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.
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ABSTRACT: As with many other types of malignancies, sustainable eradication of leukemia has been a challenge. This is related to the inevitable failure of conventional chemotherapeutic agents and radiation therapy to target the relatively quiescent leukemia stem cells, which are believed to have multidrug resistance, antiapoptotic capacity and enhanced DNA repair mechanisms allowing them to evade the immune system. Considering other therapeutic options that are minimally toxic to normal cells and effectively target not only the majority and more differentiated cancer cells, but also the rare residual leukemia cells, is of paramount importance. A number of immunotherapeutic options have been proposed to counter this challenge. One of the remarkable achievements in the field of immunotherapy has been the successful use of antigen presenting cells as vehicles of tumor/pathogenic antigens to the T-cell compartments. This review will focus on advances and perspectives of this arm of immunotherapy against leukemia.Immunotherapy 04/2014; 6(4):485-96. DOI:10.2217/imt.14.12 · 2.39 Impact Factor
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ABSTRACT: Although chemotherapy and tyrosine kinase inhibitors provide high remission rates, especially prognosis of adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph(+) ALL) still remains poor. Because most adults eventually relapse without allogeneic stem cell transplantation which is not available for all patients novel strategies are required for relapse prevention. Since the integrity of the immune system is essential for the control of remaining leukaemia cells, we compared the efficacy of anthocyanins, imatinib and a DNA-based vaccine as non-immunosuppressant components with 6-mercaptopurine (6-MP) to control minimal residual disease in vitro and in vivo using different leukaemia cell lines and syngeneic mice. Proliferation of Ph(+) ALL was significantly better inhibited by anthocyanin-rich berry extract or imatinib compared to 6-MP. Although anthocyanins induced apoptosis in some leukaemia cell lines the level of caspases-3, -8 and -9 was significantly lower compared to imatinib and 6-MP. When used as single components, anthocyanins and imatinib mesylate failed to eradicate pre-existing Ph(+) ALL in syngeneic mice, while 6-MP led to 10% and DNA vaccination to 56% survival. Intriguingly, only the combination of DNA vaccination with berry extract but not with the isolated anthocyanin cyanidin-3-rutinoside or with imatinib further increased leukaemia-free and overall survival and 90% of lethally challenged mice survived. We suggest that induction and enhancement of a leukaemia specific immunity by DNA vaccination and anthocyanin-rich berry extract can also decrease the relapse rate in patients with Ph(+) ALL. Furthermore, this approach may serve as strategy for maintenance therapy of other malignancies. © 2013 John Wiley & Sons A/S.European Journal Of Haematology 01/2013; DOI:10.1111/ejh.12071 · 2.41 Impact Factor