Reports from Netherlands, Italy and Germany describe recent advances in leukemia research

06-12-2006

Data on leukemia are outlined in reports from Netherlands, Italy and Germany.

Study 1: Constitutively active STAT5b induces cytokine-independent growth of the acute myeloid leukemia-derived MUTZ-3 cell line and accelerates its differentiation into mature dendritic cells.

According to recent research from the Netherlands, "The CD34+ human acute myeloid leukemia-derived cell line MUTZ-3 is dependent on hematopoietic growth factors for its proliferation and is able to differentiate into dendritic cells (DCs) in response to the combination of granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha. This cell line carries human leukocyte antigen (HLA)-A2.1, HLA-A3, and HLA-B44, which cover most of the Caucasian population, and it could therefore be used as an off-the-shelf allogeneic DC-based vaccine."

"Signal transduction and activation of transcription (STAT) 5b is involved in cytokine signal transduction, particularly of cytokines involved in DC precursor growth and differentiation," said Hetty J. Bontkes and colleagues at the Vrije Universiteit Medical Center in Amsterdam. "The constitutively active form of STAT5b induced cytokine-independent growth of MUTZ-3 cells. Furthermore, STAT5b-transduced cells differentiated into mature DCs in three to four days after stimulation with DC differentiation-inducing cytokines, reducing the culture period to obtain mature DO with five days compared with unmodified MUTZ-3-derived mature DC cultures."

"Both DC types expressed DC maturation markers and were equally effective in inducing primary T-cell responses," reported the investigators. "DCs derived from the STAT5b-transduced cells had a more stable mature phenotype after cytokine deprivation, which was reflected in a better performance in functional assays."

The scientists concluded, "These results show that STAT5b-transduced MUTZ-3 can be propagated in cytokine-free medium and rapidly differentiated into functional mature DCs that sustain a mature phenotype over a period of three to five days in the absence of differentiation-inducing cytokines. The simplified propagation and rapid differentiation into mature DCs may facilitate clinical application of this cell line as an allogeneic DC-based vaccine."

Bontkes and associates published their study in the Journal of Immunotherapy (Constitutively active STAT5b induces cytokine-independent growth of the acute myeloid leukemia-derived MUTZ-3 cell line and accelerates its differentiation into mature dendritic cells. J Immunother, 2006;29(2):188-200).

For additional information, contact Hetty J. Bontkes, Department of Pathology, Vrije Universiteit University Medical Center, PO Box 7057, NL-1007 MB Amsterdam, The Netherlands. hj.bontkes@vumc.nl.

Study 2: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was proposed as an anticancer agent in acute myeloid leukemia (AML).

"TRAIL, a cytokine belonging to the TNF (tumor necrosis factor) family, is currently regarded as a potential anti-cancer agent. Nevertheless, several types of cancer cells display a low sensitivity to TRAIL or are completely resistant to this pro-apoptotic cytokine," scientists reported in the International Journal of Molecular Medicine.

"TRAIL signaling is dependent on 4 receptors. Two of them, death receptors 4 and 5 (DR4 and DR5), induce apoptosis, whereas decoy receptors 1 and 2 (DcR1 and DcR2) are unable to evoke cell death upon TRAIL binding. TRAIL resistance may be related to the expression of TRAIL decoy receptors. TRAIL has been proposed as a novel therapeutic agent for the treatment of hematological disorders, including AML. Surprisingly, however, very limited information is available concerning the expression of TRAIL receptors in AML blasts," explained A. Cappellini and colleagues, University of Bologna.

"Here, we have evaluated, using flow cytometry, TRAIL receptor surface expression and sensitivity to TRAIL-dependent apoptosis of AML blasts from 30 patients. We observed frequent expression of TRAIL DcR1 and DcR2, while expression of DR4 and DR5 was less frequent. Nevertheless, the expression of DR4 or DR5 in leukemic cells was always matched by a similar expression of one of the decoy receptors. Leukemic blasts were invariably resistant, even to a high concentration (1000 ng/ml) of TRAIL."

The researchers concluded, "We suggest that AML blasts are resistant to TRAIL apoptosis in vitro. Therefore, it is unlikely that TRAIL alone might be used in the future as an innovative pharmacological agent for the treatment of AML."

Cappellini and colleagues published their study in International Journal of Molecular Medicine (Application of flow cytometry to molecular medicine: Detection of tumor necrosis factor-related apoptosis-inducing ligand receptors in acute myeloid leukemia blasts. Int J Mol Med, 2005;16(6):1041-1048).

Additional information can be obtained by contacting A.M. Martelli, University of Bologna, Dipartimento Science Anatomy Umane & Fisiopatol Apparato, Via Irnerio 48, I-40126 Bologna, Italy.

Study 3: Investigators have used allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia.

According to recent research published in the journal Leukemia, "Recently, immunotherapies with allogeneic dendritic cells (DCs) pulsed with tumor antigens to generate specific T-cell responses have been tested in clinical trials for patients with solid tumors. This is the first report on a clinical vaccination study with DCs for patients with B-cell chronic lymphocytic leukemia (B-CLL). The potential of allogeneic DCs pulsed ex vivo with tumor cell lysates or apoptotic bodies to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated."

"Monocyte-derived DCs were obtained from unrelated healthy donors," said I. Hus and collaborators at the Medical University of Lublin in Poland and University of Ulm in Germany. "Nine patients (clinical stage 0 and 1 according to Rai) were vaccinated five times with a mean number of 32 x 106 stimulated DCs administered intradermally once every 2 to 3 weeks. No signs of autoimmunity were detected, and only mild local skin reactions were noted. During the treatment period, we observed a decrease of peripheral blood leukocytes and CD19+/CD5+ leukemic cells."

"In one patient, a significant increase of specific cytotoxic T lymphocytes against RHAMM/CD168, a recently characterized leukemia-associated antigen, could be detected after DC vaccination," reported the scientists. "Taken together, the study demonstrated that DC vaccination in CLL patients is feasible and safe. Immunological and to some extent hematological responses could be noted, justifying further investigation on this immunotherapeutical approach."

Hus and associates published their study in Leukemia (Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia. Leukemia, 2005;19(9):1621-1627).

For additional information, contact Michael Schmitt, Third Department of Internal Medicine, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany. michael.schmitt@uni-ulm.de.

Keywords: Ulm, Germany, Leukemia Vaccine, Vaccine Development, Cancer Vaccine, Dendritic Cell Vaccine, Chronic Lymphocytic Leukemia, Immunology, Immunotherapy, Oncology.

This article was prepared by Cancer Vaccine Week editors from staff and other reports. Copyright 2006, Cancer Vaccine Week via NewsRx.com.