Many treatments for cancer are notoriously wild on the body. Drugs often attack both healthy cells and tumor cells, causing a number of side effects. Immunotherapies that help the immune system recognize and attack cancer cells are no different. Although they have prolonged the lives of countless patients, they only work in a subset of patients. One study found that less than 30% of breast cancer patients responded to one of the most common forms of immunotherapy.
But what if it was possible to make drugs that only attack cancer cells and save the rest of the body? To that end, colleagues at the Pritzker School of Molecular Engineering at the University of Chicago have proposed a method to prevent one promising cancer drug from causing confusion by “masking” it until it reaches a tumor.
The promise of IL-12
Cytokines are proteins that can modulate how the immune system responds to threats. One way to do this is to activate killer T cells, a type of white blood cell that can attack cancer cells. Because cytokines can train the immune system to kill tumors, they are very promising as cancer treatments.
One such cytokine is interleukin-12 or IL-12. Although it was discovered more than 30 years ago, IL-12 is still not an FDA-approved therapy for cancer patients due to its serious side effects, such as liver damage. This is partly because IL-12 instructs immune cells to produce large amounts of inflammatory molecules that can damage the body.
Researchers have since worked to redesign IL-12 to make it more tolerable while retaining its strong cancer killing effects.
To create a safer version of IL-12, my colleagues and I used one of the main differences between healthy and cancerous tissue: an excess of growth-promoting enzymes in cancer. Because cancer cells multiply very rapidly, they overproduce certain enzymes that help them penetrate nearby healthy tissue and metastasize to other parts of the body. Healthy cells grow much slower and produce fewer of these enzymes.
With this in mind, we “masked” IL-12 with a cap that covers the portion of the molecule that normally binds to immune cells to activate them. The cap is only removed when it comes in contact with enzymes that are close to the tumors. When these enzymes cut off the lid, IL-12 reactivates and stimulates nearby killer T cells to attack the tumor.
When we applied these masked IL-12 molecules to both healthy and tumor tissue donated by patients with melanoma and breast cancer, our results confirmed that only tumor samples were able to remove the occlusion. This suggests that masked IL-12 could potentially drive a strong immune response against tumors without causing damage to healthy organs.
We then examined how safe IL-12 is 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 for several weeks, indicating improved safety.
In breast cancer models, our masked IL-12 resulted in 90% cure, while treatment with commonly used immunotherapy called a checkpoint inhibitor resulted in only 10% cure. In a colon cancer model, masked IL-12 showed a 100% cure rate.
Our next step is to test modified IL-12 in cancer patients. While it will take some time for this encouraging development to reach patients directly, we believe that a promising new treatment is on the horizon.
The ‘masked’ cancer drug penetrates the body and provides anti-cancer treatment with fewer side effects
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