Researchers have designed a method to keep one promising cancer drug from wreaking havoc by “masking” it until it reaches a tumour, thereby preventing an attack on healthy cells.
Many cancer treatments are notoriously savage on the body. Drugs often attack both healthy cells and tumour cells, causing a plethora of side effects. Immunotherapies that help the immune system recognise and attack cancer cells are no different. Though they have prolonged the lives of countless patients, they work in only a subset of patients. One study found that fewer than 30% of breast cancer patients respond to one of the most common forms of immunotherapy.
Now Aslan Mansurov and his colleagues at the University of Chicago’s Pritzker School of Molecular Engineering have come up with a method to prevent this dual cell attack.
Mansurov writes:
"Cytokines are proteins that can modulate how the immune system responds to threats. One way they do this is by activating killer T cells, a type of white blood cells that can attack cancer cells. Because cytokines can train the immune system to kill tumours, this makes them very promising as cancer treatments.
One such cytokine is interleukin-12, or IL-12. Though it was discovered more than 30 years ago, IL-12 still isn’t an FDA-approved therapy for cancer patients because of its severe side effects, such as liver damage. This is in part because IL-12 instructs immune cells to produce a large amount of inflammatory molecules that can damage the body.
Scientists have since been working to re-engineer IL-12 to be more tolerable while retaining its powerful cancer-killing effects.
Masking 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: an excess of growth-promoting enzymes in cancers. Because cancer cells proliferate very rapidly, they over-produce certain enzymes that help them invade the nearby healthy tissue and metastasise to other parts of the body. Healthy cells grow at a much slower pace 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 immune cells to activate them. The cap is removed only when it comes into contact with enzymes found in the vicinity of tumours. When these enzymes chop off the cap, IL-12 is reactivated and spurs nearby killer T cells to attack the tumour.
When we applied these masked IL-12 molecules to both healthy and tumour tissue donated by melanoma and breast cancer patients, our results confirmed that only the tumour samples were able to remove the cap. This indicated that masked IL-12 could potentially drive a strong immune response against tumours without causing damage to healthy organs.
We then examined how safe masked IL-12 is by measuring liver damage biomarkers in mice. We found that immune-related 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 safety.
In breast cancer models, our masked IL-12 resulted in a 90% cure rate, while treatment with a commonly used immunotherapy called a checkpoint inhibitor 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 the 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.
Study details
Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker
Aslan Mansurov, Peyman Hosseinchi, Kevin Chang, Abigail L. Lauterbach, Laura T. Gray, Aaron T. Alpar, Erica Budina, Anna J. Slezak, Seounghun Kang, Shijie Cao, Ani Solanki, Suzana Gomes, John-Michael Williford, Melody A. Swartz, Juan L. Mendoza, Jun Ishihara & Jeffrey A. Hubbell
Published in Nature Biomedical Engineering on 9 May 2022
Abstract
Immune-checkpoint inhibitors have shown modest efficacy against immunologically ‘cold’ tumours. Interleukin-12 (IL-12)—a cytokine that promotes the recruitment of immune cells into tumours as well as immune cell activation, also in cold tumours—can cause severe immune-related adverse events in patients. Here, by exploiting the preferential overexpression of proteases in tumours, we show that fusing a domain of the IL-12 receptor to IL-12 via a linker cleavable by tumour-associated proteases largely restricts the pro-inflammatory effects of IL-12 to tumour sites.
In mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signalling and eliminated systemic immune-related adverse events, led to potent therapeutic effects via the remodelling of the immune-suppressive microenvironment, and rendered cold tumours responsive to immune-checkpoint inhibition.
We also show that masked IL-12 is activated in tumour lysates from patients. Protease-sensitive masking of potent yet toxic cytokines may facilitate their clinical translation.
Aslan Mansurov is a Postdoctoral Researcher in Molecular Engineering, University of Chicago Pritzker School of Molecular Engineering
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