Cancer immunotherapy, which uses drugs that stimulate the body’s immune cells to attack tumors, is a promising approach to treating many types of cancer. However, it doesn’t work well for some tumors, including ovarian cancer.

To elicit a better response, MIT researchers have designed new nanoparticles that can deliver an immune-stimulating molecule called IL-12 directly to ovarian tumors. When given along with immunotherapy drugs called checkpoint inhibitors, IL-12 helps the immune system launch an attack on cancer cells.

Studying a mouse model of ovarian cancer, the researchers showed that this combination treatment could eliminate metastatic tumors in more than 80 percent of the mice. When the mice were later injected with more cancer cells, to simulate tumor recurrence, their immune cells remembered the tumor proteins and cleared them again.

“What’s really exciting is that we’re able to deliver IL-12 directly in the tumor space. And because of the way that this nanomaterial is designed to allow IL-12 to be borne on the surfaces of the cancer cells, we have essentially tricked the cancer into stimulating immune cells to arm themselves against that cancer,” says Paula Hammond, an MIT Institute Professor, MIT’s vice provost for faculty, and a member of the Koch Institute for Integrative Cancer Research.

Hammond and Darrell Irvine, a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the new study, which appears today in Nature Materials. Ivan Pires PhD ’24, now a postdoc at Brigham and Women’s Hospital, is the lead author of the paper.

“Hitting the gas”

Most tumors express and secrete proteins that suppress immune cells, creating a microenvironment in which the immune response is weakened. One of the main players that can kill tumor cells are T cells, but they get sidelined or blocked by the cancer cells and are unable to attack the tumor. Checkpoint inhibitors are an FDA-approved treatment designed to take those brakes off the immune system by removing the immune-suppressing proteins so that T cells can mount an attack on tumor cells

For some cancers, including some types of melanoma and lung cancer, removing the brakes is enough to provoke the immune system into attacking cancer cells. However, ovarian tumors have many ways to suppress the immune system, so checkpoint inhibitors alone usually aren’t enough to launch an immune response.

“The problem with ovarian cancer is no one is hitting the gas. So, even if you take off the brakes, nothing happens,” Pires says.

IL-12 offers one way to “hit the gas,” by supercharging T cells and other immune cells. However, the large doses of IL-12 required to get a strong response can produce side effects due to generalized inflammation, such as flu-like symptoms (fever, fatigue, GI issues, headaches, and fatigue), as well as more severe complications such as liver toxicity and cytokine release syndrome — which can be so severe they may even lead to death.

In a 2022 study, Hammond’s lab developed nanoparticles that could deliver IL-12 directly to tumor cells, which allows larger doses to be given while avoiding the side effects seen when the drug is injected. However, these particles tended to release their payload all at once after reaching the tumor, which hindered their ability to generate a strong T cell response.

In the new study, the researchers modified the particles so that IL-12 would be released more gradually, over about a week. They achieved this by using a different chemical linker to attach IL-12 to the particles.

“With our current technology, we optimize that chemistry such that there’s a more controlled release rate, and that allowed us to have better efficacy,” Pires says.

The particles consist of tiny, fatty droplets known as liposomes, with IL-12 molecules tethered to the surface. For this study, the researchers used a linker called maleimide to attach IL-12 to the liposomes. This linker is more stable than the one they used in the previous generation of particles, which was susceptible to being cleaved by proteins in the body, leading to premature release.

To make sure that the particles get to the right place, the researchers coat them with a layer of a polymer called poly-L-glutamate (PLE), which helps them directly target ovarian tumor cells. Once they reach the tumors, the particles bind to the cancer cell surfaces, where they gradually release their payload and activate nearby T cells.

Disappearing tumors

In tests in mice, the researchers showed that the IL-12-carrying particles could effectively recruit and stimulate T cells that attack tumors. The cancer models used for these studies are metastatic, so tumors developed not only in the ovaries but throughout the peritoneal cavity, which includes the surface of the intestines, liver, pancreas, and other organs. Tumors could even be seen in the lung tissues.

First, the researchers tested the IL-12 nanoparticles on their own, and they showed that this treatment eliminated tumors in about 30 percent of the mice. They also found a significant increase in the number of T cells that accumulated in the tumor environment.

Then, the researchers gave the particles to mice along with checkpoint inhibitors. More than 80 percent of the mice that received this dual treatment were cured. This happened even when the researchers used models of ovarian cancer that are highly resistant to immunotherapy or to the chemotherapy drugs usually used for ovarian cancer.

Patients with ovarian cancer are usually treated with surgery followed by chemotherapy. While this may be initially effective, cancer cells that remain after surgery are often able to grow into new tumors. Establishing an immune memory of the tumor proteins could help to prevent that kind of recurrence.

In this study, when the researchers injected tumor cells into the cured mice five months after the initial treatment, the immune system was still able to recognize and kill the cells.

“We don’t see the cancer cells being able to develop again in that same mouse, meaning that we do have an immune memory developed in those animals,” Pires says.

The researchers are now working with MIT’s Deshpande Center for Technological Innovation to spin out a company that they hope could further develop the nanoparticle technology. In a study published earlier this year, Hammond’s lab reported a new manufacturing approach that should enable large-scale production of this type of nanoparticle.

The research was funded by the National Institutes of Health, the Marble Center for Nanomedicine, the Deshpande Center for Technological Innovation, the Ragon Institute of MGH, MIT, and Harvard, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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