Stimulating the body’s immune system to attack tumors is a promising way to treat cancer. Scientists are working on two complementary strategies to achieve this: eliminate the brakes that tumors put on the immune system; and “walking on the gas,” or delivering molecules that jump-start immune cells.
However, when reviving the immune system, researchers must be careful not to over-stimulate it, which can cause serious and potentially fatal side effects. A team of researchers at MIT has now developed a new way to deliver a stimulator molecule called IL-12 directly to tumors, avoiding the toxic effects that can occur when immunostimulating drugs are administered throughout the body.
In a study in mice, this new treatment eliminated many tumors when given with an FDA-approved drug that suppresses the immune system.
“Even beyond this particular case of IL-12, which we really hope will have some impact, it’s a strategy you could apply to any of these immunostimulant drugs,” says Darrell. Irvine, who is Professor Underwood-Prescott with appointments at MIT. departments of biological engineering and materials science and engineering; associate director of the Koch Institute for Integrative Cancer Research at MIT; and Fellow of the Ragon Institute of MGH, MIT and Harvard.
The researchers have filed patents on their strategy, and the technology has been licensed to a startup that hopes to begin clinical trials by the end of 2022.
Irvine and Dane Wittrup, Carbon P. Dubbs professor of chemical and electrical engineering and fellow of the Koch Institute, are the lead authors of the study, which appears today in Nature Biomedical Engineering. MIT graduate student Yash Agarwal is the lead author of the article.
Walk on gas
As tumors grow, they secrete molecules that deactivate nearby T cells and other immune cells, allowing tumors to grow unchecked. Medicines known as checkpoint blockade inhibitors, which can slow down the immune system, are now used to treat some types of cancer, but many other types are resistant to this type of treatment.
Combining checkpoint inhibitors with drugs that boost the immune system could potentially make cancer immunotherapy work for more patients. Cytokines, which are immune chemicals naturally produced by the body, are a class of drugs that researchers have tried as a way to “put the foot on the gas.” However, in clinical trials these drugs have shown too many toxic side effects, ranging from flu-like symptoms to organ failure.
“If you soak the patient in cytokines, their whole body reacts and you get such a strong and toxic side effect that you can’t reach the levels that you want to be able to reach in the tumor and get the effects that you want,” explains Wittrup.
To try to avoid these side effects, Wittrup and Irvine worked on ways to deliver cytokines in a more targeted manner. In a 2019 study, they showed that they could deliver cytokines IL-12 and IL-2 directly to tumors by attaching the cytokines to a collagen-binding protein. This protein then adheres to the collagen present in tumors, which usually contain large amounts of collagen.
This strategy worked well in a study in mice, but the researchers wanted to find a way to make cytokines bind to tumors even more strongly. In their new study, they replaced the collagen-binding protein with aluminum hydroxide. This compound, also called alum, is often used as a vaccine adjuvant (a medicine that helps stimulate the immune response to vaccination).
“One of the main advantages of alum is that the particles are on a micron scale, so when you inject them into people or mice, they stay wherever you inject them for weeks or even months. sometimes, ”Agarwal explains.
To test the effectiveness of this treatment, the researchers gave mice an injection of IL-12 or IL-2 bound to alum particles and treated the mice with a checkpoint blocking inhibitor. called anti-PD1 every few days.
In mouse models of three types of cancer, the researchers found that tumors were cleared in 50 to 90 percent of the mice. In a model where breast cancer cells were transplanted into mice and then metastasized into the lungs, injection into the site of breast cancer also ruled out metastatic tumors, although IL-12 was not injected into the lungs.
Alum-IL-12 particles administered without the checkpoint blocking inhibitors have also shown some ability to stimulate the immune system to fight tumors.
Other studies have shown that IL-12 stimulates the production of another cytokine called interferon gamma, and these two molecules work together to activate T cells as well as dendritic cells and macrophages. The treatment also stimulates memory T cells which may be able to respond to growing tumors.
The researchers also found that the treated mice exhibited none of the side effects seen when IL-12 was administered systemically. The startup that licensed the technology plans to test IL-12 alum particles first, and if the treatment proves safe, hopes to test Il-12 in combination with blocker inhibitors. checkpoints.
The new approach of attaching molecules to alum could also be used to deliver other types of immunostimulatory drugs, the researchers said.
“This whole class of drugs that involves walking on gas has largely not been successful yet. Our hope is that this paves the way for a trial of one of these drugs, ”said Irvine.
The research was funded in part by the Marble Center for Nanomedicine at the Koch Institute; the Ragon Institute of MGH, MIT and Harvard; and the National Cancer Institute’s Koch Institute Support (core) grant.