Our researchers are changing the way cancer is treated worldwide
For many years, scientists have dreamed of using the body’s own immune defenses to fight cancer. Over the past five years, remarkable progress has been made in our basic understanding of the immune system. Using this new knowledge, researchers at the University of Minnesota are designing new treatment approaches to mobilize the body’s immune defenses to defeat cancer.
Funding from the Children’s Cancer Research Fund has been crucial in developing new treatment approaches and moving them rapidly into the clinical setting.
Current developments include:
Using a natural protein to decrease leukemia recurrence
In experiments using mice with leukemia, the University of Minnesota laboratory is testing the effectiveness of a protein known as Flt3 ligand in stimulating immune response. The body produces this protein naturally. In studies, Flt3 ligand was effective in reducing the rate of recurrence of leukemia in mice that had received a bone marrow transplant.
Building on this success, Drs. Jeffrey Miller and Bruce Blazar are conducting trials of Flt3 ligand among cancer patients at the University of Minnesota. They have been able to show that this protein does stimulate the immune system for patients receiving autologous transplantation. (A procedure in which a patient’s own bone marrow is harvested and then “re-inserted” after the patient undergoes a conditioning regimen to ensure that he or she is free of disease.) These studies were the first to test Flt3 ligand protein administration after transplant.
Developing a cancer vaccine
The immune system produces many different types of cells that fight disease. One type of immune cell is the dendritic cell. Dendritic cells are capable of surrounding and incorporating certain proteins from leukemia cells. Once this happens, the dendritic cells can act like a vaccine against the leukemia cells. In preliminary studies, these dendritic cell vaccines reduced the recurrence rate of leukemia in mice.
In addition, Dr. Wei Chen’s lab has shown that dendritic cells can be fused to leukemia cells by using an electric current. In Dr. Chen’s tests on non-transplanted mice, these “fusion vaccines” are showing great promise in preventing leukemia recurrence. Researchers hope to begin trials in leukemia patients in the near future.
Using DNA to stimulate the immune system of lymphoma patients
In pre-clinical studies supported in part by Children’s Cancer Research Fund, the University of Minnesota has been testing an approach that uses pieces of DNA to stimulate the immune system. These pieces of DNA contain sequences called CpGs that can be synthesized. Researchers have found that CpG DNA successfully decreases leukemia recurrence in both transplanted and non-transplanted mice.
Based in part on these studies, researchers are collaborating with colleagues at the University of Iowa to examine the effect of this technique on the immune response of patients with lymphoma. Drs. Dan Weisdorf and Bruce Peterson lead the Lymphoma Study in collaboration with Dr. Blazar.
Using a natural protein to inhibit the side-effects of transplant
Before receiving a bone marrow transplant, patients must first undergo a conditioning regimen that includes high doses of chemotherapy and radiation therapy. The conditioning regimen is designed to wipe out diseased cells so that the healthy transplanted cells can take over. Unfortunately, transplant conditioning regimens produce serious side effects. They can damage organs and injure the immune system itself.
In laboratory studies, researchers have been working with a protein that is naturally produced by the body, called keratinocyte growth factor (KGF). Researchers have found that KGF administered before the conditioning regimen inhibits side effects, including those resulting in organ system and immune system injuries.
The KGF lab studies were funded in part by Children’s Cancer Research Fund. They have provided a foundation for clinical trials that are now being conducting among transplant patients. One of these studies is testing the effectiveness of KGF in patients who receive a sibling donor transplant.
This study is led by Dr. Blazar in collaboration with University of Minnesota physicians Daniel Weisdorf and Margaret MacMillan and investigators at the University of Michigan. Another multi-institutional trial, led by Drs. Blazar and Weisdorf, is testing KGF among patients who receive autologous transplants.
Reducing the amounts of chemotherapy and radiation
Pre-clinical trials funded by Children’s Cancer Research Fund have found that the amounts of chemotherapy and radiation can be reduced if adverse immune effects are decreased.
Our immune system works by identifying material as either “self” or “not self.” It tries to destroy everything it perceives as “not self.” When a patient receives a bone marrow transplant, two different adverse reactions can take place. In one, the transplanted marrow identifies the patient’s body as “not self.” This results in a condition called graft-versus-host disease that can be life threatening. In the other, the patient’s body tries to destroy the transplanted material. This process is called graft rejection. Both reactions can result in a failure of therapy.
Based in part upon this work, clinical trials at the University of Minnesota have begun to test lowered conditioning regimens. These studies are being led by Drs. John Wagner, and Scott Baker in collaboration with Dr. Blazar.
Rebuilding the immune system after bone marrow transplant
The thymus is an organ that is located just above the heart. Hormones produced by this organ stimulate the production of certain infection-fighting cells. Patients undergoing a blood or marrow transplant for treatment of their disease are subjected to multiple rounds of chemotherapy and/or radiation prior to their transplant, and may also suffer from a post-transplant related complication called Graft versus Host Disease, all of which injure the thymus.
With the thymus injured, the body is not at peak performance in educating immune cells to fight off foreign invaders that can cause infection, a complication post transplant that can result in death.
Dr. Bruce Blazar, Professor of Pediatrics in the Division of Hematology-Oncology and Blood and Marrow Transplantation, and investigators in his lab at the Masonic Cancer Center are currently searching for ways to reduce damage done to the thymus pre- and post-transplant or regenerate the thymus more quickly post-transplant, enabling the body’s natural immune system to return to a healthy state.
Super-charging immune cells to kill cancer
Dr. Xianzheng Zhou, Assistant Professor of Pediatrics, Division of Hematology-Oncology and Blood and Marrow Transplantation, has been working diligently for the past three years on development of a new and more efficient way to treat leukemia. He is driven by his desire to see his innovative, focused efforts in the lab move forward into clinical trials with patients.
Zhou’s research involves using the Sleeping Beauty transposon system technology, initially developed at the University of Minnesota in 1997, to engineer human T-cells that seek out and destroy specific leukemia cells.
T-cells are a type of immune cells that play a central role in cellular immunity and that produce proteins which enable the body’s cells to communicate with each other to fight foreign invaders. Leukemia and lymphoma occurs when T-cells are not able to effectively kill the cancer cells, which may occur for various reasons; however, Zhou’s research hopes to change that.
Using umbilical cord blood (UCB), Zhou and his colleagues isolate T-cells from the UCB unit. The Sleeping Beauty transposon system is a molecular biology tool that allows researchers to insert small segments of a specific DNA sequence into the UCB derived T-cells, which enhances their ability to specifically recognize and kill leukemia and lymphoma cells.
This “smart therapy” could have the potential to kill only the cancer cells while minimizing the effects on other parts of the patient’s body.