By the University at Buffalo
One challenge of treating cancer is the propensity of tumors to hide.
The tumor stroma, a matrix of proteins and cells including a thick layer of collagen and collagen-producing cells, acts as a barrier to a promising type of immunotherapy treatment – chimeric antigen receptor (CAR) T-cell therapy.
“Certain types of cancers, such as pancreatic, have thick tumor stroma, making them more resistant to all treatments – chemotherapy, radiation and immunotherapy,” Zhao said. “This is why they are so deadly.”
Zhao now has an opportunity to search for a way through the barriers. The National Cancer Institute (NCI) awarded him and a colleague a five-year, $3 million R01 research grant to study immune cell therapy for solid tumors.
While CAR T-cell therapy has shown promise in the treatment of hematopoietic cancers – ones primarily found in the blood – and has received Federal Drug Administration (FDA) approval, its application to solid tumors, such as those found in the lung, kidney or stomach, has not proven successful. This is primarily because of the stroma that encase tumors, he said.
Zhao, who is the contact principal investigator on the research project, is working with co-principal investigator Richard Koya, M.D., Ph.D., a professor at the University of Chicago Medicine Comprehensive Cancer Center and the department of obstetrics and gynecology.
Koya previously worked at Roswell Park Comprehensive Cancer Center, where Zhao met him. They started a collaboration while Koya was developing an engineered T-cell receptor (TCR) therapy to target ovarian cancer.
“Dr. Koya has been at the forefront of research for T-cell therapy,” Zhao said. “He pioneered a two-pronged engineered TCR therapy that targets a tumor antigen – a type of tumor cell surface marker that the T cells can recognize – while blocking immunosuppressive signaling at the same time.”
Zhao, who in 2013 joined UB’s biomedical engineering department, a joint program of the School of Engineering and Applied Sciences and the Jacobs School of Medicine and Biomedical Sciences, specializes in the organotypic modeling of fibrotic diseases and anti-fibrosis drug development.
“I’ve always been interested in tissue fibrosis, which I consider scars,” he said. “Internal organs all have the potential to develop fibrosis. Tumor stroma, which is serving as a barrier to immunotherapy, is very much a scar.”
While the TCR therapy seems more promising with solid tumors, resistance from the tumor stroma is still a problem. Zhao said he and Koya wanted to study how the stroma affects the T-cell infiltration into the tumor and then produce therapies to dissolve or disrupt the stroma.
Two complementary experimental approaches will be used in this project. Koya will perform his research using animal tumor models, while Zhao will employ a tumor stroma-on-a-chip technology that can model the architecture of a human tumor stroma and its suppressive functions to the therapeutic T cells.
“The tumor stroma-on-a-chip model allows the testing of T-cell therapy in human relevant conditions,” Zhao explained. “These therapies have the potential for improved efficacy in T-cell therapy. Our ultimate goal is to have a combination therapy that can be used for the clinical treatment of solid tumors.”