Done in mouse models, the study serves as the first proof-of-principle that blood stem cells, which make every type of cell found in the blood, can be genetically altered in a living organism to create an army of melanoma-fighting T-cells, said Jerome Zack, the study’s senior author and a scientist with UCLA’s Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.
Antigen-targeted tumors on right dis-appeared; control tumors on left remained.
“We knew from previous studies that we could generate engineered T-cells. But would they work to fight cancer in a relevant model of human disease, such as melanoma?” asked Zack, a professor of medicine and microbiology, immunology and molecular genetics in the UCLA Life Sciences Division. “We found with this study that they do work in a human model to fight cancer, and it’s a pretty exciting finding.”
The study appeared Nov. 28 in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.
Researchers used a T-cell receptor — cloned by other scientists from a cancer patient — that seeks out an antigen expressed by a certain type of melanoma. They then genetically engineered the human blood stem-cells by importing genes for the T-cell receptor into the stem cell nucleus using a viral vehicle. The genes integrate with the cell DNA and are permanently incorporated into the blood stem cells, theoretically enabling them to produce melanoma-fighting cells indefinitely and when needed, said Dimitrios N. Vatakis, the study’s first author and an assistant researcher in Zack’s lab.
“The nice thing about this approach is a few engineered stem cells can turn into an army of T-cells that will respond to the presence of this melanoma antigen,” Vatakis said. “These cells can exist in the periphery of the blood, and if they detect the melanoma antigen, they can replicate to fight the cancer.”
In the study, the engineered blood stem cells were placed into human thymus tissue that had been implanted in the mice, allowing Zack and his team to study the human immune system reaction to melanoma in a living organism. Over about six weeks, the engineered blood stem cells developed into a large population of mature, melanoma-specific T-cells that were able to target the right cancer cells.
The mice were then implanted with two types of melanoma tumors, one that expressed the antigen complex that attracts the engineered T-cells and one that did not. The engineered cells specifically went after the antigen-expressing melanoma, leaving the control tumor alone, Zack said.
The study included nine mice. In four animals, the antigen-expressing melanomas were completely eliminated, while in the other five, these melanomas decreased in size, Zack said — an impressive finding.
Response was assessed not only by measuring physical tumor size but by monitoring the cancer’s metabolic activity using positron emission tomography (PET), which measures how much energy the cancer is “eating” to drive its growth.
“We were very happy to see that four tumors were completely gone and the rest had regressed, both by measuring their size and actually seeing their metabolic activity through PET,” Zack said.
This approach to immune system engineering has intriguing implications, Zack said. T-cells can be engineered to fight disease, but their function is not long-lasting in most cases, and more engineered T-cells ultimately are needed to sustain a response. This new approach engineers the cells that give rise to the T-cells so that “fresh” cancer-killing cells could be generated when needed, perhaps protecting against cancer recurrence later.
Going forward, the team would like to test this approach in clinical trials. One possible approach would be to engineer both the peripheral T-cells and the blood stem cells that give rise to T-cells. The peripheral T-cells would serve as the front-line cancer fighters, while the blood stem cells are creating a second wave of warriors to take up the battle as the front line T-cells are losing function.
Zack said he hopes this engineered immunity approach will translate to other cancers as well, including breast and prostate cancers.
The four-year study was funded in part by the National Institutes of Health, the California Institute for Regenerative Medicine, the Caltech-UCLA Joint Center for Translational Medicine, the UCLA Center for AIDS Research and the UCLA AIDS Institute.
UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.