Many cancer treatments are notoriously wild on the body; they attack healthy cells along with tumor cells, causing a plethora of side effects. Now, researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have devised a method to prevent a promising cancer drug from wreaking such havoc. The team has developed a new ‘masked’ version of the immunotherapeutic drug interleukin-12, which is only activated when it reaches a tumour. 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, yet has the same anti-tumor efficiency like the original.”
Aslan Mansurov, postdoctoral researcher and first author of the new paper
He carried out the engineering work of IL-12 with Jeffrey Hubbell, Eugene Bell Professor of Tissue Engineering, who co-leads PME’s immunoengineering research theme with Professor Melody Swartz.
Researchers know that IL-12 powerfully activates lymphocytes, immune cells capable of destroying tumor cells. But, in the 1990s, early clinical trials of IL-12 were halted due to severe and toxic side effects in patients. The same immune activation that set off a cascade of cancer cell-killing events also led to severe inflammation throughout the body. IL-12, at least in its natural form, has been abandoned.
But Mansurov, Hubbell, Swartz and their colleagues came up with an idea to reinvigorate the possibility of IL-12. What if the drug could slip into the body without activating the immune system? They designed a “masked” molecule with a cap covering the section of IL-12 that normally binds immune cells. The cap can only be removed by tumor-associated proteases, a set of molecular scissors found near tumors to help them break down surrounding healthy tissue. When the proteases cut the cap, IL-12 becomes active, able to stimulate an immune response against the tumor.
“Masked IL-12 is largely inactive anywhere in the body except at the tumor site, where these proteases can cleave the mask,” Mansurov explained.
Take off the mask
The researchers conducted a series of experiments showing that the masked molecule did not cause the inflammation attributed to unmodified IL-12. In fact, when they tested the effect of modified IL-12 on colon cancer, they found that the drug resulted in the complete elimination of cancer cells. In breast cancer models studied in the laboratory, masked IL-12 was even more effective than the anti-PD1 antibody, an immune therapy commonly used in humans.
To further explore the new drug’s potential usefulness in treating humans, Mansurov and his colleagues turned to melanoma and breast cancer biopsies collected and donated by patients. The team wanted to make sure that human cancers contained high enough levels of tumor-associated proteases to unmask IL-12. Indeed, when the modified IL-12 was exposed to the biopsy samples, its molecular mask detached, unleashing its full immune power.
“For decades, the field has hoped that IL-12 could one day become a viable therapeutic in the fight against cancer and we have now shown that it is possible,” said Mansurov. “We would like to translate this molecule into the clinic and are currently talking to a number of potential partners to make this happen.”
Although it will take some 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 in the humanities. Immunoengineering takes an interdisciplinary approach to research, allowing us to develop new ways to fight disease,” Hubbell said. “This is a very promising development for those battling cancer.”
Mansurov, A. et al. (2022) Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumor protease-cleavable linker. Nature Biomedical Engineering. doi.org/10.1038/s41551-022-00888-0.
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