Researchers from UCLA’s 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 percent 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.
Antigen-targeted tumors on right dis-appeared; control tumors on left remained.
PNAS – Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells
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.
The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201–restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific naïve CD8+ T-cell population. Following tumor challenge, these transgenic CD8+ T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non–HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.
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