title: Prevention and synergistic control of Ph(+) ALL by a DNA vaccine and 6-mercaptopurine.
abstract: Although the outcome of patients with acute lymphoblastic leukemia (ALL) has been improved continuously by chemotherapy and tyrosine kinase inhibitors, prognosis of patients with Philadelphia chromosome positive (Ph(+)) ALL still remains poor. Since further intensification of chemotherapy is limited by toxic side effects and patients with high risk of transplant-related mortality are not eligible for allogeneic stem cell transplantation new treatment strategies are urgently needed for the prevention of Ph(+) ALL relapse. There is increasing evidence that the immune system plays an essential role for the eradication or immunologic control of remaining leukemia cells. We developed several DNA-based vaccines encoding a BCR-ABL(p185) specific peptide and GM-CSF, and CD40-L, IL-27 or IL-12 and evaluated the preventive and therapeutic efficacy against a lethal challenge of syngeneic Ph(+) ALL in Balb/c mice. In vivo cell depletion assays and cytokine expression studies were performed and the efficacy of the DNA vaccine was compared with 6-mercaptopurine (6-MP) alone and the combination of the DNA vaccine and 6-MP. Preventive immunization with the vaccine BCR-ABL/GM-CSF/IL-12 and the TLR-9 agonist dSLIM induced an innate and adaptive immune response mediated by NK-cells, CD4(+) T-cells and CD8(+) T-cells leading to a survival rate of 80%. Therapeutic vaccination resulted in a significantly longer leukemia-free survival (40.7 days vs. 20.4 days) and a higher survival rate (56% vs. 10%) compared to chemotherapy with 6-MP. Remarkably, in combination with the vaccine 6-MP acted synergistically and led to 100% survival. These results demonstrate that minimal residual disease of Ph(+) ALL can be significantly better controlled by a combined treatment approach of immunotherapy and chemotherapy. This provides a rationale for improving maintenance therapy in order to reduce the relapse rate in patients with Ph(+) ALL.
authors: Department of Pediatrics, Universität zu Lübeck, UKSH, Campus Lübeck, Germany. koechling.luebeck@freenet.de
authors: Joachim
authors: J
authors: Köchling
authors: Yvonne
authors: Y
authors: Rott
authors: Stefanie
authors: S
authors: Arndt
authors: Christina
authors: C
authors: Marschke
authors: Manuel
authors: M
authors: Schmidt
authors: Burghardt
authors: B
authors: Wittig
authors: Katrin
authors: K
authors: Kalies
authors: Jürgen
authors: J
authors: Westermann
authors: Günter
authors: G
authors: Henze
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D003131:Combined Modality Therapy; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D015122:Mercaptopurine / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018365:Neoplasm, Residual / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D020381:Interleukin-17; D012333:RNA, Messenger; D019444:Vaccines, DNA; D023201:CD40 Ligand; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015122:Mercaptopurine; D016044:Fusion Proteins, bcr-abl