PMID- 29385852
OWN - NLM
STAT- MEDLINE
DCOM- 20190520
LR  - 20190520
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Linking)
VI  - 29
IP  - 8
DP  - 2018 Aug
TI  - Clinical Trial of MGMT(P140K) Gene Therapy in the Treatment of Pediatric Patients 
      with Brain Tumors.
PG  - 874-885
LID - 10.1089/hum.2017.235 [doi]
AB  - Gene transfer targeting hematopoietic stem cells (HSC) in children has shown 
      sustained therapeutic benefit in the treatment of genetic diseases affecting the 
      immune system, most notably in severe combined immunodeficiencies affecting 
      T-cell function. The HSC compartment has also been successfully targeted using 
      gene transfer in children with genetic diseases affecting the central nervous 
      system, such as metachromatic leukodystrophy and adrenoleukodystrophy. HSCs are 
      also a target for genetic modification in strategies aiming to confer drug 
      resistance to chemotherapy agents so as to reduce off-target toxicity, and to 
      allow for chemotherapy dose escalation with the possibility of enhanced 
      therapeutic benefit. In a trial of this strategy in adult glioma patients, 
      significant engraftment of gene-modified HSCs expressing a mutant of the DNA 
      repair protein O6-methyl-guanine-methyl-transferase (MGMT(P140K)) showed 
      potential in conferring drug resistance against the combined effect of 
      O6-benzylguanine (O6BG)/temozolomide (TMZ) chemotherapy. The aim was to test the 
      safety and feasibility of this approach in children with poor prognosis brain 
      tumors. In this Phase I trial, seven patients received gene-modified HSC 
      following myelo-suppressive conditioning, but with only transient low-level 
      engraftment of MGMT(P140K) gene-modified cells detectable in four patients. All 
      patients received O6BG/TMZ chemotherapy following infusion of gene-modified 
      cells, with five patients eligible for chemotherapy dose escalation, though in 
      the absence of demonstrable transgene-mediated chemoprotection. Since all 
      gene-modified cell products met the criteria for release and assays for 
      engraftment potential met expected outcome measures, inadequate cell dose, 
      conditioning chemotherapy, and/or underlying bone-marrow function may have 
      contributed to the lack of sustained engraftment of gene-modified cells. We were 
      able to demonstrate safe conduct of a technically complex Phase I study 
      encompassing manufacture of the gene therapy vector, genetically modified cells, 
      and a drug product specifically for the trial in compliance with both local and 
      national regulatory requirements.
FAU - Kramer, Belinda
AU  - Kramer B
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Singh, Radhika
AU  - Singh R
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Wischusen, Jessica
AU  - Wischusen J
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Dent, Rebecca
AU  - Dent R
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Rush, Amanda
AU  - Rush A
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Middlemiss, Shiloh
AU  - Middlemiss S
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Ching, Yu Wooi
AU  - Ching YW
AD  - 1 Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, 
      Australia.
FAU - Alexander, Ian E
AU  - Alexander IE
AD  - 2 Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, 
      Australia and the Children's Hospital at Westmead, Westmead, Australia.
AD  - 3 The University of Sydney , Discipline of Paediatrics and Child Health, 
      Westmead, Australia .
FAU - McCowage, Geoffrey
AU  - McCowage G
AD  - 4 Children's Cancer Centre, The Children's Hospital at Westmead, Westmead, 
      Australia.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180323
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (Tumor Suppressor Proteins)
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 5Z93L87A1R (Guanine)
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  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Brain Neoplasms/*drug therapy/genetics/pathology
MH  - Child
MH  - DNA Modification Methylases/genetics/*therapeutic use
MH  - DNA Repair Enzymes/genetics/*therapeutic use
MH  - Drug Resistance, Neoplasm/genetics
MH  - Female
MH  - *Genetic Therapy
MH  - Guanine/administration & dosage/analogs & derivatives
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Hematopoietic Stem Cells/metabolism
MH  - Humans
MH  - Male
MH  - Temozolomide/administration & dosage
MH  - Tumor Suppressor Proteins/genetics/*therapeutic use
OTO - NOTNLM
OT  - cancer
OT  - clinical trial
OT  - gene therapy
OT  - pediatric brain tumors
EDAT- 2018/02/02 06:00
MHDA- 2019/05/21 06:00
CRDT- 2018/02/02 06:00
PHST- 2018/02/02 06:00 [pubmed]
PHST- 2019/05/21 06:00 [medline]
PHST- 2018/02/02 06:00 [entrez]
AID - 10.1089/hum.2017.235 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2018 Aug;29(8):874-885. doi: 10.1089/hum.2017.235. Epub 2018 Mar 
      23.