A Cancer Treatment That Sticks Around
A new study in mice may help revive the clinical prospects of the cytokine interleukin-12 (IL-12), a drug that stimulates the immune system to attack tumors. Based on the results of this study and an earlier study by the same group of researchers, a phase I clinical trial is being planned to test the treatment in patients with bladder cancer. The new study will be published in the September Journal of Immunotherapy.
IL-12, a protein that has been the subject of intense investigation for several decades, modulates important components of the immune system and has demonstrated dramatic antitumor effects in numerous laboratory and animal model studies. Its clinical development, however, has been stunted by significant toxicities seen in several human trials in which it was given intravenously or subcutaneously.
In an effort to circumvent that problem, Dr. John Greiner of the Laboratory of Tumor Immunology and Biology in NCI’s Center for Cancer Research and colleagues mixed IL-12 with a compound called chitosan, a biological adhesive that can bind synthetic or biological molecules to tissue. The resulting mixture was injected directly into a tumor.
Chitosan, which is a polysaccharide derived from the shells of crustaceans such as shrimp or lobster, is an important part of a “delivery system” that brings IL-12 “directly into the tumor environment,” explained Dr. Greiner. The treatment was not only effective in the mouse studies, but appears to be very safe with no apparent toxic side effects.
In the team’s previous study, chitosan/IL-12 eradicated tumors in a mouse model of bladder cancer. In this new study, they used mouse models of colorectal and pancreatic cancer. First, using noninvasive imaging techniques, they showed that after injecting tumors with chitosan/IL-12 the cytokine remained within the tumor microenvironment for nearly a week, but when IL-12 alone was injected it remained there for only a day.
Study co-author Dr. David Zaharoff, now at the University of Arkansas, who initially developed the idea for combining IL-12 with a bioadhesive, likened chitosan to maple syrup. “The high viscosity of chitosan inhibits diffusion of co-formulated molecules,” he said. “As a result, chitosan is able to hold IL-12 in the tumor microenvironment and maintain it there for a long period of time.”
In a second set of experiments, they showed that intratumoral injection of chitosan/IL-12 once a week for 3 weeks completely eradicated tumors in 90 percent of the mice, whereas IL-12 alone had only limited efficacy. There was little impact on tumor shrinkage or survival when chitosan was combined with GM-CSF and IFN-γ, two other proteins that can stimulate the immune system. “This complete tumor regression seems to be unique to chitosan/IL-12,” the researchers wrote.
The treatment triggered the activity of two powerful types of immune cells, CD8+ T cells and natural killer cells. And in certain circumstances, when the researchers “rechallenged” the cured mice with tumor cells, the initial treatment offered lasting immune protection against cancer. But the extent of the protection, they cautioned, was dependent on how many tumor cells were injected into the mice and how often, and must be examined in “a more clinically relevant [animal] model.”
Despite its robust antitumor effects, the toxicities IL-12 induced in the initial human trials drove away industry interest in it, explained Dr. Jeffrey Weber from the H. Lee Moffitt Cancer Center & Research Institute in Tampa, FL. “But I still think that this is a drug that needs to be pursued,” he said.
Even so, Dr. Weber, who was not involved in the study and whose work focuses on vaccines to treat melanoma and other tumors, expressed doubts about the long-term prospects of IL-12 as a stand-alone therapy, arguing that the available evidence suggests it would be best pursued as an adjuvant to boost the performance of therapeutic vaccines. A requirement to inject the treatment directly into the tumor may also “limit its appeal and its indications,” he continued.
The phase I trial, which will be conducted at the NIH Clinical Center in Bethesda, MD, will enroll patients with superficial bladder cancer (cancer limited to the lining of the bladder wall) whose disease has returned after standard first-line therapy. In the case of bladder cancer, Dr. Greiner added, because chitosan/IL-12 appears to generate a strong adaptive immune response—that is, immune cells are spurred to action and develop a “memory” of the pathogens or cells that mandate a similar response in the future—it may also present “an opportunity for evaluating this approach in patients with metastatic lesions who cannot undergo surgical removal of the bladder.”
Similar efforts to target the delivery of IL-12 to tumors, including encapsulating the protein in viruses and liposomes, are being investigated. But combining IL-12 with chitosan may offer several advantages over these other approaches. Chitosan, for example, is already used in humans to promote blood clotting and reduce lipid absorption in the stomach, and it has a proven track record for safety, Dr. Zaharoff stressed, and the once-a-week treatment schedule will limit the type of systemic exposure that can cause toxicities.
In addition, unlike some other approaches to improve IL-12 delivery, preparing the IL-12 and chitosan mixture doesn’t require solvents and other processes that break down the protein, and it can actually be made at the bedside just prior to administration.
“It’s a very simple approach, but it was designed to be that way so it can be moved into human trials in a short period of time,” Dr. Zaharoff said. “As far as translational research goes, you can’t get much more efficient than this.”