Many cancer treatments are notoriously barbaric on the body. The drugs often attack both healthy cells and tumor cells, causing a lot 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 respond to one of the most common forms of immunotherapy.
But what if drugs could be engineered to attack only tumor cells and protect the rest of the body? To this end, my colleagues at the University of Chicago’s Pritzker School of Molecular Engineering and I have devised a method that wreaks havoc by “masking” a promising cancer drug until it reaches the tumor.
IL-12. promise of
Cytokines are proteins that can control how the immune system reacts 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, this makes them 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 because of 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 harm the body.
Since then scientists have been working to make IL-12 more tolerable while maintaining its potent cancer-killing effect.
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 and cancerous tissue: the abundance of enzymes that promote growth in cancer. Because cancer cells grow so rapidly, they overproduce certain enzymes that help them invade nearby healthy tissue and metastasize to other parts of the body. Healthy cells grow very slowly and produce fewer of these enzymes.
With this in mind, we “masked” IL-12 with a cap that covers the part of the molecule that normally binds to activate immune cells. The cap is only removed when it comes into contact with enzymes found around the tumor. When these enzymes cut off the cap, IL-12 is reactivated and prompts 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 cap. This indicated that masked IL-12 could potentially drive a strong immune response against tumors without harming healthy organs.
We then examined how safe IL-12 is in mice by measuring liver damage biomarkers. We found that the immunological side effects typically associated with IL-12 were notably absent in mice treated with masked IL-12 over a period of several weeks, indicating improved protection.
In the breast cancer model, our masked IL-12 resulted in a 90% cure rate, whereas treatment with a commonly used immunotherapy called checkpoint inhibitors resulted in only a 10% cure rate. In a 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 a promising new treatment is on the horizon.
‘Masked’ cancer drug enters body to deliver anti-tumor treatment with fewer side effects
provided by conversation
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