University of California, Los Angeles (UCLA) scientists have successfully completed a proof-of-principle experiment in mice that shows that blood cells can be re-engineered to become melanoma fighting immune cells.
Senior author on this study, Jerome Zack, who is also 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, noted that genetic engineering techniques can remodel the blood cells of the mouse so that they form cancer-killing T-cells that seek out the tumor and destroy it. Zack stated: “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. We found with this study that they do work in a human model to fight cancer, and it’s a pretty exciting finding.”
White blood cells come in several different varieties, but one group of white blood cells is the “lymphocytes,” which play an exceedingly central role in adaptive immunity. There are two main types of lymphocytes; B-lymphocytes, also known as B-cells and T lymphocytes or T-cells. T-cells receive their name from an organ that sits over the top part of the heart called the thymus. Once T-cells are born, they migrate to the thymus where they undergo a complex maturation process. Once they are released from the thymus into the peripheral circulation, they are ready to serve the immune system. T-cells differ from B-cells in that they possess a surface protein called the “T-cell receptor.” The T-cell receptor recognized foreign substances or “antigens” that are bound to the surfaces of cells. When the T-cell binds to this antigen, it becomes activated and begins to divide and initiates the formation of an immune response against this antigen.
In this experiment, Zack and his co-workers used a T-cell receptor that they had isolated from a cancer patient. This particular T-cell receptor recognized an antigen that is specific to melanomas. The UCLA group then used genetic engineering techniques to place the T-cell receptor gene into the blood-making stem cells in the bone marrow of laboratory mice. After re-introducing these engineered blood-making stem cells into the experimental mice. Next, Zack and his colleagues transplanted a small piece of human thymus into the experimental mice. This gave the mice a place to allow the newly made T-cells to mature.
After approximately six weeks, engineered blood stem cells had formed a large population of mature, melanoma-specific T-cells that were able to target the particular cancer cells. To demonstrate this, the experimental mice were then implanted with two types of melanoma, one that expressed the antigen complex recognized by the T-cell receptor introduced into the bone marrow stem cells, and another tumor that did not. The engineered cells specifically went after the melanoma that expressed the particular antigen, but they left the other tumor alone. Of the nine nude mice used in this study, four animals showed complete elimination of the antigen-expressing melanomas, and the other five showed a marked decrease in the size of the tumors. The immune response against the tumors was determined 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.
Zach noted: “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 has the advantage of engineering only a few cells that can produce a veritable army of cancer-fighting T-cells. Furthermore, these cells can exist in the circulating blood in low numbers, but if they detect the melanoma antigen, they can replicate and expand their numbers quickly and home to the tumor where they will fight it. Other advantages of this strategy are that the function of the engineered T-cells is not long-lasting in most cases. More engineered T-cells ultimately are needed to sustain a response, but some of these cells will probably become “memory cells.” Memory cells are inactive cells that remember the infection they recently fought, but can be reactivated if they encounter the antigen once again. This suggests that “fresh” cancer-killing cells could be easily generated when needed, perhaps protecting against cancer recurrence later.
The team would like to test this approach in clinical trials. One possible approach would be to engineer both the circulating 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 also said that he hopes that this technique could adapted for protocols the battle other cancers like breast and prostate cancers.