Ways to deliver immune system-stimulating drugs enhance cancer immunotherapy

Stimulating the body's immune system to attack tumors is a promising treatment for cancer
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Scientists are working on two complementary strategies to achieve this goal: unblocking the immune system from the tumor; and "stepping on the gas," or delivering molecules that prime immune cells

However, when priming the immune system, researchers must be careful not to overstimulate it, which can lead to serious and potentially fatal side effects
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A research team at MIT has now developed a new way to deliver a stimulating molecule called IL-12 directly to tumors, avoiding the toxic effects that immune-stimulating drugs can have when administered systemically

In a study in mice, the new therapy, used with an FDA-approved drug, removes the "brake" of the immune system, eliminating many tumors
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IL-12 "even beyond this particular case, where we really hope there will be some impact, this is a strategy that can be applied to any of these immunostimulatory drugs," said Darrell Owen, who is an Underwood-Prescott professor by appointment in Bioengineering, Materials Science and Engineering at MIT; associate director of the Koch Institute for Integrative Cancer Research at MIT; and a member of the Ragon Institute at MGH, MIT, and Harvard
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The researchers have patented their strategy, and the technology has been licensed to a startup that hopes to begin clinical trials by the end of 2022
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Irvine and Dane Wittrup, the Carbon P.
Dubbs Professor of Chemical Engineering and Electrical Engineering and members of the Koch Institute, are senior authors of the study, published today in Nature Biomedical Engineering
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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 the tumor to grow uncontrollably
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Drugs called checkpoint blockade inhibitors are now used to treat some types of cancer, but many others are resistant to this treatment

Combining checkpoint inhibitors and drugs that stimulate the immune system may make cancer immunotherapy effective for more patients
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Cytokines are immune chemicals that are naturally produced by the body and are a class of drugs that researchers are trying to "speed up

"If you soak a patient in cytokines, and their whole body responds, you get such strong toxic side effects, you can't get the levels you want in the tumor, and you can't get the effects you want," Witte said.

Rupp said

To avoid these side effects, Wittrup and Irvine have been working on ways to deliver cytokines in a more targeted way
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In a 2019 study, they showed that they could deliver the cytokines IL-12 and IL-2 directly to tumors by attaching the cytokines to collagen-binding proteins

The strategy worked well in mice, but the researchers wanted to find a way to make the cytokine bind more strongly to the tumor
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In their new study, they replaced the collagen-binding protein with aluminum hydroxide

"A major advantage of alum is that the particles are micron-sized, so when you inject them into a human or mouse, they stay where you inject them for weeks, sometimes months," Agarwal said
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fight tumor

To test the effectiveness of the treatment, the researchers injected mice with a form of IL-12 or IL-2 bound to alum particles and injected the mice with a checkpoint called anti-PD1 every few days.
Blockade inhibitors
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In three mouse models of cancer, the researchers found that tumors were eliminated in 50 to 90 percent of the mice
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In a model in which breast cancer cells were transplanted into mice and then transferred to the lungs, a single injection at the breast cancer site also cleared metastatic tumors, although IL-12 was not injected into the lungs
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AL-IL-12 particles without checkpoint blockade inhibitors also showed the ability to stimulate the immune system to fight tumors
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Further studies showed that IL-12 stimulates the production of another cytokine called interferon, and the two molecules work together to activate T cells, dendritic cells and macrophages
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The therapy also stimulates memory T cells that respond to tumor regeneration
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The researchers also found that the mice treated with IL-12 did not experience any of the side effects seen with systemic injections of IL-12
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The startup that licensed the technology plans to test Il-12-alum particles on its own for the first time, and if the therapy proves to be safe, they hope to test Il-12 in combination with a checkpoint blockade inhibitor
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The new method of attaching molecules to alum could also be used to deliver other types of immune-stimulating drugs, the researchers said
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"This class of drugs that involves stepping on the gas pedal has largely not been successful
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We hope this opens the door to testing these drugs," Owen said
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This research was supported in part by grants from the Koch Institute's Marble Center for Nanomedicine; the Ragon Institute at MGH, MIT, and Harvard; and Koch Institute Support (Core) grants at the National Cancer Institute
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