Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT hi ). Coadministration of O 6 -benzylguanine (O 6 BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O 6 BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome. METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMT hi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O 6 BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patientspecific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated. RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O 6 BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57 + ) months and OS of 20 (range 13–57 + ) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O 6 BG. CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O