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Protection of Mice against Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia by Cell-based Vaccination Using Nonviral, Minimalistic Expression Vectors and Immunomodulatory Oligonucleotides¹

Department of Pediatric Hematology, Children’s Hospital, University of Tübingen, D-72076 Tübingen, Germany [J. K.]; Department of Pediatric Oncology/Hematology, Charité, Humboldt University, Berlin, Germany [J. K., D. B., A. K., H. G. v. E., G. H., K. S.]; Mologen GmbH, Berlin, Germany [S. A. K-M., B. W., M. S.]; Institute for Genetic Medicine, University of Southern California, Los Angeles, California [R. S.]; and Department of Molecular Biology and Bioinformatics, Free University, Berlin, Germany [F. S., B. W.]

Purpose: Childhood Philadelphia chromosome positive (Ph⁺) acute lymphoblastic leukemia (ALL) has a poor prognosis. Because leukemia cell burden is reduced but not eradicated by polychemotherapy, improved treatment strategies should enhance those immune mechanisms responsible for the maintenance of complete remission. The aim of this study was to evaluate the protection of mice challenged with the syngeneic Ph⁺ ALL cell line BM185 using genetically modified leukemia cell vaccines and immunomodulating oligonucleotides.

Experimental Design: Because retroviral vectors are ineffective at transducing nondividing primary cells from human hematopoietic malignancies, we first evaluated nonviral techniques (electroporation and ballistic transfer) using minimalistic immunogenically defined gene expression vectors to generate B7.1 or granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing BM185 cells. Subsequently, protective vaccination experiments with these cells were performed in a leukemia challenge mouse model.

Results: Electroporation yielded a high transfection rate (82.6% for B7.1) with moderate GM-CSF secretion/1 x 10⁶ cells (228 pg), whereas ballistic transfer led to a lower transfection rate (30.9%) with high GM-CSF secretion (614 pg). Secondly, we immunized mice with B7.1/interleukin 2- or B7.1/GM-CSF-expressing BM185 cell vaccines. We observed a better protection of mice that received the B7.1/GM-CSF vaccine compared with these receiving the B7.1/interleukin 2 vaccine. Protection was additionally enhanced by application of a double stem-loop immunomodulating oligonucleotide containing CpG motifs.

Conclusion: Our data indicate that immunization with B7.1/GM-CSF-expressing cell vaccines generated by electroporation and application of double stem-loop immunomodulating oligonucleotide protected mice against a murine Ph⁺ ALL challenge. Ultimately, this approach may also lead to clinical benefit in patients with Ph⁺ ALL.

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