By exploiting microparticles made of new biodegradable plastics and building blocks made of DNA, Darrell J. Irvine hopes to imbue the body’s natural defenses with superhero powers.
“We combine state-of-the-art chemistry, polymer science, materials science, and immunology to address critical biological questions and medical challenges,” says Irvine, an associate professor in the Department of Biological Engineering and the Department of Materials Science and Engineering.
The goal: focused, tumor-killing immunotherapies and targeted vaccines with minimal side effects. The challenges — and the potential rewards — are great. “The idea behind immunotherapy is that it can be curative rather than providing only a temporary reprieve from disease, via the power of the immune response and immunological memory,” says Irvine, a Howard Hughes Medical Institute investigator affiliated with the David H. Koch Institute for Integrated Cancer Research at MIT. Applied to cancer and HIV, that’s saying a lot.
His laboratory is developing polymer-based microparticles and hydrogels as tools to study immune cells’ migration through the body; nanoparticles that serve as vehicles to deliver drug- or vaccine-boosting agents and molecules designed to stimulate the immune system; and biodegradable, nontoxic nanoparticles that deliver proteins directly into immune cells.
While the concept of immunotherapy has long been touted as a possibility for defeating cancer, Irvine says new understanding of fundamental disease mechanisms is giving him and the latest crop of researchers a boost in delivering on the hype. “Tumors have been known for many years to interfere with the immune response, but the signaling pathways responsible for this immunosuppression are beginning to be mechanistically defined, enabling us to begin devising ways to interfere with the interference,” he said.
FORMIDABLE FOES
Tumors have the ability to subvert the immune system, making themselves virtually invisible and invincible to T-cells, the white blood cells that play a major role in immunity. “If the immune system is the army fighting cancer, it’s not seeing an enemy, and its armaments aren’t working when it does recognize it,” he said. “The immune system has a hard time knowing what it should be fighting.”
What’s more, different kinds of tumors may employ different mechanisms to outwit the immune system. Yet many tumors display unusual antigens or cell surface receptors, rare or absent on healthy cells, that provide handy tumor-specific targets for immunotherapy.
“The ultimate goal is to stimulate the immune system to begin attacking tumors as it would an infectious agent,” Irvine says. “The holy grail of immunotherapy is to elicit a systemic immune response, complete with memory, to eliminate a cancer and prevent it from recurring” — the T-cell equivalent of leaping tall buildings in a single bound.
One of Irvine’s strategies involves injecting a tumor with agents that kill some of its cells in a way that wakes up the immune system to recognize the tumor as the enemy. Another strategy uses synthetic materials to modulate the function of immune cells by mimicking signals derived from the immune system or foreign pathogens.
Critical to Irvine’s efforts are mice genetically engineered at the Koch Institute to develop tumors gradually, more akin to how human cancers develop and mutate to foil the immune system.
“This is an exciting time to be doing this work because underlying molecular mechanisms are starting to be understood, and chains of cause and consequence are now being established,” he says.
Irvine also creates models that can be used on the lab bench or in a living animal to better understand immunobiology in health and disease. He makes artificial cells with surfaces structurally similar to the surface of infected cells to see how killer T-cells interact with them. He attaches tiny cargoes of drugs and magnetic nanoparticles to living cells and uses magnetic fields to manipulate their movements. Three-dimensional culture models model living cells and tissues to shed light on how T-cells from HIV patients whose virus is under control differ from those in chronically infected patients who develop full-blown AIDS.
One of his postdoctoral fellows is building particles and hydrogels out of DNA that could become innovative vehicles for drug delivery or RNA snippets that silence genes.
Irvine’s cancer and HIV immunotherapies are being tested in animal models, with the hope of moving to human trials within a few years.
MAGIC IN THE MIX
Growing up in western Pennsylvania, Irvine thought he would end up in computer science until he met polymer theorist Anna C. Balazs at the University of Pittsburgh. Balazs’ enthusiasm for her subject, her skill as a mentor, and her gung-ho admiration for her alma mater, MIT, convinced Irvine “there was no place else to go” for graduate studies.
Working with materials scientist Anne M. Mayes and chemical engineering faculty such as Linda G. Griffith, now director of the Biotechnology Process Engineering Center, Irvine became interested in polymers for medical applications. He eventually focused on immunotherapy, an area “bioengineers had not looked at very closely yet.” Immunotherapy turned out to encompass a mother lode of potential applications; but before Irvine could mine them, he decided he had to learn as much as he could about immunology. After earning a Ph.D. in 2000, he spent two years with Mark M. Davis at Stanford University in the Department of Microbiology & Immunology studying basic mechanisms of T-cell activation.
Irvine cautioned that immunotherapy will not be a silver bullet. Cures for diseases such as cancer and HIV will most likely involve the multi-pronged approach of boosting the immune system, delivering targeted new drugs, and manipulating complex molecular mechanisms. “To meet our goals, engineering must be married to an in-depth appreciation for the biology behind these processes,” he says. No one knows better than Irvine that the magic is in the mix.