From Cold to Hot Tumors: Combating Cancer with the Flu Vaccine

Viola Lee | kyounga.lee@yale.edu March 15, 2020

From Cold to Hot Tumors: Combating Cancer with the Flu Vaccine

Illustration by Sophia Zhao.

The ability to harness the body’s immune system to fight cancer has transformed medicine in recent years. A new study from the Zloza research group at the The State University of New Jersey suggests that we may be able to use the flu vaccine to improve patient outcomes in cancer, potentially saving millions of lives and tremendously reducing the financial burden of cancer patients.

Oncologists call a tumor “cold” when there are very few immune cells infiltrating the tumor, and “hot” when the tumor is characterized by significant immune cell infiltration. Cancer patients whose treatment regimens are unsuccessful often have cold tumors. Even with novel therapies such as immune checkpoint inhibitors that allow immune cells to engage in antitumor activity, patients with cold tumors simply do not have enough immune cells at the tumor site for the checkpoint inhibitors to make tangible impacts. Because immune cells’ migration to the tumor site is highly correlated with the patient’s clinical outcomes, developing an effective method to induce immune cell migration to the tumor site is absolutely critical to the advancement of immuno-oncology therapies.

Another challenge of cancer immunotherapy is its affordability. Current estimates of immuno-oncology drug costs are about $270,000 per patient, an expense that is burdensome—if not unaffordable—for many patients. The possibility of injecting the fifteen-dollar seasonal flu vaccine to transform “cold” tumors unresponsive to treatment regimens to “hot” tumors could transform both the accessibility and efficacy of cancer therapy. Vaccination is an old idea in medicine, dating back to over a hundred years ago, but using FDA-approved vaccines against pathogens has never been suggested as a method for enhancing the body’s ability to fight cancer, until now.

When Andrew Zloza, the principal investigator of this study, was a postdoctoral associate in Chicago studying tumor immunology, he recognized an increasing number of epidemiological studies showing that patients with an HIV infection developed more cancers and had less favorable outcomes. This was happening even when the patients were treated for HIV and their immune system was able to prevent AIDS-defining infections. Hypothesizing that there was some connection between the immune system having to fight foreign pathogens and cancer at the same time, Zloza and his group began investigating the interference of foreign infections with the body’s ability to fight tumors.

“When the body has two things to fight, the immune system sends most of its resources to fight the greater danger,” Zloza said. “And when there is an infection like HIV or influenza in a cancer patient, the immune system appears to see the infection as a greater danger than the tumor.” This results in fewer immune cells infiltrating the patient’s tumor, and a greater number sent to fight the infection elsewhere in the body. The researchers wondered how the body would respond if the infection was at the same site of the tumor. According to their hypothesis, the immune cells might migrate to the tumor to fight the infection. This might serve as a way to draw the attention of the immune system to a cancer patient’s tumor.

Zloza’s group tried injecting live influenza virus in the tumors of mice with melanoma. But it didn’t work—live influenza virus injections did not induce immune cells to migrate to the tumor site or cause the tumor to shrink. So, what had gone wrong?

It turns out that live viruses are limited to specific sites of infection. Because the live influenza virus infects the lungs, but not the skin, the injection of live influenza virus to tumors of the skin of mice was not going to infect the tumor, and thus could not induce immune cells to migrate to the tumor. Instead, the researchers came up with a new approach: to inactivate the influenza virus with heat or chemicals, then introduce the inactivated influenza viral components to the tumor. This approach could circumvent the problem of having to infect the skin tumor with live influenza. The easiest way to obtain large quantities of inactivated influenza virus that is cheap and commercially available was the seasonal flu vaccine, a concoction of inactivated strains of influenza virus. They set out to test their hypothesis that the tumor site-directed injection of the flu vaccine could stimulate antitumor activity of immune cells.

Zloza’s group used two types of commercially available mouse cancer models—melanoma and breast cancer—in addition to generating their own mouse model where immune cells and tumor tissue from the same patient were transplanted into a mouse that does not have an immune system of its own. They call this model AIR-PDX, or autologous immune reconstituted patient-derived xenograft. The AIR-PDX model, according to Zloza, allowed the researchers to model the patient’s immune system in these mice as accurately as possible, especially compared to observing the mouse’s immune cells’ response to mouse tumors. “The PDX mouse models are as close as we can get to modeling human immune cells’ response to human tumors. We were essentially recreating the patient’s immune system in these mice,” he said.

Following the injection of the flu vaccine, the researchers evaluated the efficacy of their method by measuring immune cell infiltration at the tumor site as well as tumor size. “We evaluated immune cell infiltration using flow cytometry. We would take a biopsy of the tumor, then dissociate the tumor into single cells, stain with antibodies against different immune cell proteins to visualize how many immune cells were infiltrating the tumor, as well as which specific subtypes of immune cells were there,” Zloza said. They obtained a very exciting finding—after injecting the flu vaccine at the tumor site, previously ‘cold’ tumors went from having no immune cell infiltration to being highly infiltrated.

After verifying that the flu shot was in fact responsible for the antitumor immune response, Zloza’s group then injected the flu shot in mice in conjunction with an antitumor immunotherapy, expecting that the antitumor effect would be further enhanced. In mice with intratumoral injection of the flu vaccine, they administered an immune checkpoint inhibitor—a class of therapeutics that reverses tumoral suppression of the immune system by releasing the breaks on the immune system put in place by the tumor. As expected, the addition of the immune checkpoint inhibitor increased the antitumor response and caused more tumor shrinkage.

Interestingly, in mice with multiple tumors, injecting the flu vaccine at one of the tumor sites appeared to result in tumor shrinkage in other tumors that were not injected. This suggested that artificially targeting one tumor apparently directed the immune system to all the tumors. Even better, the injection of the flu vaccine at the tumor site also protected the mice against live lung influenza infections, exerting a dual protective function combating both influenza and tumor progression.

“If you can put a needle into something to take something out, like a biopsy, for example, then you can also put a needle into something to put something in, say to inject the flu vaccine. Any tumor that can be biopsied can be injected with the flu vaccine, which makes this a highly feasible treatment option for patients,” Zloza said. The next steps in advancing the flu vaccine for oncology applications will entail receiving approval and funding for clinical trials. While clinical trials take 8 to 10 years on average to receive FDA approval for a treatment, the researchers expect that receiving approval for this application could be expedited. After all, the flu vaccine is already FDA-approved, and the objective is to simply repurpose it for cancer patients. The goal, Zloza says, is to get this to patients as soon as possible.

Citations:

Newman, J. H., Chesson, C. B., Herzog, N. L., Bommareddy, P. K., Aspromonte, S. M., Pepe, R., … Zloza, A. (2019). Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer. Proceedings of the National Academy of Sciences117(2), 1119–1128. doi: 10.1073/pnas.1904022116

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