‘Masked’ cancer drug stealthily trains immune system to kill tumors while sparing healthy tissue

Many cancer treatments are notoriously wild on the body. The drugs often attack both healthy cells and tumor cells, causing a plethora 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 on a subset of patients. A study revealed that less than 30% of patients with breast cancer respond to one of the most common forms of immunotherapy.

But what if drugs could be designed to attack only tumor cells and spare the rest of the body? To this end, my colleagues and me at the University of Chicago Pritzker School of Molecular Engineering have designed a method to prevent a promising cancer drug from wreaking havoc by “masking” it until it reaches a tumour.

The promise of IL-12

Cytokines are proteins that can modulate how the immune system responds to threats. To do this, they activate in particular killer T cellsa type of white blood cells 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. Even though it was discovered more than 30 years agoIL-12 is still not an FDA approved therapy for cancer patients because of his serious side effectssuch as liver damage. This is partly because IL-12 instructs immune cells to produce large amounts of inflammatory molecules that can damage the body.

Scientists have since worked to redesign IL-12 so that it is more tolerable while retaining its powerful anti-cancer effects.

Immunotherapies help the immune system recognize and target cancer cells.

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 excess of growth-promoting enzymes in cancers. Because cancer cells proliferate very quickly, they overproduce certain enzymes which help them invade nearby healthy tissue and metastasize to other parts of the body. Healthy cells grow at a much slower rate and produce fewer of these enzymes.

With that in mind, we’ve “masked” IL-12 with a cap that covers the part of the molecule that normally binds to immune cells to activate them. The cap is only removed when it comes into contact with enzymes present near the tumors. When these enzymes sever 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 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 indicated that masked IL-12 could potentially elicit a strong immune response against tumors without damaging healthy organs.

Killer T cells (green and red) can attach to cancer cells (blue, center) and kill them by releasing toxic chemicals (red), a move scientists have dubbed “the kiss of death”. Credit: NIH/Flickr

We then examined the safety of masked IL-12 by measuring liver injury biomarkers In mice. We found that side effects related to the immune system associated with IL-12 were notably absent in mice treated with masked IL-12 over 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 checkpoint inhibitor only resulted in a 10% cure rate. 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 time to bring this encouraging development directly to patients, we believe a promising new treatment is on the horizon.

‘Masked’ cancer drug sneaks into body to provide tumor treatment with fewer side effects

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