Fewer than one-fifth of children with high-grade glioma have long-term survival when treated with the conventional approach of surgery, irradiation, and nitrososurea-based chemotherapy. While use of the newer DNA methylating agent temozolomide (TEM) may improve survival, benefits are limited by tumor cell resistance and therapy-related hematologic toxicity. We now propose an innovative strategy to overcome both of these limitations. O6-Benzylguanine (BG) is a chemosensitizing agent which effectively reverses the primary mechanism by which tumor cells are resistant to TEM. However, concomitant use of TEM + BG causes severe hematologic toxicity, requiring the dose of TEM to be significantly reduced. This toxicity can be overcome by using autologous hematopoietic stem cells genetically modified for protection against the combination of TEM and BG. The proposed clinical trial directly extends preclinical experiments which demonstrated that retroviral transduction of hematopoietic stem cells with the chemoprotection gene MGMTP140K can circumvent hematologic toxicity from subsequent chemotherapy, resulting in improved dose intensity, greater antitumor efficacy, and increased transgene expression in the bone marrow over time with the selective pressure of further chemotherapy. This novel pilot trial will be the first to attempt stem cell selection by treating patients with six courses of TEM + BG following infusion of gene-modified stem cells. In addition to investigating the safety and feasibility of this approach, we also will assess the extent of in vivo stem cell selection and the ability to safely dose-escalate TEM. This trial uses a retroviral vector produced in a GMP facility and approved for human use. The protocol has now been reviewed and accepted by all pertinent institutional and federal regulatory bodies, and the trial will open in September 2005. We hypothesize this strategy will be well tolerated and allow for meaningful dose escalation through chemoprotection afforded by gene transfer into hematopoietic stem cells. ? ? ?
