Although interleukin-12 caused adverse side effects, researchers have long hypothesized that it would be a potent cancer treatment. A new form of the molecule has been created by Pritzker Molecular Engineering researchers that does not activate until it enters a tumor, where it kills cancer cells.
Scientists have created a new powerful “masked” cancer drug.
Numerous cancer treatments are notoriously harsh on the body; they assault healthy cells simultaneously with tumor cells and result in a wide range of side effects. The Pritzker School of Molecular Engineering (PME) at the University of Chicago has now developed a strategy to prevent one potential cancer drug from causing such damage. Interleukin-12 has been modified by scientists into a new, “masked” form that is only activated when it comes into contact with a tumor. The study on the molecule, also known as IL-12, was published in the journal Nature Biomedical Engineering.
“Our research shows that this masked version of IL-12 is much safer for the body, but it possesses the same anti-tumor efficacy as the original,” said Aslan Mansurov, a postdoctoral research fellow and first author of the new paper. He carried out the IL-12 engineering work with Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering, who co-leads PME’s Immunoengineering research theme with professor Melody Swartz.
Overcoming Toxicity
Researchers have discovered that IL-12 strongly activates lymphocytes, which are immune cells with the ability to kill tumor cells. Early IL-12 clinical studies, however, were stopped in the 1990s due to the patients’ harsh, toxic side effects. The same immune activation that set off a series of events that killed the cancer cells also caused significant inflammation throughout the body. The study of IL-12 was discontinued, at least in its natural form.
However, Mansurov, Hubbell, Swartz, and others came up with a plan to revive the potential of IL-12. What if the medication could pass through the body without triggering the immune system? They created a “masked” molecule with a cap covering the region of IL-12 that typically binds immune cells. Only tumor-associated proteases, a collection of molecular scissors located close to tumors to aid them in destroying the good tissue around them, can cut off the cap. The IL-12 becomes active and is then able to activate an immune response against the tumor when the proteases remove the cap.
“The masked IL-12 is largely inactive everywhere in the body except at the site of the tumor, where these proteases can cleave off the mask,” explained Mansurov.
Taking off the mask
The researchers carried out a series of experiments showing that the masked molecule did not cause the inflammation attributed to the unmodified IL-12. In fact, when they tested the effect of the engineered IL-12 in colon cancer, they found that the drug led to the complete elimination of the cancer cells. In models of breast cancer studied in the lab, 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 treating humans, Mansurov and his colleagues turned to melanoma and breast cancer biopsies collected and donated from patients. The team wanted to ensure that human cancers contained high enough levels of tumor-associated proteases to unmask the IL-12. Indeed, when the engineered IL-12 was exposed to the biopsy samples, its molecular mask came off, unleashing its full immune power.
“For decades, the field has hoped that IL-12 could someday become a viable therapeutic in the fight against cancer and we’ve now shown that it is possible,” said Mansurov. “We’d like to translate this molecule to the clinic and are now talking to a number of potential partners to make that happen.”
While 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 humanity’s biggest challenges. Immunoengineering takes an interdisciplinary approach to research, which allows us to develop novel methods to fight disease,” said Hubbell. “This is a very promising development for those fighting cancer.”
Reference: “Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker” by 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, and Jeffrey A. Hubbell, 9 May 2022, Nature Biomedical Engineering.
DOI: 10.1038/s41551-022-00888-0