- Email: [email protected]
Shaped-beam radiotherapy targets brain tumours
Newsdesk Shaped-beam radiotherapy targets brain tumours Spanish radiation oncologists have obtained encouraging preliminary results with the Novalis shapedbeam surgery system. Installed in February 2001, at the Teknon Medical Centre (Barcelona, Spain), this type of accelerator is one of only four in Europe. The aim of the machine is to provide stereotactic radiosurgery with a high level of precision. Patients are placed inside a threedimensional stereotactic frame to pinpoint the tumour from different angles. Scans from computed tomography and magnetic resonance imaging are then fused to record anatomical characteristics. When a computer processes this information,
“These are only very preliminary results”, says Villà, “they should not be compared with any others at the moment, but things look encouraging”. Twenty-seven patients have so far received treatment, 23 with brain tumours (including meningiomas, pineal tumours, malignant gliomas, pituitary adenomas and tumours of the glomus). One patient had a complete remission, while six showed a partial response, and another nine achieved stable disease. There was also a complete remission
a three-dimensional model of the tumour is built up. The computer then calculates the delivery of the radiation beam and, using a mobile micromultileaf collimator, adapts the beam to the tumour’s exact form. Such accuracy allows a high intensity beam to be focused on the tumour, while avoiding damage to surrounding tissue. Manuel Llorente, radiophysicist at the MD Anderson Cancer Centre (Madrid, Spain) comments, “This type of system represents the current trend in radiotherapy, involving better beam conformation, which allows the use of higher radiation dosages”. This technique also facilitates treatment, particularly for brain tumours, when surgery or more conventional radiotherapy would be dangerous or impossible. Speaking at the I Novalis Symposium in Barcelona (October 2001), Salvador Villà, a radiation oncologist at the Teknon Centre, reported the team’s early experience. 712
Adrian Burton
Second-generation oncolytic adenoviruses near clinical pipeline
Courtesy of S Villà
The Novalis Linear Accelerator
in a patient with a liver metastasis from a pancreatic primary tumour, stabilisation of a tumour in the pillar of the diaphragm, and early responses in two cases of prostate cancer (as measured by prostatespecific antigen concentration). “The system has the advantages that treatment is quick and secondary effects are minimal”, adds Villà. In 8 months of treatments, only one patient has suffered a relapse.
Last month, US scientists published encouraging in vitro and in vivo results on a second-generation engineered adenovirus that replicates in, and kills, tumour cells, but not normal cells. “Additional experiments are ongoing, to obtain the data necessary to support the initiation of clinical trials”, says Paul Shabram (Canji Inc, San Diego, CA, USA). Adenoviruses engineered to kill tumour cells, but not normal cells, have been actively researched for about 10 years. The approach most often used to achieve this has been to alter the viral genome so that viral replication is attenuated in tumour cells. To develop dl1520 (Onyx 015), a first-generation oncolytic adenovirus, researchers removed E1b, a viral gene essential for replication in normal cells but not in tumour cells with defective P53 function. However, dl1520 has little antitumour activity on its own and ongoing phase III trials involve combinations of dl1520 and chemotherapy. Efforts are now underway to develop second-generation oncolytic viruses that have both selectivity and potent antitumour activity. 01/PEME, the virus developed by Canji Inc, is one of these. “Tumour cells are very heterogeneous”, explains Canji’s Murali Ramachandra, “so we focused on normal cells. In particular, we exploited the P53 and E2F pathways, which are intact in normal
cells, but altered in nearly all tumour cells”. Among the many modifications built into it, 01/PEME contains an E2F antagonist gene, expression of which is P53-dependent. When normal cells are infected with 01/PEME, P53 induces E2F antagonist expression and, because E2F activity is essential for viral replication, the virus cannot replicate. In tumour cells, E2F activity is often increased and P53 activity is absent or reduced. Thus, the virus can replicate in tumour cells because the virally encoded E2F antagonist is not expressed or is expressed too late. “01/PEME replication is similar to that of a wild-type virus in tumour cells, but about 100-fold attenuated in normal cells”, explains Ramachandra. 01/PEME also showed enhanced effectiveness in a human xenograft when compared with dl1520 (Nat Biotech 2001; 19: 1035–41). David Kirn (Imperial Cancer Research Fund, London, UK), who helped to develop dl1520, says that the 01/PEME results are promising. “Several second-generation oncolytic adenoviruses have come online since dl1520”, he explains, “and in general these viruses seem to be more selective and more potent”. One of these is dl922-947, a virus developed by Kirn and which, he says, “should be in early clinical trials next year”. Jane Bradbury THE LANCET Oncology Vol 2 December 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
“These are only very preliminary results”, says Villà, “they should not be compared with any others at the moment, but things look encouraging”. Twenty-seven patients have so far received treatment, 23 with brain tumours (including meningiomas, pineal tumours, malignant gliomas, pituitary adenomas and tumours of the glomus). One patient had a complete remission, while six showed a partial response, and another nine achieved stable disease. There was also a complete remission
a three-dimensional model of the tumour is built up. The computer then calculates the delivery of the radiation beam and, using a mobile micromultileaf collimator, adapts the beam to the tumour’s exact form. Such accuracy allows a high intensity beam to be focused on the tumour, while avoiding damage to surrounding tissue. Manuel Llorente, radiophysicist at the MD Anderson Cancer Centre (Madrid, Spain) comments, “This type of system represents the current trend in radiotherapy, involving better beam conformation, which allows the use of higher radiation dosages”. This technique also facilitates treatment, particularly for brain tumours, when surgery or more conventional radiotherapy would be dangerous or impossible. Speaking at the I Novalis Symposium in Barcelona (October 2001), Salvador Villà, a radiation oncologist at the Teknon Centre, reported the team’s early experience. 712
Adrian Burton
Second-generation oncolytic adenoviruses near clinical pipeline
Courtesy of S Villà
The Novalis Linear Accelerator
in a patient with a liver metastasis from a pancreatic primary tumour, stabilisation of a tumour in the pillar of the diaphragm, and early responses in two cases of prostate cancer (as measured by prostatespecific antigen concentration). “The system has the advantages that treatment is quick and secondary effects are minimal”, adds Villà. In 8 months of treatments, only one patient has suffered a relapse.
Last month, US scientists published encouraging in vitro and in vivo results on a second-generation engineered adenovirus that replicates in, and kills, tumour cells, but not normal cells. “Additional experiments are ongoing, to obtain the data necessary to support the initiation of clinical trials”, says Paul Shabram (Canji Inc, San Diego, CA, USA). Adenoviruses engineered to kill tumour cells, but not normal cells, have been actively researched for about 10 years. The approach most often used to achieve this has been to alter the viral genome so that viral replication is attenuated in tumour cells. To develop dl1520 (Onyx 015), a first-generation oncolytic adenovirus, researchers removed E1b, a viral gene essential for replication in normal cells but not in tumour cells with defective P53 function. However, dl1520 has little antitumour activity on its own and ongoing phase III trials involve combinations of dl1520 and chemotherapy. Efforts are now underway to develop second-generation oncolytic viruses that have both selectivity and potent antitumour activity. 01/PEME, the virus developed by Canji Inc, is one of these. “Tumour cells are very heterogeneous”, explains Canji’s Murali Ramachandra, “so we focused on normal cells. In particular, we exploited the P53 and E2F pathways, which are intact in normal
cells, but altered in nearly all tumour cells”. Among the many modifications built into it, 01/PEME contains an E2F antagonist gene, expression of which is P53-dependent. When normal cells are infected with 01/PEME, P53 induces E2F antagonist expression and, because E2F activity is essential for viral replication, the virus cannot replicate. In tumour cells, E2F activity is often increased and P53 activity is absent or reduced. Thus, the virus can replicate in tumour cells because the virally encoded E2F antagonist is not expressed or is expressed too late. “01/PEME replication is similar to that of a wild-type virus in tumour cells, but about 100-fold attenuated in normal cells”, explains Ramachandra. 01/PEME also showed enhanced effectiveness in a human xenograft when compared with dl1520 (Nat Biotech 2001; 19: 1035–41). David Kirn (Imperial Cancer Research Fund, London, UK), who helped to develop dl1520, says that the 01/PEME results are promising. “Several second-generation oncolytic adenoviruses have come online since dl1520”, he explains, “and in general these viruses seem to be more selective and more potent”. One of these is dl922-947, a virus developed by Kirn and which, he says, “should be in early clinical trials next year”. Jane Bradbury THE LANCET Oncology Vol 2 December 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.