A ‘Pacman Strategy’ to Boost the Immune System to Fight Cancer

A molecule that lies dormant until it encounters a cancer cell, then suddenly activates and rouses the body’s immune system to fight cancer cells directly, marks the latest step in scientists’ efforts to tap the body’s own resources to fight the disease.

The developers of the technology, graduate student John Puskas and Professor John Frelinger, Ph.D., of the Wilmot Cancer Center, dub it the “Pacman strategy” because it hinges upon molecular machines produced in abundance by tumors to chew through and gobble up particular chains of molecules. The study was published online recently in the journal Immunology. Puskas is first author of the paper.

The key feature of the work is a new type of fusion molecule with three parts: a potent immune cell activator; a second molecule to keep that molecule quiescent, or inactive, until it’s needed; and a link between the two that gives scientists control over how the two interact.

The overall fusion molecule acts like a tiny anti-cancer grenade: The portion designed to arouse the immune system to attack cancer is inactive until it’s freed, which occurs when the link between it and its inhibitory counterpart is split by specialized tumor proteins that chew up such molecules.

In its experiments, the team used Interleukin-2 (IL-2), a chemical messenger that amplifies the effects of the immune system. IL-2 has been central to the burgeoning field known as cancer immunotherapy; it activates T cells and natural killer cells that recognize and kill cancer cells. It’s approved by the U.S. Food and Drug Administration for the treatment of melanoma and kidney cancer, but it can have serious side effects and harm healthy tissue, limiting its use in patients dramatically.

“One reason we chose IL-2 is that it’s approved and used to treat patients today. If we’re able to reduce the toxicity associated with it, perhaps it could be used more broadly,” said Frelinger, professor of Microbiology and Immunology.

In experiments using the technology in the lab in experiments in mice with cancer, tumor growth was inhibited in mice where IL-2 was turned on using the technology compared to mice in which it was not. In many of the treated mice, tumor cells could not be detected after one week.

A key to the technology is the molecular link between IL-2 and its inhibitor. Puskas and Frelinger built that link out of a chain of amino acids – building blocks of proteins. Such chains are broken or cleaved constantly in the body by enzymes known as proteases. In these experiments, when the link is broken, IL-2 breaks free from its inhibitor and is suddenly available to activate other immune cells.
Puskas and Frelinger created links that are cleaved by molecules found much more commonly in cancer cells than other cells. The approach is designed to activate the immune system powerfully right in the neighborhood of cancer cells, to destroy those cells, but to avoid a system-wide immune response that could cause severe side effects. This approach is quite different from other experimental anti-cancer efforts that have involved fusion proteins where the molecules are active throughout the body.

“The beauty of this approach is that you can change any part of the molecule you want,” said Frelinger. “If you want to target a specific type of cancer, you change the protease sequence to tailor it to particular types of tumors. If you want to change the part of the immune system activated, you change the cytokine. Our hope is that an approach like this might someday be coupled with other types of therapy, so that the body could initiate and maintain a vigorous immune response to kill tumors.”

Other authors besides Puskas and Frelinger include graduate students Denise Skrombolas and Abigail Sedlacek, and faculty members Edith Lord, Ph.D., and Mark Sullivan, Ph.D. The work was supported by the National Institutes of Allergy and Infectious Diseases as well as by Steven and Alison Krausz and F.C. Blodgett.

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