RESEARCH HIGHLIGHTS Nature Reviews Cancer | AOP, published online 5 September 2014; doi:10.1038/nrc3821
THERAPEUTICS
Protective packaging
chemoprotective gene therapy in combination with O6BG and TMZ might also be effective in the treatment of other tumours that overexpress MGMT
Glioblastoma is one of the most aggressive primary brain tumours in adults, with a median overall survival of just over a year after diagnosis. Although treatment with temozolomide (TMZ)— the current standard chemotherapy— is effective, more than 50% of tumours are resistant to this agent as a consequence of the overexpression of methylguanine methyltransferase (MGMT), which repairs TMZ-induced cytotoxic DNA damage. The small nucleoside inhibitor O6-benzylguanine (O6BG) can bind to MGMT and deplete its activity, therefore restoring TMZ sensitivity. However, administration of O6BG causes myelosuppression, rendering this treatment toxic and difficult to tolerate. Adair et al. have carried out a prospective clinical trial to test whether gene therapy can prevent haematopoietic toxicity and promote tolerance and efficacy of the combination regimen with O6BG and TMZ. The study included seven patients with newly diagnosed malignant grade IV glioma with unmethylated MGMT promoter, who had received surgery and radiotherapy. Previous studies had demonstrated that haematopoietic stem cells (HSCs) carrying a mutant MGMT gene (MGMTP140K) — which confers resistance to O6BG
but displays the same activity as wild-type MGMT — protected these cells and their differentiated progeny from chemotherapyassociated toxicity after autologous transplantation. On the basis of these results, the authors isolated enriched autologous CD34+ cells from the blood of each patient and genetically modified them with a retroviral vector encoding the MGMTP140K transgene. The engineered cells were then injected back into patients. Subsequently, the patients received an average of 4.4 cycles of adjuvant chemotherapy with O6BG and TMZ and up to 9 cycles of treatment in one patient who is now — more than five years after diagnosis — without evidence of recurrent disease. Three of seven patients were alive at two years, a considerable improvement compared with historical survival data. The authors also used a patientspecific mathematical model of tumour growth to determine the potential benefits achieved with the addition of O6BG to TMZ therapy, using data from patients treated with standard care regimens as controls.
NATURE REVIEWS | CANCER
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They examined two magnetic resonance imaging (MRI) scans — at presentation and before surgical resection — and used this mathematical model to predict the growth of the tumours, had they been left untreated. The mathematical model showed a marked delay in predicted tumour growth in tumours treated with lower cumulative doses of TMZ when administered with O6BG. The authors conclude that further development of chemoprotective gene therapy in combination with O6BG and TMZ might also be effective in the treatment of other tumours that overexpress MGMT. M. Teresa Villanueva ORIGINAL RESEARCH PAPER Adair, J. E. et al. Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J. Clin. Invest. http://dx.doi.org/10.1172/JCI76739 (2014)
VOLUME 14 | O CTOBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
PG /N
THERAPEUTICS
Protective packaging
chemoprotective gene therapy in combination with O6BG and TMZ might also be effective in the treatment of other tumours that overexpress MGMT
Glioblastoma is one of the most aggressive primary brain tumours in adults, with a median overall survival of just over a year after diagnosis. Although treatment with temozolomide (TMZ)— the current standard chemotherapy— is effective, more than 50% of tumours are resistant to this agent as a consequence of the overexpression of methylguanine methyltransferase (MGMT), which repairs TMZ-induced cytotoxic DNA damage. The small nucleoside inhibitor O6-benzylguanine (O6BG) can bind to MGMT and deplete its activity, therefore restoring TMZ sensitivity. However, administration of O6BG causes myelosuppression, rendering this treatment toxic and difficult to tolerate. Adair et al. have carried out a prospective clinical trial to test whether gene therapy can prevent haematopoietic toxicity and promote tolerance and efficacy of the combination regimen with O6BG and TMZ. The study included seven patients with newly diagnosed malignant grade IV glioma with unmethylated MGMT promoter, who had received surgery and radiotherapy. Previous studies had demonstrated that haematopoietic stem cells (HSCs) carrying a mutant MGMT gene (MGMTP140K) — which confers resistance to O6BG
but displays the same activity as wild-type MGMT — protected these cells and their differentiated progeny from chemotherapyassociated toxicity after autologous transplantation. On the basis of these results, the authors isolated enriched autologous CD34+ cells from the blood of each patient and genetically modified them with a retroviral vector encoding the MGMTP140K transgene. The engineered cells were then injected back into patients. Subsequently, the patients received an average of 4.4 cycles of adjuvant chemotherapy with O6BG and TMZ and up to 9 cycles of treatment in one patient who is now — more than five years after diagnosis — without evidence of recurrent disease. Three of seven patients were alive at two years, a considerable improvement compared with historical survival data. The authors also used a patientspecific mathematical model of tumour growth to determine the potential benefits achieved with the addition of O6BG to TMZ therapy, using data from patients treated with standard care regimens as controls.
NATURE REVIEWS | CANCER
ra La
ow Cr
They examined two magnetic resonance imaging (MRI) scans — at presentation and before surgical resection — and used this mathematical model to predict the growth of the tumours, had they been left untreated. The mathematical model showed a marked delay in predicted tumour growth in tumours treated with lower cumulative doses of TMZ when administered with O6BG. The authors conclude that further development of chemoprotective gene therapy in combination with O6BG and TMZ might also be effective in the treatment of other tumours that overexpress MGMT. M. Teresa Villanueva ORIGINAL RESEARCH PAPER Adair, J. E. et al. Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J. Clin. Invest. http://dx.doi.org/10.1172/JCI76739 (2014)
VOLUME 14 | O CTOBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
PG /N
