Graft versus leukemia effect observed after allogeneic bone marrow transplant for chronic myelogenous leukemia (CML) demonstrates that CML can be recognized by the immune system. Nonetheless, the disease does not elicit a spontaneous effective immune response. The applicant postulates that CML-associated antigens do not stimulate immunity because they are not presented in the proper cellular and molecular context. He hypothesizes that ex vivo matured dendritic cells (DC) provide proper presentation of CML-associated antigens and that such DC are effective in stimulating CML-specific immunity in patients. In this translational project, he proposes to prime the immune response against CML by ex vivo matured reinfused autologous leukemic dendritic cells and to define methods to further enhance the effectiveness of priming and boosting the immune response.
In Specific Aim 1, he will maximize expression and presentation of endogenous CML-associated antigens by mature autologous leukemic dendritic cells and stimulate a CML-specific immune response in a Phase I/II clinical trial. He will measure immunization-induced changes in CML-specific immune effector cells and correlate the changes with the status of disease; immunotherapy protocols often involve boosting with dendritic cells, yet the effects on the dynamics of T cell response are not fully understood.
In Specific Aim 2, he will compare the effectiveness of cells presenting bcr-abl in the presence and in the absence of costimulatory molecules for boosting the immune response.
In Specific Aim 3, he will express in dendritic cells the human IL-2 gene introduced by infection with recombinant adenovirus and test the cells for efficacy of expanding the CML-specific T cell response in vitro. The clinical study will provide information on: 1. the safety of autologous ex vivo matured dendritic cells derived from CD14-selected cells; 2. efficacy of mature leukemic dendritic cells in controlling CML, and 3. the relationship between the level of T-cell response and tumor burden in CML patients. Laboratory studies will 1) identify the cells optimal for boosting immunity in vitro and 2) maximize CML-specific T-cell responses using CML-DC genetically modified to express and secrete IL-2. The combined data will provide a comprehensive understanding of the interaction of the immune system and CML and will yield information required for the rational design of more effective clinical protocols in the future.
| Litzow, M R; Dietz, A B; Bulur, P A et al. (2006) Testing the safety of clinical-grade mature autologous myeloid DC in a phase I clinical immunotherapy trial of CML. Cytotherapy 8:290-8 |
| Dietz, Allan B; Bulur, Peggy A; Emery, Richard L et al. (2006) A novel source of viable peripheral blood mononuclear cells from leukoreduction system chambers. Transfusion 46:2083-9 |
| Dietz, A B; Padley, D J; Butler, G W et al. (2004) Clinical-grade manufacturing of DC from CD14+ precursors: experience from phase I clinical trials in CML and malignant melanoma. Cytotherapy 6:563-70 |
| Dietz, Allan B; Souan, Lina; Knutson, Gaylord J et al. (2004) Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 104:1094-9 |
| Padley, D J; Dietz, A B; Gastineau, D A et al. (2001) Mature myeloid dendritic cells for clinical use prepared from CD14+ cells isolated by immunomagnetic adsorption. J Hematother Stem Cell Res 10:427-9 |
