Mask On: Researchers Engineer “Masked” IL-12 Treatment to Fight Cancer

Ever since their discovery, researchers have been trying to find a way to harness the power of exogenous cytokines, small proteins that are important in the cell signaling process to produce immunomodulatory changes. In the 1990s, researchers and drug developers were eager to find a way to deliver interleukin (IL)-12, to patients. Now, researchers at the University of Chicago’s Pritzker School of Molecular Engineering may have found a way. 

A History of Toxicity 

IL-12 is a potent, pro-inflammatory cytokine that could be used to help treat malignancies due to its ability to inhibit or reprogram immunosuppressive cells and modulate tumor cells so that the immune system is more likely to degrade those cells. In clinical trials, IL-12 has demonstrated robust antitumor activity and efficacy in a variety of cancers including melanoma and renal cancer with some patients achieving a complete response or minor tumor shrinkage. Unfortunately, IL-12 as a treatment for those with cancer hasn’t come to fruition because it is incredibly toxic to patients.

In the late ‘90s, researchers from the Genetics Institute of Cambridge, Massachusetts in conjunction with now-defunct Wyeth-Ayerst were conducting a Phase II clinical trial evaluating IL-12 in patients with advanced renal cell carcinoma that was halted by the U.S. Food and Drug Administration. The study resulted in the hospitalization of 12 patients - and the death of two - from the toxic effects of the treatment. The drug caused clinical adverse experiences and laboratory abnormalities were seen in many organ systems for a rampant inflammatory response.

Pritzker Researchers Break Through 

But some researchers haven’t given up hope for the possibility of a successful IL-12 treatment for patients with cancer. Research headed by postdoctoral research fellow, Aslan Mansurov, Ph.D., in collaboration with Jeffrey Hubbell, Ph.D., has found a way to “mask” IL-12 so that the immunotherapy is safer for patients while still delivering the same punch.

“Immunotherapy is currently being implemented by many clinicians in cancers such as melanoma and breast cancer. However, current therapies, known as checkpoint inhibitor therapies, do not produce durable responses as tumors often come back and are not effective in the majority of patients. Our therapy can help patients who have not been responsive to the standard-of-care checkpoint inhibitor antibodies,” Mansurov told BioSpace in an interview.

Mansurov and his team created a molecular mask for IL-12 that allows the therapeutic to enter the body and bypass the immune system, which causes inflammatory reactions that are toxic to patients.

“Our molecular mask is derived from the extracellular portion of the IL-12 receptor and is fused to IL-12 via a linker that is sensitive to tumor-associated enzymes,” Mansurov said. “When the molecule comes into contact with enzymes found in the tumor, these enzymes digest the linker, liberating IL-12 from its molecular mask.”

Once IL-12 is released from its mask, it is able to activate nearby immune cells found in the tumor, resulting in an inflammatory response that enables the immune system to attack and eliminate cancerous cells. If masked, IL-12 does not come into contact with enzymes found in the tumor. It remains masked and invisible to immune cells, avoiding a systemic inflammatory response.

“This masking approach allows for simultaneous reduction of toxicity in healthy tissues and therapeutic activity in the tumor,” Mansurov explained.

Testing the Hypothesis 

To test the efficacy of their engineered masked IL-12 treatment, Mansurov et. al utilized models of colon and breast cancer in the lab. They found that the therapy led to the complete elimination of cancer cells and didn’t cause the inflammation seen in previous clinical studies of unmodified IL-12. The group found that in models of breast cancer, masked IL-12 was a more effective treatment than an anti-programmed cell death protein (PD)-1 antibody, a commonly used immunotherapy that eliminates cancer by activating an immune response against the tumor.

Next, the team utilized cancer biopsies donated by patients to determine if the malignancies were able to produce sufficient enzymes to activate the unmasking of IL-12. They found that the tumors did indeed produce enough of the enzyme to activate IL-12’s full power, demonstrating proof of concept. The results of these studies were published in Nature Biomedical Engineering, showing that in mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signaling and eliminated systemic immune-related adverse events. The treatment also led to potent therapeutic effects via the remodeling of the immune-suppressive microenvironment.

The Next Steps 

Although the treatment is far from being clinically available to patients, the research group has plans to continue its development and translate its work to the clinic.

“Currently, our masked IL-12 molecule is in the pre-clinical stage of development, meaning that it has not undergone extensive safety evaluations. We are currently in discussion with potential partners to bring this molecule to the next step in the clinical development process,” Mansurov said, noting that the team is not at liberty to specify who they plan to partner with.

Currently, there are no approved therapies based on IL-12, making the masked therapy a novel approach to treating a variety of cancers. Mansurov stated that right now, the team is developing the treatment for solid tumor indications where checkpoint-blocking antibodies have shown only marginal efficacy.

“Our data suggest that masked IL-12 can convert checkpoint-resistant tumors to checkpoint-responsive ones. The ability of IL-12 to inflame tumors also suggests that masked IL-12 and checkpoint blockade can work together in combination,” he said.

This is especially important because several types of cancers including pancreatic, prostate and glioblastoma are especially resistant to immunotherapies that utilize checkpoint blockades. Cancer patients may also be at risk for acquired resistance to immune checkpoint inhibitors, with one study finding that in a cohort of 1,124 patients with advanced gastrointestinal cancers, 46.4% had acquired resistance to immunotherapies. Resistance to common therapies can leave patients with few options to control their disease.

“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,” Mansurov said. “We believe that our masking approach brings this promising molecule one step closer to its clinical translation. This is a very promising development for those fighting cancer.”