Research Project: We propose to genetically modify AML cells to produce molecules that promote potent immune-stimulation. HIV-derived lentiviral vectors can efficiently transduce primary AML cells and promote stable and high levels of transgene expression. Novel self-inactivating (SIN) vectors have been recently developed, providing additional biosafety to the lentiviral vector system. We will employ the SIN-lentivirus to deliver genes encoding immunomodulators that function in various pathways of immune-stimulation (CD80, CD70, GM-CSF, CD40L, FLT3L, IL-4). AML cells expressing a single or a combination of immunomodulators will be evaluated by in vitro assays on their ability to promote T-cell, B-cell, dendritic cell mediated immune responses. The biosafety of the lentiviral vectors will be evaluated by in vitro culture systems. Ultimately, we propose to develop a clinical protocol for immunization of AML patients with irradiated, lentivirus transduced cell vaccines. Long-term, disease-free survival is currently achieved in only approximately 30 percent of patients with AML. Major improvement in long-term survival for AML patients could possibly be achieved by active immunotherapy during remission to eradicate minimal residual disease, thus lowering the risks of relapse.
| Stripecke, R; Levine, A M; Pullarkat, V et al. (2002) Immunotherapy with acute leukemia cells modified into antigen-presenting cells: ex vivo culture and gene transfer methods. Leukemia 16:1974-83 |
| Koya, R C; Kasahara, N; Pullarkat, V et al. (2002) Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses. Leukemia 16:1645-54 |
