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Research Profile: Josh Leonard Programs Cells to Target Tumors

A major challenge in the treatment of cancer is that tumors can evade and co-opt the immune response to further their own survival.

But what if scientists and engineers could reprogram immune cells to go directly to the site of the tumor and reverse the immune dysfunction that the tumor causes?

"This could allow the natural immune response, which would otherwise be impaired, to take over and clear the cancer," says Josh Leonard, assistant professor of chemical and biological engineering. And that is exactly what Leonard and his research group are trying to do. Fresh from a postdoctoral fellowship at the Experimental Immunology Branch of the National Cancer Institute, Leonard is now building a research program at the McCormick School of Engineering and Applied Science at Northwestern University that applies his expertise in immunology, gene therapy, and protein engineering to meet pressing medical needs.

"We're using genetic engineering to custom-design immune responses," he says. In this case, Leonard is working to modify dendritic cells and macrophages — cells that can regulate the overall immune response. By introducing new genetic "programs" into these cells, researchers can change the way cells gather information and respond to their environment. For example, engineered protein-based sensors can be built to allow a cell to detect molecules produced by tumors. These sensors can be coupled through signaling networks to genes encoding immune stimulating proteins, such as particular cytokines. Thus, when the engineered cell encounters a tumor, it responds by producing cytokines that recruit and activate the body's immune defenses against the tumor.

In this way, Leonard looks at cells as devices that can process information and perform useful functions and that eventually can be programmed and designed. By changing the way that a cell interprets inputs and regulates outputs, Leonard hopes to build cells that function in ways that natural cells do not — for example, by marshalling a potent immune response in the normally immune-suppressive microenvironment surrounding a tumor.

These efforts to construct sophisticated cellular "software" build upon developments in synthetic biology — an emerging discipline that seeks to streamline the engineering of biological systems for useful purposes.

"As engineers, we look at these cellular networks as systems that can be understood and modulated quantitatively," Leonard says. "We use computational modeling to help us determine how cells make decisions in these environments and translate this insight into strategies for reprogramming. By understanding and modifying the cellular control structure, we can customize and tune the ways these cells will function in different environments."

As an engineer, Leonard conducts his research with multiple end applications in mind. In addition to the treatment of cancer, such technology could be applied to the treatment of chronic infectious diseases, in which impaired immune function is also problematic. This technology could also be helpful in areas such as transplant tolerance and tissue engineering, where the goal is to program the body's immune system to accept the new organ or tissue, rather than reject it through immunological attack.

In each case, because Leonard's strategy involves a targeted manipulation of the local immune response, at either the site of the tumor or in the transplanted tissue, this approach may be inherently safer and more well-tolerated by patients than treatments that affect the entire immune system.

"We also need this technology platform be modifiable," he says. "Cancer is a term that describes hundreds of different diseases, and different cancers will require different therapeutic strategies. One important aspect of our approach is that we're not limiting our efforts to targeting the unique proteins, or antigens, that might be expressed on a particular type of cancer. Instead, our strategy is based on the theory that if there is an established tumor, then it must be modifying the local immune response in order to survive. We target the impaired local immune response."

Leonard's approach could complement other ongoing efforts to develop immune therapies such as cancer vaccines. Leonard hopes that this work may help to realize the promise of personalized therapy for cancer.

Through these efforts, Leonard is also seeking to answer some fundamental scientific questions about the complex and dynamic interaction between the immune system and cancer.

"Each immune response consists of the coordinated actions of a network of many different cells sharing many different interactions," he says. "In the case of cancer, these networks become dysfunctional. We need to better understand not only how individual cells function in these environments, but also how all these pieces fit together in order to initiate and maintain these pathological states. Then we will better understand how to alter or repair the network, which should be useful for treating a wide variety of diseases."