New Method for Delivering Immune System-Stimulating Drugs

This image shows the tumor immediately after treatment with alum-bound IL12. Pink indicates IL-12 and yellow alum. Credits: Courtesy of the researcher

The targeted approach eliminated tumors in mice, with minimal side effects.

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: removing the brakes that tumors put on the immune system; and “gasing” or delivering molecules that drive immune cells.

However, when triggering the immune system, researchers must be careful not to overstimulate it, which can cause serious and potentially deadly side effects. Team of WITH Researchers have now developed a new way to deliver a stimulant molecule called IL-12 directly to tumors, avoiding the toxic effects that can occur when immunostimulating drugs are given throughout the body.

In a study in mice, this new treatment eliminated many tumors when delivered along with an FDA-approved drug that inhibits 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 immunostimulatory drugs,” says Darrell Irvine, an Underwood-Prescott professor with appointments at MIT -in the Department of Biological Engineering and Materials Science and Engineering; Assistant Director of MIT’s Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute MGH, MIT and Harvard.

Researchers have filed patents for their strategy, and the technology is licensed to a startup hoping to begin clinical trials by the end of 2022.

Irvine and Dane Wittrup, Carbon P. Dubbs professor of chemical engineering and electrical engineering and a member of the Koch Institute, are senior authors of a study published on January 10, 2022. Biomedical engineering of nature. MIT graduate student Yash Agarwal is the lead author of the paper.

Step on the gas

As tumors develop, they secrete molecules that disable nearby T cells and other immune cells, allowing tumors to grow uncontrollably. Drugs known as checkpoint blockade inhibitors, which can remove these brakes from 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 immune-stimulating drugs could potentially make cancer immunotherapy work on more patients. Cytokines, which are immune chemicals that the body naturally produces, are one class of drugs that researchers have tried as a way to “gauze on 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 a patient with cytokines, his whole body reacts and you get such a strong, toxic side effect that you can’t achieve the levels you wish you could inside the tumor and achieve the desired effects,” Wittrup says.

To try to avoid these side effects, Wittrup and Irvine worked on ways to deliver cytokines in a more targeted way. A 2019 study showed that they can deliver cytokines IL-12 and IL-2 directly to tumors by binding cytokines to collagen-binding protein. This protein then sticks to the collagen found in tumors, which usually have large amounts of collagen.

This strategy worked well in a study in mice, but the researchers wanted to find a way to make cytokines even more strongly bound to tumors. In their new study, they replaced collagen-binding protein with aluminum hydroxide. This compound, also called alum, is often used as a vaccine adjunct (a drug that helps boost the immune response to vaccination).

“One of the main benefits of alum is that the particles are micron-sized, so when you inject them into humans or mice, they stay wherever you inject them for weeks, sometimes months,” Agarwal says.

Fight against tumors

To test the effectiveness of this treatment, the researchers gave the mice a single injection of alum-bound IL-12 or IL-2, and treated the mice every few days with a checkpoint blocker inhibitor called anti-PD1.

In mouse models of three cancers, the researchers found that tumors were eliminated in 50 to 90 percent of mice. In a model where breast cancer cells were transplanted into mice and then metastasized to the lungs, a single injection at the breast cancer site also cleared metastatic tumors, although IL-12 was not injected into the lungs.

Alum-IL-12 particles given without checkpoint blocker inhibitors also showed some ability to stimulate the immune system to fight tumors.

Further studies have shown that IL-12 stimulates the production of another cytokine called interferon gamma, and the two molecules work together to activate T cells as well as dendritic cells and macrophages. The treatment also stimulates memory T cells that could respond to growing tumors.

The researchers also found that the treated mice did not show any side effects seen when IL-12 is given systemically. The startup company, which has licensed the technology, plans to first test IL-12 alum particles on its own, and if that treatment proves to be safe, they hope to test Il-12 in combination with checkpoint blocker inhibitors.

A new approach to binding alum molecules could also be used to deliver other types of immunostimulatory drugs, the researchers say.

“This whole class of drugs, which includes trampling on gas, has largely failed. We hope this paves the way for testing any of these drugs, ”says Irvine.

Reference: “Intratumor injected alum-bound cytokines elicit potent and safer local and systemic immunity against cancer” Yash Agarwal, Lauren E. Milling, Jason YH Chang, Luciano Santollani, Allison Sheen, Amy A. Lutz, Anthony Tabet, Jordan Stinson, Kai Ni , Kristen A. Rodrigues, Tyson J. Moyer, Mariane B. Melo, Darrell J. Irvine and K. Dane Wittrup, January 10, 2022, Biomedical engineering of nature.
DOI: 10.1038 / s41551-021-00831-9

The research was partly funded by the Marble Center for Nanomedicine of the Koch Institute; Ragon Institute of MGH, MIT and Harvard; and support from the Koch (core) Grant Institute from the National Cancer Institute.

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