Many cancer treatments are notoriously wild for the body. Drugs often attack both healthy cells and tumor cells, causing a large number of side effects. Immunotherapies that help the immune system recognize and attack cancer cells are no different. Although they have extended the lives of countless patients, they only work in a subset of patients. One study found that less than 30% of breast cancer patients respond to one of the most common forms of immunotherapy.
But what if the drugs could be designed to attack only the tumor cells and save the rest of the body? To that end, my colleagues and I at the Pritzker School of Molecular Engineering at the University of Chicago have designed a method to prevent a promising cancer drug from wreaking havoc by “masking” it until it reaches a tumor.
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Immunotherapies help the immune system recognize and target cancer cells.
The promise of IL-12
Cytokines are proteins that can modulate how the immune system responds to threats. One way to do this is by activating killer T cells, a type of white blood cell that can attack cancer cells. Because cytokines can train the immune system to kill tumors, this makes them very promising as cancer treatments.
One of these cytokines is interleukin-12 or IL-12. Although discovered more than 30 years ago, IL-12 is not yet an FDA-approved therapy for cancer patients because of its serious side effects, such as liver damage. This is partly because IL-12 instructs immune cells to produce a large number of inflammatory molecules that can damage the body.
Since then, scientists have been working to redirect IL-12 to make it more tolerable while retaining its powerful anti-cancer effects.
Mask the killer
To create a safer version of IL-12, my colleagues and I took advantage of one of the main differences between healthy tissue and carcinogen: an excess of enzymes that promote growth in cancers. Because cancer cells proliferate very quickly, they overproduce certain enzymes that help them invade nearby healthy tissue and metastasize to other parts of the body. Healthy cells grow at a much slower rate and produce less of these enzymes.
With that in mind, we “masked” IL-12 with a cap that covers the part of the molecule that normally binds to immune cells to activate them. The plug is only removed when it comes in contact with enzymes found in the vicinity of tumors. When these enzymes cut the lid, IL-12 reactivates and stimulates nearby killer T cells to attack the tumor.
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Killer T cells (green and red) can bind to cancer cells (blue, in the center) and kill them by releasing toxic (red) chemicals, a move that scientists have dubbed “the kiss of death”. NIH / Flickr
When we applied these masked IL-12 molecules to both healthy tissue and tumor given by patients with melanoma and breast cancer, our results confirmed that only tumor samples were able to remove the cap. This indicated that masked IL-12 could drive a strong immune response against tumors without causing damage to healthy organs.
We then examined the safety of masked IL-12 by measuring biomarkers of liver damage in mice. We found that the immunity-related side effects normally associated with IL-12 were markedly absent in mice treated with masked IL-12 for a period of several weeks, indicating improved safety.
In breast cancer models, our masked IL-12 resulted in a 90% cure rate, while treatment with a commonly used immunotherapy called a control point inhibitor only resulted in a cure rate. 10% cure. In one model of colon cancer, masked IL-12 showed a 100% cure rate.
Our next step is to test modified IL-12 in cancer patients. While it will take time to bring this encouraging development directly to patients, we believe there is a promising new treatment on the horizon.
Aslan Mansurov, Postdoctoral Researcher in Molecular Engineering, Pritzker School of Molecular Engineering, University of Chicago
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This article is republished from The Conversation under a Creative Commons license. Read the original article.
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