Many cancer treatments are notoriously wild for the body; they attack healthy cells at the same time as tumor cells, causing a lot of side effects. Researchers at the University of Chicago’s Pritzker School of Molecular Engineering (SME) have now devised a method to prevent a promising cancer drug from falling so badly. The team has designed a new “masked” version of the interleukin-12 immunotherapy drug that is only activated when it reaches a tumor. Research on the molecule, also known as IL-12, is described in the journal Nature Biomedical Engineering.
Our research shows that this masked version of IL-12 is much safer for the body, but has the same antitumor efficacy as the original. “
Aslan Mansurov, postdoctoral researcher and first author of the new article
He conducted IL-12 engineering work with Jeffrey Hubbell, Professor Eugene Bell in Tissue Engineering, who co-directs the SME Immunoengineering Research topic with Professor Melody Swartz.
Overcoming toxicity
Researchers know that IL-12 potently activates lymphocytes, immune cells with the potential to destroy tumor cells. But in the 1990s, the first clinical trials of IL-12 were stopped due to the serious and toxic side effects in patients. The same immune activation that triggered a cascade of events that killed cancer cells also caused severe inflammation throughout the body. IL-12, at least in its natural form, was filed.
But Mansurov, Hubbell, Swartz and colleagues had an idea to reinvigorate the possibility of IL-12. What if the drug could slip through the body without activating the immune system? They designed a “masked” molecule with a cap covering the section of IL-12 that normally binds to immune cells. The cap can only be removed by tumor-associated proteases, a set of molecular scissors found in the vicinity of tumors to help degrade the surrounding healthy tissue. When proteases cut the lid, IL-12 is activated, capable of stimulating an immune response against the tumor.
“Masked IL-12 is largely inactive throughout the body, except at the site of the tumor, where these proteases can cleave the mask,” Mansurov explained.
Take off your mask
The researchers conducted a series of experiments that showed that the masked molecule did not cause the inflammation attributed to unmodified IL-12. In fact, when they tested the effect of the designed IL-12 on colon cancer, they found that the drug caused the complete elimination of the cancer cells. In laboratory-studied breast cancer models, masked IL-12 was even more effective than anti-PD1 antibody, an immune therapy commonly used in humans.
To further explore the potential utility of the new drug in the treatment of humans, Mansurov and colleagues used melanoma and breast cancer biopsies collected and donated from patients. The team wanted to make sure that human cancers contained high enough levels of tumor-associated proteases to unmask IL-12. In fact, when the designed IL-12 was exposed to biopsy samples, its molecular mask came off, releasing all of its immune power.
“For decades, the camp has hoped that IL-12 could one day become a viable therapy in the fight against cancer, and we have now shown that it is possible,” Mansurov said. “We would like to translate this molecule into the clinic and now we are talking to several potential partners to make that happen.”
While it will take time to bring this new development to patients, the new treatment is clearly on the horizon.
“Our goal at the Pritzker School of Molecular Engineering is to provide solutions to some of the greatest challenges facing the humanities. Immunoengineering takes an interdisciplinary approach to research, which allows us to develop new methods to fight disease,” he said. Hubbell. “This is a very promising development for those fighting cancer.”
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Magazine reference:
Mansurov, A., et al. (2022) Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor using a tumor protease-cleavable linker. Biomedical Engineering of Nature. doi.org/10.1038/s41551-022-00888-0.