The long-term goal of the proposed research is to determine whether the. therapeutic efficacy of pretransplant conditioning regimens in clinical bone marrow transplant protocols for high risk acute lymphoblastic leukemia (ALL) patients can be enhanced by using immunotoxins (IT) containing the plant hemitoxin pokeweed antiviral protein (PAP). It is our central working hypothesis that the combination of pretransplant radiochemotherapy with PAP containing IT will prove more effective in eradicating the residual leukemia burden of high risk remission ALL patients than radiochemotherapy alone and will thus decrease the incidence of relapse. Punctum saliens of this proposal will therefore be to conduct clinical and preclinical research to generate critical information regarding the optimal use of IT in bone marrow transplant settings so that improved and more effective conditioning regimens can be developed. Our first major goal is to conduct a clinical phase I B43-PAP dose escalation study to (a) determine the safety and tolerance of intravenous infusions of B43-PAP in therapy refractory B-lineage ALL patients, (b) determine the chemical, innumological, and biological stability of B43-PAP in vivo, (c) assess the ability of relapsed B-lineage ALL patients to develop a host immune response to the toxin and MoAb moieties of the IT, and (d) obtain preliminary information on the in vivo anti-leukemic activity of B43-PAP against B-lineage ALL. A second major goal is to develop more effective IT against ALL blasts. We will prepare IT directed against novel antigens, homogeneous IT, and IT with different types of intermolecular toxin-MoAb linkages. These IT will be compared for in vitro and in vivo anti-leukemic activity using leukemic progenitor cell colony assays and a SCID mouse model system of human ALL. Finally, studies are designed to evaluate the combined effects of radiochemotherapy plus B43-PAP in a syngeneic mouse BMT model system for CD19+ B-lineage ALL. We will attempt to determine the treatment protocol(s) with the highest therapeutic index by comparing different dose combinations and application sequences of total body irradiation (TBI), cyclophosphamide, and B43-PAP relative to anti-leukemic efficacy as well as toxicity. It is anticipated that successful completion of the proposed studies will constitute a good start towards the potential application of radio-chemo-immunotherapy regimens in BMT for ALL. This project will likely provide the foundation for novel and more effective pretransplant conditioning strategies for ALL.
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