title: Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00669669.
  
  
  BACKGROUND
  R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Adair
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Johnston
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Mrugala
authors.forename: Brian C
authors.initials: BC
authors.lastname: Beard
authors.forename: Laura A
authors.initials: LA
authors.lastname: Guyman
authors.forename: Anne L
authors.initials: AL
authors.lastname: Baldock
authors.forename: Carly A
authors.initials: CA
authors.lastname: Bridge
authors.forename: Andrea
authors.initials: A
authors.lastname: Hawkins-Daarud
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gori
authors.forename: Donald E
authors.initials: DE
authors.lastname: Born
authors.forename: Luis F
authors.initials: LF
authors.lastname: Gonzalez-Cuyar
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Silbergeld
authors.forename: Russell C
authors.initials: RC
authors.lastname: Rockne
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.forename: Jason K
authors.initials: JK
authors.lastname: Rockhill
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Swanson
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
mesh_terms: D000328:Adult; D001853:Bone Marrow / Q000187:drug effects; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D002330:Carmustine / Q000009:adverse effects; D003131:Combined Modality Therapy; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015316:Genetic Therapy; D005909:Glioblastoma / Q000401:mortality / Q000628:therapy*; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D025521:Tumor Suppressor Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D002330:Carmustine; D000077204:Temozolomide
references.citation: Lancet Oncol. 2009 May;10(5):459-66
references.pmid: 19269895
references.citation: J Neuropathol Exp Neurol. 2007 Jan;66(1):1-9
references.pmid: 17204931
references.citation: PLoS One. 2013;8(1):e51951
references.pmid: 23372647
references.citation: Mol Ther. 2006 Aug;14(2):212-7
references.pmid: 16631413
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1262-7
references.pmid: 19204199
references.citation: Neuro Oncol. 2009 Oct;11(5):556-61
references.pmid: 19289491
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Clin Oncol (R Coll Radiol). 2008 May;20(4):301-8
references.pmid: 18308523
references.citation: Cell Prolif. 2000 Oct;33(5):317-29
references.pmid: 11063134
references.citation: Br J Cancer. 2002 Jan 7;86(1):14-8
references.pmid: 11857005
references.citation: Cancer Res. 2013 May 15;73(10):2976-86
references.pmid: 23400596
references.citation: Blood. 1995 Jun 1;85(11):3342-51
references.pmid: 7756667
references.citation: PLoS One. 2014 Jan 13;9(1):e85102
references.pmid: 24454798
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):328-31
references.pmid: 16428468
references.citation: Cancer Res. 2009 May 15;69(10):4502-9
references.pmid: 19366800
references.citation: Nat Rev Clin Oncol. 2013 Jan;10(1):14-26
references.pmid: 23183634
references.citation: Ann Neurol. 2003 Apr;53(4):524-8
references.pmid: 12666121
references.citation: J Clin Oncol. 2010 Apr 10;28(11):1963-72
references.pmid: 20231676
references.citation: Br J Cancer. 2008 Jan 15;98(1):113-9
references.pmid: 18059395
references.citation: J Clin Invest. 2010 Jul;120(7):2345-54
references.pmid: 20551514
references.citation: Sci Transl Med. 2012 May 9;4(133):133ra57
references.pmid: 22572881
references.citation: Phys Med Biol. 2010 Jun 21;55(12):3271-85
references.pmid: 20484781
references.citation: Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):623-30
references.pmid: 20888136
references.citation: Cancer Res. 2009 Dec 1;69(23):9133-40
references.pmid: 19934335