Many cancer treatments are notorious for being brutal on the body. Medicines often attack healthy cells and cancer cells, causing a large number of side effects. Immunotherapy treatments that help the immune system recognize and attack cancer cells are no different. Despite extending the life of countless patients, they work in only 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 drugs could be engineered to attack only cancer cells and spare the rest of the body? To that end, colleagues at the University of Chicago’s Pritzker School of Molecular Engineering and I have designed a way to keep a promising cancer drug from wreaking havoc by “hiding” it until it reaches a tumor.
Cytokines are proteins that can modify 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 treatments for cancer.
One of these cytokines is interleukin-12 or IL-12. Despite its discovery more than 30 years ago, IL-12 is still not FDA-approved for cancer patients due to its severe side effects, such as liver damage. This is partly because IL-12 directs immune cells to produce a large amount of inflammatory molecules that can do damage to the body.
Since then, scientists have worked to re-engineer IL-12 to be more tolerable while retaining its powerful cancer-killing effects.
hide the killer
To create a safer version of IL-12, my colleagues and I took advantage of one of the key differences between healthy and cancerous tissue: an increase in growth-promoting enzymes in cancers. Because cancer cells multiply so rapidly, they overproduce certain enzymes that help them invade nearby healthy tissues and spread to other parts of the body. Healthy cells grow much slower and produce fewer of these enzymes.
With this in mind, we “hide” IL-12 with a cap that covers the part of the molecule that normally binds to immune cells to activate it. The cap is removed only when it comes into contact with enzymes located near the tumors. When these enzymes cut the cap, IL-12 reactivates and stimulates nearby killer T cells to attack the tumor.
When we applied masked IL-12 molecules to both healthy and tumor tissue donated by melanoma and breast cancer patients, our results confirmed that only tumor samples were able to remove the cap. This indicates that masked IL-12 can trigger a robust 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 immune-related side effects typically associated with IL-12 were significantly absent in mice treated with masked IL-12 over several weeks, indicating improved safety.
In models of breast cancer, our masked IL-12 resulted in a 90% cure rate, whereas treatment with a commonly used immunotherapy called a checkpoint inhibitor resulted in only a 10% cure rate. In a colon cancer model, masked IL-12 showed a 100% cure rate.
Our next step is to test for modified IL-12 in cancer patients. While it will take time to deliver this encouraging development directly to patients, we believe a promising new treatment is on the horizon.
The ‘masked’ cancer drug sneaks through the body to deliver an anti-tumor treatment with fewer side effects
Introduction of the conversation
This article has been republished from The Conversation under a Creative Commons license. Read the original article.
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