuvant thinking it will help — this paper says maybe we should not. What they saw could be specific only to this particular adjuvant, but it raises a red flag that the use of adjuvant may be counterproductive,” said Dr Hu-Lieskovan, suggesting that the finding warrants a re-evaluation of adjuvant use in other viral therapy approaches.

The particularly exciting component of this work appears to be that a widely available, cheap vaccine with a proven safety profile could have utility in a field of cancer therapy currently dominated by options that are costly in terms of both money and production time.

“I think definitely its worth trying, and this is the interesting cheaper option for the patient to perhaps get a similar outcome as with other similar injectables,” said Dr Hu-Lieskovan, who added that the approach will still have to overcome the hurdles that other, similar therapies experience, such as delivery to the tumor site and efficacy concerns.

“This paper has confirmed potential for what we would consider a benign, innocuous virus to have a very impressive antitumor effect. The beauty of this is that it’s the flu vaccine; it’s been tested on millions of people and it’s safe,” said Dr Pandha, explaining that the proven safety profile would make it easy to get the vaccine into the clinic if its efficacy is proven in clinical trials.

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Dr Zloza and his team are currently planning the first clinical trials to use the flu vaccine on a set of readily accessible solid tumors, including cutaneous squamous cell carcinomas, and breast, lung, and head and neck cancers to see whether the promising preclinical data can be replicated in human trials.

“It’s a good proof of principle, but of course, it has to be tested in humans. I think [it should] go to human clinical trials as soon as possible,” said Dr Hu-Lieskovan.

Disclosure: Some of the authors disclosed financial relationships with the pharmaceutical and medical device industries. For a full list of disclosures, please refer to the original study.

Reference

Newman JH, Chesson CB, Herzog NL, et al. Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancerProc Natl Acad Sci U S A. 2020;117(2):1119-1128.