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Kara Vonasek, Spectrum Science
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Aislinn Raedy, American Society of Hematology
202-776-0544

RECRUITMENT OF IMMUNE RESPONSE IN TREATMENT OF LEUKEMIA

(SAN DIEGO, December 5, 2004) – Leukemia, a malignant disorder usually of white blood cells, originates in the bone marrow but quickly spreads to the blood and many organs. In a patient who has leukemia, young and dysfunctional blood cells divide at an uncontrollable rate, and do not mature and die, thus producing an enormous number of leukemic cells that invade organs and impair their function. Normally white blood cells fight infection, and when their function is impaired, death usually from infection eventually follows. Because of its complexity and varying courses in each patient, the development of new and effective treatments has been challenging for scientists.

Researchers presented new findings on promising “molecular targeting” therapies at the 46th Annual Meeting of the American Society of Hematology, offering more hope for developing effective immunotherapy to treat this deadly disease.

“Recent advances have identified the mechanisms that turn on and off the various types of hematologic cancers. We are optimistic that they may develop better treatment options for patients with leukemia,” said Richard Larson, M.D., Professor of Medicine and Director of the Hematologic Malignancies Clinical Research Program at the University of Chicago.

Vaccination with the PR1 Leukemia-Associated Antigen Can Induce Complete Remission in Patients with Myeloid Leukemia [Abstract 259]

Vaccines made from peptides that are found on the surface of leukemia cells may make the body gnerate an immune response and kill cancer cells. Recently, studies have shown promise for the PR1 peptide vaccine, a nine amino acid HLA-A2 restricted peptide derived from proteinase 3. A team of researchers from The University of Texas M.D. Anderson Cancer Center presented data from their study of myeloid leukemia patients, showing complete molecular remissions in some, which significantly improved progression-free survival. According to the researchers, this is the first study to show complete molecular remission induced by peptide vaccination.

A total of 35 patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS) were enrolled in the study and treated with the PR1 peptide and 75 mg of GM-CSF (granulocyte-macrophage colony-stimulating factor, which helps bone marrow produce new white blood cells). Patients were randomized into three treatment groups to receive a 0.25mg, 0.50mg, or 1.0mg dose of PR1 every three weeks for a total of three injections.

Each patient was injected with a vaccine made from the PR1 peptide, which is a small part of a protein. An immune response to this particular peptide has been seen in leukemia patients who were in remission. Additionally, each patient was injected with hematopoietic growth factors that work by encouraging the bone marrow to produce more white blood cells, which are essential for fighting infection. Patients were treated at a median of 26 months from the time of their diagnosis. Follow-up ranged from one to four years. Clinical responses were assessed by bone marrow biopsy before entering the study and three weeks after the final vaccination.

Immune responses were elicited in 60 percent of the evaluated patients, and, of those, 33 percent survived four years or longer. Progression-free survival for patients with or without immune responses was 6.4 months compared to 2.4 months, respectively.

The data demonstrated both an immunological and clinical response in patients with refractory and relapsed myeloid leukemia, and more importantly, patients with immune responses to PR1 had significantly improved survival rates. However, further study of immunization strategies in the treatment of leukemia is warranted.

Acute myeloid leukemia develops when there is an accumulation of immature cells in the bone marrow. The disease progresses quickly and occurs in all ages, although it is the most common type of acute leukemia in adults. CML, a more chronic and indolent disorder, is also characterized by replacement of the bone marrow but with less immature cells. MDS is a malignant bone marrow disorder characterized by the production of too few functional blood cells, which typically affects adults over the age of 60. Bleeding and infection are the causes of death for a majority of these patients, and the survival time, depending on the severity of their disorder, is typically only about six months to a few years.

Successful Remission of Poor Prognosis AML after Adoptive Transfer and In Vivo Expansion of Human Haploidentical NK Cells [Abstract 260]

Researchers at the University of Minnesota Cancer Center have successfully demonstrated that haploidentical natural killer (NK) cells can persist and survive when transplanted into patients. The researchers reported that their findings indicate that NK cells may have a role in the treatment of acute myeloid leukemia (AML) when used alone or as an adjunct therapy to hematopoietic (formation of blood cells) cell transplantation (HCT). AML is a highly fatal cancer of the bone marrow that has become resistant to standard treatment with chemotherapy.

NK cells are a part of the body’s immune system and play an important role in defending the body against infection and against some cancers, particularly leukemia. Patients with leukemia often have low NK cell activity. In patients with AML, the NK cells have lost most of their natural ability to fight the aggressive cancer cells.

The research team had previously demonstrated that autologous (derived from the same individual) NK cell therapy after HCT is safe, but does not provide an anti-tumor effect. In this study the team set out to determine if allogeneic (from a different individual) NK cell infusions could have an anti-tumor effect by comparing treatment of 19 AML patients who had poor prognosis to a control group of eight renal carcinoma patients. The renal carcinoma patients received a low intensity outpatient immune suppressive regimen containing fludarabine (Flu), a chemotherapy agent. The AML patients received a higher intensity inpatient regimen of high dose chemotherapy of cyclophosphamide and Flu (Hi-Cy/Flu). In addition to NK cell therapy and chemotherapy, all patients received Interleukin-2 (IL-2), an immune stimulant, administered subcutaneously. IL-2 is a protein substance naturally produced by the body to stimulate natural killer cells and other cells to do their job of fighting infections and cancer. In patients with AML, the cancer may suppress the ability of IL-2 to optimally stimulate the patient’s own NK cells.

The results suggest that expansion of NK cells is required to achieve an anti-tumor effect. There were no responses seen in the renal carcinoma patients. In marked contrast, however, the NK cells thrived in some patients for more than 28 days, and five of 19 AML patients achieved remission.

The study also demonstrated the role of IL-15 (a potent T-cell growth factor that is produced by a wide variety of cells and tissues) in promoting NK cell expansion, suggesting that Hi-Cy/Flu therapy allows for the expansion of allogeneic NK cells in patients, in part through increased secretion of IL-15. Renal cell patients showed only a slight increase in IL-15 after several days compared to the AML patients, who had significant increases in plasma IL-15 levels after Hi-Cy/Flu therapy. The IL-15 appeared before the haploidentical cell infusions and was sustained for several weeks.

“Admittedly we need to do more research, but we believe that we may have found another option, opened another door to potentially broaden our treatment capabilities of AML, and give more hope to some patients who have been told there was nothing more that could be done for them,” said Jeffrey Miller, M.D., professor of medicine at the University of Minnesota Medical School, leader of The Cancer Center’s Blood and Marrow Transplant Program, and lead investigator of the study. “We are encouraged by our findings. Now we have data indicating that haploidentical natural killer cells have a role in the treatment of AML, whether used alone or in combination with a bone marrow transplant.”

AML is the most common acute leukemia. In people over 65 years of age, AML has increased approximately 10 percent in the last 25 years. Of the nearly 12,000 people who will be diagnosed this year with AML, about 90 percent will be adults aged 65 and older. Approximately 8,870 people with AML will die this year.

The American Society of Hematology is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

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