Despite their potential, cytokines have yet to be successfully developed into effective cancer therapies because they are highly toxic to both healthy tissue and tumors alike. That might be changing, according to a recent study that describes how attaching a Velcro-like molecule may prevent cytokines from leaking out of cancerous tissue after injection.
Researchers at the Koch Institute for Integrative Cancer Research at MIT hope their method will limit the harm caused to healthy tissue, while prolonging the treatment's ability to attack the tumor. To develop their technique, which they describe in a recently published Science Translational Medicine paper, the researchers first investigated the different proteins found in tumors, to find one that could be used as a target for the cytokine treatment. They chose collagen, which is expressed abundantly in solid tumors.
They then undertook an extensive literature search to find proteins that bind effectively to collagen. They discovered a collagen-binding protein called lumican, which they then attached to the cytokines. "When we inject (a collagen-anchoring cytokine treatment) intratumorally, we don't have to worry about collagen found elsewhere in the body; we just have to make sure we have a protein that binds to collagen very tightly," says lead author Noor Momin.
To test the treatment, the researchers used two cytokines known to stimulate and expand immune cell responses. The cytokines, interleukin-2 (IL-2) and interleukin-12 (IL-12), are also known to combine well with other immunotherapies. Although IL-2 already has FDA approval, its severe side effects have so far prevented its clinical use. Meanwhile IL-12 therapies have not yet reached phase 3 clinical trials due to their severe toxicity.
The researchers tested the treatment by injecting the two different cytokines into tumors in mice. To make the test more challenging, they chose a type of melanoma that contains relatively low amounts of collagen, compared to other tumor types. They then compared the effects of administering the cytokines alone and of injecting cytokines attached to the collagen-binding lumican.
"In addition, all of the cytokine therapies were given alongside a form of systemic therapy, such as a tumor-targeting antibody, a vaccine, a checkpoint blockade, or chimeric antigen receptor (CAR)-T cell therapy, as we wanted to show the potential of combining cytokines with many different immunotherapy modalities," Momin adds.
They found that when any of the treatments were administered individually, the mice did not survive. Combining the treatments improved survival rates slightly, but when the cytokine was administered with the lumican to bind to the collagen, the researchers found that over 90 percent of the mice survived with some combinations.
"So we were able to show that these combinations are synergistic, they work really well together, and that cytokines attached to lumican really helped reap the full benefits of the combination," Momin says.