In a development that could affect 40 percent of caucasians with the malignancy, researchers have demonstrated that blood stem cells can be engineered to create cancer-killing T-cells that seek out and attack human melanoma.
"Done in mouse models, this 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-
"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?" said Zack. "We found with this study that they do work in a human model to fight cancer, and it's a pretty exciting finding."
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.
"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," said Dimitrios N. Vatakis an assistant researcher in Zack's lab. "These cells can exist in the periphery of the blood, and if they detect the melanoma antigen, they can replicate to fight the cancer."
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.
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," said Zack, "an impressive finding."
This approach to immune system engineering has intriguing implications. 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.
Adapted from the UCLA announcement.
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