Antigen-targeted tumors on right disappeared; control tumors on left remained. Image: UCLA |
Researchers from University of California, Los
Angeles’ cancer and stem cell centers have demonstrated for the first time that
blood stem cells can be engineered to create cancer-killing T-cells that seek
out and attack a human melanoma. The researchers believe the approach could be
useful in about 40% of Caucasians with this malignancy.
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, says 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.
“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 in the early online edition
of the 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, says Dimitrios
N. Vatakis, the study’s first author and an assistant researcher in Zack’s laboratory.
“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 says. “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
says.
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 says—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 says.
This approach to immune system engineering
has intriguing implications, Zack says. 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 says he hopes this engineered immunity
approach will translate to other cancers as well, including breast and prostate
cancers.