PMID- 25105369 OWN - NLM STAT- MEDLINE DCOM- 20150120 LR - 20211021 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 124 IP - 9 DP - 2014 Sep TI - Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. PG - 4082-92 LID - 76739 [pii] LID - 10.1172/JCI76739 [doi] AB - 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 O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG 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 O6BG/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. Patient-specific 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 O6BG/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 O6BG. CONCLUSION: These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT. TRIAL REGISTRATION: Clinicaltrials.gov NCT00669669. FUNDING: R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970. FAU - Adair, Jennifer E AU - Adair JE FAU - Johnston, Sandra K AU - Johnston SK FAU - Mrugala, Maciej M AU - Mrugala MM FAU - Beard, Brian C AU - Beard BC FAU - Guyman, Laura A AU - Guyman LA FAU - Baldock, Anne L AU - Baldock AL FAU - Bridge, Carly A AU - Bridge CA FAU - Hawkins-Daarud, Andrea AU - Hawkins-Daarud A FAU - Gori, Jennifer L AU - Gori JL FAU - Born, Donald E AU - Born DE FAU - Gonzalez-Cuyar, Luis F AU - Gonzalez-Cuyar LF FAU - Silbergeld, Daniel L AU - Silbergeld DL FAU - Rockne, Russell C AU - Rockne RC FAU - Storer, Barry E AU - Storer BE FAU - Rockhill, Jason K AU - Rockhill JK FAU - Swanson, Kristin R AU - Swanson KR FAU - Kiem, Hans-Peter AU - Kiem HP LA - eng SI - ClinicalTrials.gov/NCT00669669 GR - R01AI080326/AI/NIAID NIH HHS/United States GR - R01CA164371/CA/NCI NIH HHS/United States GR - P01 AI097100/AI/NIAID NIH HHS/United States GR - R01 HL098489/HL/NHLBI NIH HHS/United States GR - P30DK056465/DK/NIDDK NIH HHS/United States GR - R01 AI080326/AI/NIAID NIH HHS/United States GR - R01NS060752/NS/NINDS NIH HHS/United States GR - K01 DK076973/DK/NIDDK NIH HHS/United States GR - R01 CA164371/CA/NCI NIH HHS/United States GR - P30 CA015704/CA/NCI NIH HHS/United States GR - R01CA114218/CA/NCI NIH HHS/United States GR - R01 NS060752/NS/NINDS NIH HHS/United States GR - R01HL074162/HL/NHLBI NIH HHS/United States GR - K01DK076973/DK/NIDDK NIH HHS/United States GR - R01 CA114218/CA/NCI NIH HHS/United States GR - P30 DK056465/DK/NIDDK NIH HHS/United States GR - U54CA143970/CA/NCI NIH HHS/United States GR - U54 CA143970/CA/NCI NIH HHS/United States GR - R01 HL074162/HL/NHLBI NIH HHS/United States GR - R01HL098489/HL/NHLBI NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140808 PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (Tumor Suppressor Proteins) RN - 01KC87F8FE (O(6)-benzylguanine) RN - 5Z93L87A1R (Guanine) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2.1.1.- (DNA Modification Methylases) RN - EC 2.1.1.63 (MGMT protein, human) RN - EC 6.5.1.- (DNA Repair Enzymes) RN - U68WG3173Y (Carmustine) RN - YF1K15M17Y (Temozolomide) SB - IM CIN - Nat Rev Cancer. 2014 Oct;14(10):646-7. PMID: 25190084 MH - Adult MH - Bone Marrow/drug effects MH - Brain Neoplasms/mortality/*therapy MH - Carmustine/adverse effects MH - Combined Modality Therapy MH - DNA Modification Methylases/genetics MH - DNA Repair Enzymes/genetics MH - Dacarbazine/analogs & derivatives/pharmacology MH - Drug Resistance, Neoplasm MH - Female MH - *Genetic Therapy MH - Glioblastoma/mortality/*therapy MH - Guanine/analogs & derivatives/pharmacology MH - Hematopoietic Stem Cell Transplantation MH - Humans MH - Male MH - Middle Aged MH - Models, Biological MH - Prospective Studies MH - Temozolomide MH - Tumor Suppressor Proteins/genetics PMC - PMC4151207 EDAT- 2014/08/12 06:00 MHDA- 2015/01/21 06:00 PMCR- 2014/08/08 CRDT- 2014/08/09 06:00 PHST- 2014/04/29 00:00 [received] PHST- 2014/07/01 00:00 [accepted] PHST- 2014/08/09 06:00 [entrez] PHST- 2014/08/12 06:00 [pubmed] PHST- 2015/01/21 06:00 [medline] PHST- 2014/08/08 00:00 [pmc-release] AID - 76739 [pii] AID - 10.1172/JCI76739 [doi] PST - ppublish SO - J Clin Invest. 2014 Sep;124(9):4082-92. doi: 10.1172/JCI76739. Epub 2014 Aug 8.