Tough cancer treatments can severely weaken the body’s natural ability to attack cancer cells. To improve immune recovery and function in patients who have undergone these treatments, especially those who may later receive a stem cell transplant, researchers are turning to natural killer cells that have been expanded in the laboratory.
Rationale and development
Treatment of high-risk hematological cancers such as acute myelogenous leukemia and chronic lymphocytic leukemia typically requires myeloablative chemotherapy and/or radiation therapy usually followed by hematopoietic stem cell transplantation. Unfortunately, the myeloablative regimens typically cause patients to become immunocompromised at a time when they would most benefit from a robust immune response to their disease.
“The very cells we have in our body that are able to kill our cancer, we wipe out every time we give cytotoxic therapy,” said Dean Lee, M.D., Ph.D., an associate professor in the Division of Pediatrics at The University of Texas MD Anderson Cancer Center. And the allogeneic stem cell transplants often used to restore the immune system after myeloablative treatment can take a long time to regenerate immune cells and can lead to graft-versus-host disease, which itself can threaten survival.
A promising approach for boosting patients’ immune function is the use of natural killer cells, which have an innate, selective cytotoxicity against all cancerous and precancerous cells. Thus, Dr. Lee and others reason that treatment with natural killer cells—alone or as a bridge to autologous or allogeneic stem cell transplantation—following chemotherapy could improve the immunologic response against cancer and protect against some of the adverse effects of stem cell transplantation.
“We’ve been interested in how immunotherapy with natural killer cells after chemotherapy can be a possible middle ground between chemotherapy alone and chemotherapy followed by an allogeneic transplant in terms of adverse effects,” said Nina Shah, M.D., an assistant professor in the Department of Stem Cell Transplantation and Cellular Therapy.
The great majority of clinical trials that have tested natural killer cell therapy so far have derived the natural killer cells from apheresis, in which white blood cells are removed from a donor’s blood, the T cells are removed from the pool of white blood cells, and the remaining white blood cells are given as treatment. For some patients, including some with acute myelogenous leukemia, the results of this treatment have been promising. However, the number of cells that can be obtained by this approach is limited, and such infusions are relatively impure, containing only 20%–30% natural killer cells.
A recent breakthrough has enabled researchers to achieve higher concentrations of natural killer cells for patient infusions. Dr. Lee said, “Our laboratory genetically engineered a feeder cell with all the right signals that a natural killer cell needs to proliferate. Now we can grow billions of natural killer cells from a vial of blood in a couple weeks.”
The method for expanding natural killer cells ex vivo developed by Dr. Lee’s laboratory uses artificial antigen-presenting cells expressing membrane-bound interleukin-21. This method has yielded greater expansions of natural killer cells after 3 weeks of culture than any other method so far, with a final concentration of natural killer cells greater than 99%. Using this expansion technique, MD Anderson researchers have launched a series of phase I clinical trials testing natural killer cells for patients with hematological cancers, brain cancers, and other solid tumors.
In addition to its potential selective effects against cancer, natural killer cell therapy would likely be easier to obtain than other immune cell therapies. In contrast to T cell therapy, for which T cells that recognize the specific tumor must be selected or engineered, natural killer cells already have the receptors for recognizing cancerous cells. “We don’t have to individually select just the right natural killer cell for every single patient,” Dr. Lee said. Furthermore, the evidence so far suggests that natural killer cells can treat all kinds of cancer. Thus, natural killer cells may not need to be produced in different ways for different types of cancer and would likely be less costly than custom-made cell therapies.
In fact, Dr. Lee said that natural killer cells probably could be obtained from ordinary blood donations. “Right now, blood banks discard the white blood cells from the typical pint of blood that is donated,” he said. “But we’ve figured out that you can take those white blood cells and use them to grow large numbers of natural killer cells. What we routinely throw away may actually be an important clinical product; we just have to rescue and process it.”
If natural killer cells can be obtained and prepared efficiently, then natural killer cell therapy could become readily available to cancer patients. One of the upcoming solid tumor studies will test whether natural killer cells can feasibly be generated from blood bank products as an off-the-shelf product to be stored frozen and ready to thaw and infuse into patients.
Although most of the natural killer cell trials that are starting up at MD Anderson derive those cells from peripheral blood, Dr. Shah has adapted the approach to grow natural killer cells obtained from umbilical cord blood. In her research, Dr. Shah made use of the large cord blood bank at MD Anderson headed by Elizabeth Shpall, M.D. “An advantage of using banked cord blood is that it’s an already collected unit sitting in a freezer, so nobody has to go through the procedure of drawing blood,” Dr. Shah said.
Furthermore, with the help of the new artificial antigen-presenting cells to expand the cord blood’s natural killer cells, it can take as few as 2 weeks to grow enough cells for use in natural killer cell therapy. “People have expanded natural killer cells from cord blood before,” Dr. Shah said, “but not this quickly or reliably and not in a way that translates to the clinic like we’re able to do.”
Dr. Shah has been leading a phase I trial in which these cord blood–derived natural killer cells are given in combination with high-dose chemotherapy followed by autologous stem cell transplantation to patients with multiple myeloma. The patients thus receive an allogeneic immunotherapy without undergoing an allogeneic stem cell transplant.
Natural killer cells do not need to be matched to the recipient to achieve a therapeutic effect. In fact, certain major histocompatibility complex (MHC) mismatches between donor and recipient result in more effective natural killer cell therapy than do MHC matches. In studies of patients with hematological cancers who received MHC-mismatched bone marrow transplants, certain mismatches predicted better natural killer cell responses and longer survival times. Furthermore, the inheritance of certain genes that affect natural killer cell function varies widely, so it is possible that donors with favorable immunogenetic traits could be tapped as sources of particularly effective natural killer cells.
In addition, natural killer cell therapy could be delivered directly to the tumor site rather than intravenously. In a recently approved trial at MD Anderson, patients with brain cancer will receive infusions of their own expanded natural killer cells into the locations from which their brain tumors have been resected. This trial will test the hypothesis that natural killer cells are able to recognize brain tumors but unable to reach them because of the blood-brain barrier.
Allogeneic natural killer cells, even those expanded using the new artificial antigen-presenting cells, may have limited lifespans after infusion. “We don’t know whether natural killer cells proliferate in the body in response to the tumor the way T cells do,” Dr. Lee said. In leukemia patients who undergo T cell therapy, under the right circumstances the T cells will grow to outnumber the tumor cells, but patients who undergo natural killer cell therapy will likely require multiple infusions or some other means of sustaining the number of cells.
It also is not known how well natural killer cell therapy will be tolerated by recipients, and any patient characteristics that may be contraindications to this treatment have yet to be determined. Although infusions of natural killer cells are unlikely to cause graft-versus-host disease, the allogeneic natural killer cell infusions still could have adverse effects related to their stimulation of the immune system. Such effects might include allergic responses, fever, leaky blood vessels, or low blood pressure; however, these adverse effects have not been seen in any of the natural killer cell therapy trials ongoing at MD Anderson. The upcoming phase I trials at MD Anderson will continue to test patients’ tolerance of this treatment.
Although natural killer cells are associated with fewer adverse effects than allogeneic stem cell transplantation, they also are less specific than T cells, which target particular tumor markers. Engineering natural killer cells to recognize certain tumors may increase the effectiveness of natural killer cell therapy. Dr. Shah’s group is currently studying ways to engineer natural killer cells to target an antigen on myeloma cells.
Another possibility is banking a patient’s own natural killer cells and then re-infusing those cells after chemotherapy. Dr. Lee said, “For a long time we thought that if a patient develops cancer, then the patient’s own natural killer cells must not be very effective, suggesting that natural killer cells from a donor would be better. But now we have reason to believe that the patient’s cells can still be beneficial if given in high enough numbers or delivered to the right location.”
Yet another possibility for natural killer cell therapy is the creation of a product that clinicians can store and use when needed rather than searching for a specific donor or generating an individualized treatment. Because natural killer cells can be derived from existing peripheral blood banks and cord blood banks, expanded to very large numbers relatively quickly, frozen until needed, and then used to treat all kinds of cancer cells, this scenario seems within reach.
For more information, Dr. Dean Lee at 713-563-5404 or Dr. Nina Shah at 713-794-5745.
OncoLog, February 2015, Volume 60, Issue 2