This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this trial are: 1) to evaluate the feasibility of introducing and expressing mutant-MGMT-G156A (MGMT) cDNA in hematopoietic progenitors taken from advanced solid tumor patients using a safety modified retroviral vector MFG; 2) to determine the toxicity associated with reinfusion of ex vivo transduced hematopoietic cells into patients with advanced cancer, including the detection of replication competent retrovirus; 3) to evaluate the feasibility of identifying MGMT transduced and O6-benzylguanine (BG) & BCNU resistant hematopoietic and stromal progenitors from the bone marrow of patients infused with MGMT transduced CD34 cells; 4) to evaluate the feasibility of in vivo enrichment of the transduced hematopoietic progenitors by repeated treatment of patients with BG & BCNU; 5) to evaluate the toxicity of repeated BG & BCNU treatments in patients who received MGMT transduced CD34 cells; and 6) to define the antitumor effect of BG & BCNU treatments in patients with advanced solid tumors. Bone marrow stem cells (progenitor cells) are early types of cells that live mainly in the bone marrow and circulate in small numbers in the blood. They can be identified as a small component of all cells by the presence of a protein on their surface called CD34. These stem cells produce all of the blood cells such as red blood cells, white cells and platelets. Since these cells are sensitive to chemotherapy, only limited amounts of chemotherapy can be given to patients at regular intervals. By transferring a drug resistance gene into bone marrow stem cells, researchers hope to learn how to use these genes to lessen the side effects of chemotherapy on blood counts. This treatment program consists of several phases of treatment. Phase 1A consists of a bone marrow sampling; a small biopsy will also be taken to examine the bone marrow for the presence of cancer. If tumor cells are found, the subject will no longer be eligible. Cells from this sample will be used in the gene transfer cultures described in phase 2B. Phase 1B consists of injections of human blood cell growth factors (GM-CSF and G-CSF) in order to make stem cells grow and to leave the bone marrow and go into the blood. Both GM-CSF and G-CSF will be given as injections under the skin on a daily basis for five days. Phase 2A consists of leukapheresis. The collection of cells from the blood, will be done on day 5 and 6 after starting the growth factors. After the leukapheresis, the cells will be taken to the laboratory where the CD34 positive cells will be separated using a special device. In phase 2B, the CD34 positive stem cells will be cultured in the laboratory for three days to make them more resistant to BG and BCNU chemotherapy by introducing a gene called MGMT into the cell. The cells will be tested to be sure there are no infectious agents in the preparation before they are reinfused. In phases 3 and 4, BG will be given by vein over one hour as an outpatient. Then the chemotherapy BCNU is given by vein over one hour. Forty-eight hours after the end of the BCNU infusion, the cells from the stem cell culture which were treated to insert the MGMT gene will be given over 30 minutes. In phase 5, every six weeks after the first dose of BG and BCNU the subject will receive a treatment with BG and BCNU. Subjects will continue to receive the drug treatment until there is evidence that the treatment is no longer effective. Treatment lasts 10 weeks to 36 weeks depending on response.
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