With Pike Donation, Dr. Dean Lee to Start Clinical Phase 1 Trial

The Taylor Trudeau Cycle for Life Foundation has donated $250,000 to Dr. Dean Lee at the University of Texas MD Anderson Cancer Center.  This donation has allowed Dr. Dean Lee to start a clinical phase 1 trial using his cutting edge new method of inserting NK cells into a patient on chemotherapy.

For almost 40 years we have known that natural killer cells (NK cells), one of the specialized white blood cells of our immune system, can recognize and kill many types of cancer, including acute myelogenous leukemia (AML). However, NK cells in patients with cancer are often low in number and don’t function well. Although NK cells work well in the lab, it was difficult to show that NK cells were important in patients. In the last 10 years, however, we have found that NK cell number and function predicts survival after transplant, that NK cell types can predict responses to chemotherapy and antibody therapy, and that inheritance patterns of NK cell genes can predict the development of cancer. Unfortunately, almost all chemotherapy agents are highly toxic to NK cells, resulting in a greater reduction in their natural ability to help fight the cancer. NK cells also play an important role against many fungal and viral infections that are common in cancer patients.

In the mid 90’s, researchers finally started to understand how NK cells work, but it wasn’t until the early 2000’s that there were efficient methods to purify large numbers of clinical grade NK cells from donors. At this time, the first clinical trials of infusing NK cells into patients began. Unfortunately, this approach was expensive (~$10,000 just to collect and deliver the cells), difficult for the donor (requires harvesting of the cells from the donor by apheresis, similar to being a platelet or plasma donor), and only yielded enough cells to deliver a single, one-time dose of about 500 million cells. Unfortunately, unlike T cells, we did not yet have a way to grow large numbers of NK cells in the laboratory. Because the cell numbers were low, investigators had to give patients toxic doses of chemotherapy, radiation, and cytokines in order to push the NK cells to grow to large numbers in the patient. The chemotherapy, radiation, and cytokines were more toxic to the patient than the NK cells were. Even so, this approach proved effective, and it allowed us to learn more about how NK cells work and to see that higher numbers of cells were better.

One of the things learned over the last 10 years is that NK cells are more active against leukemia when certain features are mismatched between the donor and the recipient. NK cells are like immigration agents at the airport- they screen large numbers of cells every day, checking to make sure each cell carries the proper passport and doesn’t look dangerous. The passports in this analogy are HLA molecules, the proteins that we try to “match” for bone marrow transplants. NK cells are triggered into action by finding cells that don’t carry the proper passport or have evidence of damage or stress (danger). They balance these two signals much like the border patrol agent would- easily identifying a bad actor with no passport trying to smuggle in weapons, but finding it harder to pin down the intentions of a sweet 70-year-old grandma who lost her passport, or a young man with gang tattoos who has a valid passport. When we look for an NK cell donor, we try to find a family member who has a different type of passport (HLA) than the patient (i.e., mismatch). When we transfer the NK cells from this donor to the patient, many of the transferred NK cells have grown up learning to identify a passport in the donor that they now find missing in the patient. This results in the NK cells being very sensitive to even small levels of “danger” on the leukemia cells, resulting in greater death of the leukemia cells.

Two years ago I developed a method to grow large numbers of highly active NK cells in the laboratory, robust enough to allow repeated large doses of NK cells in clinical trials. This method allows us to take a simple blood draw from the donor (not apheresis), and in three weeks we can expand the NK cells to 30,000 times their original number for a total cell dose of 100’s of billions of NK cells, at least 200-300 times as many NK cells as are collected by apheresis. We spent the last two years developing this laboratory method into a large-scale procedure that grows clinical-grade NK cells that are compliant with FDA rules for use in humans.

Next, we needed to decide on the best possible setting to test these potent cancer-killers. First, I decided to go after AML because it is the disease for which we have the best evidence that NK cells are active. Then we needed to decide the setting in which we would deliver the NK cells. We could copy the studies that used high-dose chemotherapy, radiation, and cytokines, but the combination used in these studies is not very active against AML. MD Anderson had previously developed a combination therapy for AML called FLAG (FLudarabine, Ara-c, and G-CSF), and there were several reasons that this combination might combine well with giving NK cells.

We have now obtained approval from the FDA and from the MD Anderson review board to initiate a first-in-human study to test whether these NK cells can be safely delivered in combination with FLAG chemotherapy. This clinical study will be for patients with relapsed or resistant AML. NK cells from a family member selected to have the best possible mismatch will be expanded and delivered back to the patient three times a week for two weeks after receiving the FLAG chemotherapy. The goals of the study are to show that this approach is feasible, to determine the highest safe dose of NK cells that can be manufactured and infused, and to study the persistence and function of the infused NK cells. This will be a very short study, as we will only be giving one cycle of FLAG and six doses of NK cells, and then will follow the patients for up to 8 weeks to see how they respond. The goal will be to get patients back into remission so that they can go on to have definitive therapy such as a transplant.

This will be the first time ever that NK cells expanded with this new method will be infused into human patients. We expect that we will be able to infuse more NK cells in these patients than have ever been given before, perhaps even hundreds of times as many. Because smaller numbers of cells have already shown evidence of working in patients with resistant and relapsed AML, we expect that this approach will be even better, allowing a greater number of patients to get back into remission.

If it is successful, this approach for making large numbers of NK cells may apply to many other settings and many other types of cancer. There are already five more clinical trials under development to test these expanded NK cells in combination with stem cell transplant or antibodies, for leukemia, solid tumors, or lymphomas. One might even imagine a day when the first thing you do after being diagnosed with cancer is donate some blood to have lots of your own NK cells grown up. These could then be given back to you after every cycle of chemotherapy in order to increase the tumor kill of each cycle and help prevent infections between cycles.

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