Masonic Cancer Center of the University of Minnesota
Public and Patients
- About Us
- Cancer Information
- Clinical Trials
- Events & Outreach
- Make a Gift
- News & Feature Stories
- Survivorship
Researchers and Staff
Transplant Biology & Therapy Research Program
Immunotherapy
- Immune-Based Therapeutic Research
- T-cells
- Interleukin-2 and Natural Killer Cells
- Dendridic Cells
- Vaccines
- Augmentation of the Graft-Versus Leukemia Response by Adoptive Immunotherapy After Transplantaion
Immune-Based Therapeutic Research
Despite tremendous progress in chemotherapy and bone marrow transplantation, cancer-free survival is not achieved in every patient. New approaches are needed to boost cure rates, especially for patients at the highest risk for disease recurrence. Such new therapies ideally would have a lower incidence of side effects, as well. One such approach now being investigated at the University of Minnesota involves harnessing the body's natural immune system to kill cancer cells. Recent advances in our understanding of how the immune system functions, and specifically on how cancer cells escape the body's defenses, allow scientists to fashion immune-based cancer-fighting strategies with a powerful anti-tumor effect.
Past research has shown us that cancer cells initially escape destruction because the cancer cells themselves are capable of disarming the immune system. Our research laboratories, along with others, are finding new ways to reset the immune system to kill cancer cells.
How does this work?
The blood is composed of various cell types, which include T-cells and natural killer cells that can kill cancer cells; and dendritic cells (or helper cells) that can recognize the cancer cells as being abnormal.
T-cells
When a patient receives a blood or bone marrow transplant, the donor's blood products bring along with them a brand-new immune system, including T-lymphocytes capable of attacking any residual cancer cells left in the patient. These T-cells also provide a defense against infection, a risk to be feared while the patient's immune system is being rebuilt.
The down side is that the new, post-transplant immune response can also "fight against" the patient's original cells, a response known as graft-versus-host disease, or GVHD. If the immune response can be balanced and refined to mobile defense against infection, while at the same time preventing GVHD, the T-cells can go to work against the cancer instead of the patient.
Research is under way, both in the laboratory and in clinical practice with patients, to use both patient and donor blood cells to do just that.
By selecting subsets of cells using specialized centrifuges, it is possible to "add back" T-lymphocytes after transplantation to enhance what is called the "graft vs. tumor" effect against leukemia, for example.
This type of immune-cell "add back" is an example of what is called graft engineering, a promising approach to the treatment of certain kinds of cancer. Currently, formal clinical trials are testing the value of engineered grafts versus transplantation of whole donor bone marrow.
The desired result is a quick engraftment of new cells, potent anticancer effect, and a prompt recovery of defense against infection with minimal GVHD.
Interleukin-2 and Natural Killer Cells
During the past 10 years, investigators have infused interleukin-2, or cytokine, a protein naturally made by the body's immune system, to boost the cancer-killing abilities of certain specialized immune system cells called "natural killer" or NK cells.
Patients were injected with doses of interleukin-2 immunotherapy after transplant. Cells from the bloodstream are removed, treated with high doses of interleukin-2 overnight, and given back to the patient the following day. Although immune activation is safely achieved, we believe that this strategy will not be enough to prevent cancer relapse. The future of the immunotherapy is to target immune cells specifically to tumors and to overcome inhibitory effects of the immune system.
One way to target the immune system is to combine IL-2 with other proteins, called monoclonal antibodies, which are also infused, to attach themselves to tumor cells and make them an easier target for destruction. This strategy is currently being tested in breast cancer. The Phase I trial using this approach is complete and a Phase II trial is planned for later this year.
The last approach to increase the effectiveness of natural killer cells is by infusing them from a relative (i.e. parent, child or sibling). Although we can increase the number and activity of natural killer cells in the blood by giving IL-2 alone, we still think that a patient's own natural killer cells may not be adequate to fight cancer effectively. There are several reasons why this may be true. First, natural killer cells may themselves be weakened by the cancer and unable to fight effectively. Second, natural killer cells may have a protective mechanism that prevents them from acting against cancer cells. In either case, we may be able to get around these problems by giving natural killer cells from a normal, related donor along with daily administration of IL-2. This clinical trial was opened in April 2001 and we hope to learn more about this exciting therapy in the near future.
Dendritic Cells
Cancer investigators have recently learned how to grow, in culture, the other cell type critical to the immune response: the dendritic cell.
In clinical studies it has been shown that feeding parts of malignant cells to their own dendritic cells – and then giving these dendritic cells back to the patient – stimulates a potent immune response, resulting in a significant decrease in the number of cancer cells present.
The identification of a protein that increases the number of dendritic cells present has made another approach to therapy possible. Studies have shown that the infusion of this protein can increase the number of dendritic cells in circulation, suggesting that it may be possible to stimulate further immune-mediated destruction of cancer cells. We have initiated a clinical trial in patients after autologous transplant using the dendritic cell stimulating protein Flt3L. In the future, fusion of dendritic cells with leukemia cells may make effective cancer vaccines.
Vaccines
Injecting some component of the tumor with immune-stimulating hormones can act the same way that a vaccine acts, mobilizing the patient's defenses against a specific type of cancer.
For example, in cases of relapsed alveolar rhabdomyosarcoma, PNET and Ewing's sarcoma, tumors result in the production of a unique, tumor-specific fusion peptide that is not present in other cells of the patient. The patient's antigen-presenting cells are then incubated with a synthetic version of this tumor-specific fusion peptide to produce a tumor vaccine that is used to stimulate host T-cells to eradicate these specific cancers.
After the incubation procedure and testing of the vaccine – a process that takes several days – the patient returns to the hospital for readministration of the tumor-specific vaccine and Interleukin-2 infusions to stimulate an antitumor T-cell response. This cycle is repeated at six-week intervals for a total of three cycles, lasting approximately four to six months.
With these and other immune-mediated therapies, we are clearly on the frontier of new and exciting research that can exploit the immune systems of both the cancer patient and the transplant donor as close allies in the fight against cancer.
Augmentation of the Graft-Versus-Leukemia Response by Adoptive Immunotherapy After Transplantation
Donor lymphocyte infusions have been shown to be capable of inducing into remission patients with chronic and to a lesser extent acute leukemias. Long-term remissions have been reported in patients with chronic myelogenous leukemias, while short-term remissions have been primarily observed in patients with acute leukemias. More effective and longer lasting remissions could potentially be induced if adoptive immunotherapy is given prophylactically or if anti-leukemia specific immune effectors are used.
We will be applying the principles of adoptive immunotherapy initially to autologous and later allogeneic settings. We will take two approaches. In the first, dendritic cells from recipients will be grown, exposed to tumor cell extracts, and then used for adoptive immunotherapy for the prevention or treatment of relapse in autologous BMT recipients.
In a second approach, we will generate cytotoxic T-cells from donor leukocytes by culturing donor T cells with tumor primed dendritic cells. For allogeneic BMT recipients, if graft-versus-host disease is observed, we will first reduce T cells reactivity to host tissues and then restimulate their attack on the tumor cells.