The longterm goal of this proposal is to establish that the transplantation without marrow cytoablation of positively selected hematopoietic stem cells (HSC) transduced with drug resistance genes (DRG) will permit higher doses of chemotherapy to be administered. The successful engraftment of DRG transduced HSC, the progeny of which were drug resistant, would mean that patients with both hematological malignancies and solid tumors would be able to tolerate higher doses of chemotherapy without marrow suppressive side effects.
The Specific Aims of the present grant are the pre-clinical and clinical studies necessary before clinical trials in newly diagnosed oncology patients can be undertaken.
The Specific Aims of the grant include l) the determination that human HSC can he isolated from patients with acute lymphoblastic leukemia (ALL) without contaminating leukemic cells, 2) that the transplantation of positively selected HSC can hematopoietically reconstitute patients following marrow ablative chemotherapy, 3) the transplantation of patients with neomycin resistance (neoR) transduced HSC to determine the origin of post-transplant leukemic relapse, 4) the evaluation of vectors containing the human multiple drug resistance gene (MDR- l), and 5) the transplantation of patients with relapsed ALL with positively selected HSC, a proportion of which have been transduced with a MDR-l containing vector. HSC will be positively selected using cell sorting techniques to isolate bone marrow cells that are CD34+, CD38. The positively selected HSC will be used for autologous bone marrow transplantation (BMT). ultimately the CD34+, CD38 cells will be transduced with MDR-l containing vectors, which have been evaluated in vitro. Overall the proposal is an attempt to demonstrate that HSC can be isolated free of contaminating leukemic cells, that the hematopoietic reconstitution of patients transplanted with positively selected HSC occurs in a clinical relevant time frame, and that BMT with HSC transduced with DRG results in the presence of committed hematopoietic progenitors that express the DRG. The successful completion of these Specific Aims will allow the initiation of clinical protocols in which HSC transduced with DRG are transplanted into newly patients with either hematological.
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