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-ABLp185 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.