Introduction: Glioblastoma (GBM) is the most common malignant brain tumor with a median survival of 15 months despite surgery and aggressive radio-chemotherapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene which repairs temozolamide-induced DNA methylation. The MGMT inhibitor O6-benzylguanine (BG) has demonstrated efficacy in depleting MGMT and maximizing tumor response in early phase clinical trials. However, because MGMT expression is also low in hematopoietic cells, this has resulted in unacceptable bone marrow toxicity, and this approach has been abandoned. We hypothesized that chemoprotection of hematopoietic progenitor cells (HPC) with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity coupled with low affinity for BG, would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. We thus performed a phase I trial to test this hypothesis.
Methods: We treated 10 consecutive newly diagnosed GBM patients with standard surgery and radiation, followed by transplantation with autologous CD34+ hematopoetic progenitor cells engineered to express MGMT-P140K using a lentiviral vector using three different arms. To assess chemo-protection, patients’ blood counts and transgene marking were monitored during the treatment as was tumor growth and survival.
Results: The viral transduction rates were 2.5-75% and were clearly improved in the third arm with intra-patient dose escalation. P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2-3) mylosuppression consistent with chemo-selection and chemo-protection as hypothesized. Survival ranged from 20-36 months which exceeded their RPA predicted survival by 1.9-3.2 fold suggesting clinical benefit (mean 2.0). Viral insertion site analysis failed to demonstrate clonal dominance.
Conclusions: These preliminary results demonstrate that this chemoprotection strategy is tolerable, safe, and facilitates TMZ & BG dose escalation resulting in increased survival. A phase II study is ongoing.
Patient Care: If are phase I findings are confirmed in phase II studies now underway, we will "chemoprotect" the bone marrow, enabling patients to tolerate dose-dense chemotherapy, leading to improved survival for patients with GBM.
Learning Objectives: 1) Understand and explain the mechanism of action of temozolamide; 2) Explain the relationship between MGMT Promotor Methylation in GBM in Survival; 3. Describe the advantages and disadvantages of inhibiting MGMT in patients with GBM; 4) Describe the concept of chemoprotection