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For the past decade, a growing area of cancer research has been focused on cancer immunotherapies. From the Nobel prize-winning checkpoint inhibitor therapy to cancer vaccines, the idea behind immunotherapies is to boost or activate the immune system. While the therapies being developed may be new, the idea behind immunotherapy has been around for over a century.
One of the first observations of immunotherapy dates back to the 1890s when Dr. William Coley, now known as the Father of Cancer Immunotherapy, observed that his cancer patients who contracted infections after surgery had better outcomes than those who didn’t. He had believed that the infections triggered systems in the body which may otherwise be less active in these patients. Based on these observations, he developed Coley’s toxin, a mixture of heat-killed bacteria to be injected into cancer patients. While this procedure showed moderate success, the idea was largely dismissed by the scientific community at that time. It was not until the 1950s that other scientists followed up on these studies. Several researchers started studying different versions of Coley’s toxin with varied compositions of strains of bacteria. Around the same time, similar observations were made in patients with viral infections.
Why are these patients with bacterial or viral infections responding better to cancer?
Studies have now shown that these infections are stimulating the immune system. Immune stimulation can turn the ‘cold’ tumors, or tumors that successfully escape from the immune system, into ‘hot’ tumors by increasing immune cell infiltration, thereby exposing the cancer cells to immune-based destruction. Immunotherapies such as checkpoint inhibitor therapy work effectively in patients with “hot” tumors. Since a significant portion of patients have immunologically “cold” tumors, there is an increased demand for therapies that turn the tumors “hot”. Therefore, researchers have been interested in identifying ways of stimulating the immune system, including the usage of inactivated viruses (similar to Coley’s toxin which has inactivated bacteria).
In this context, a recent study suggests that injecting tumors with the flu vaccine can potentially act as a cancer immunotherapy by stimulating the immune system. The researchers showed in a mouse model that active flu infection in lungs reduced the occurrence of lung tumors and that the combination of influenza virus with checkpoint inhibitor therapy further improved this effect. Looking at the cancer patient data, the authors also noted that lung cancer patients with influenza virus infections lived longer than those without the infections.
To understand if this would work in cancers not associated with lungs, where the virus doesn’t show a regular infection, the authors studied skin cancer, melanoma. Injecting the regions of skin cancer with the heat-inactivated influenza virus showed a reduction in tumor growth in the skin and improved the survival of mice. In this case, the inactivated virus itself did not kill cancer cells but induced anti-tumor immune responses, making the tumors “hot”. The group also showed that injection of inactivated virus into the tumor on one side of the body reduced not only the growth of tumor with the injection but also a tumor on the other side of the body, which was not injected. This proved that the inactivated virus was inducing an immune response against the tumor systemically (throughout the body). This observation was also made in a mouse metastatic breast cancer model, with tumors in the breast and lung of the mice.
The researchers showed that this reduction in tumor growth due to a systemic antitumor immune response also works in mice previously infected with active influenza virus in the lung. This suggests that the inactivated virus can be used in those who previously had the flu. Combining this inactivated virus with checkpoint inhibitor therapy further reduced the tumor growth and improved mice survival suggesting that this inactivated virus can benefit patients undergoing checkpoint inhibitor therapy.
Injection with seasonal flu vaccine from 2018-2019 into tumors reduced the growth of tumors and made tumors “hot” in the mouse model. In mouse models, the flu vaccine used to treat lung cancer also gave protection against the flu, suggesting the dual-use of this vaccine. To further study this therapy in human cancers, the group used an engineered mouse model, into which they transplanted human cancer cells and immune cells from patients with lung cancer and melanoma. Similar to mouse tumors, they observed tumor reduction in these patient-derived human cancer models. They also noticed that the injection of this flu vaccine in patients’ tumors resistant to checkpoint blockade therapy makes them susceptible to this therapy by turning the “cold” tumors into “hot” tumors. This suggests that the combination of flu vaccine with checkpoint blockade therapy may be beneficial for unresponsive patients. It is important to note that a different seasonal flu vaccine did not show a similar anti-tumor effect despite providing protection against influenza infection, due to the presence of some inhibitory components in its formulation.
Overall, this study shows the potential of utilizing existing vaccines such as the flu vaccine for cancer treatment. Similarly, a different study showed that a rotavirus vaccine can be used in combination with checkpoint inhibitor therapy to make patients resistant to the therapy more responsive. Most recently, another study suggested the usage of yellow fever vaccine for cancer immunotherapy. If the above mentioned studies and the benefits hold true in clinical trials, using these pre-existing vaccines for cancer treatments will help reduce the costs associated with developing new therapies. This also expedites the time taken for approval of cancer therapies as these vaccines have already been tested for their safety in humans.
Newman, J. H., Chesson, C. B., Herzog, N. L., Bommareddy, P. K., Aspromonte, S. M., Pepe, R., … & Lee, M. (2020). 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 Sciences, 117(2), 1119-1128.
Shekarian, T., Sivado, E., Jallas, A. C., Depil, S., Kielbassa, J., Janoueix-Lerosey, I., … & Valsesia-Wittmann, S. (2019). Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade. Science translational medicine, 11(515).
Aznar, M. A., Molina, C., Teijeira, A., Rodriguez, I., Azpilikueta, A., Garasa, S., … & Rius‐Rocabert, S. (2020). Repurposing the yellow fever vaccine for intratumoral immunotherapy. EMBO molecular medicine, 12(1).
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Edited by Sara Musetti
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