Oncolytic viral anti-cancer therapy: a magic  bullet?  
_Jane Bradbury_ 
(http://www.thelancet.com/search/results?search_mode=cluster&search_area=cluster&search_cluster=thelancet&search_sort=date&restrictname_auth
or=author&restricttype_author=author&restrictterm_author=bradbury0j&restrictde
sc_author=Jane Bradbury)  
 
 
The next few years should see major  advances in oncolytic viral therapy for 
tumours, claims David Kirn (Imperial  Cancer Research Fund, London, UK). “The 
selective killing of tumour cells caused  by viruses replicating within them 
but not within normal cells is not a new  idea”, he explains. “Back in 1904, 
The Lancet published a report  of a woman whose leukaemia regressed after a 
viral infection. But it's only in  the past 20 years that we have been able to 
engineer safe viruses for antitumour  therapy.” 
Oncolytic viral therapy is a very broad  area of investigation, continues 
Kirn, but at its heart is the development of  viruses that kill tumour cells but 
leave normal cells unscathed. There are  several ways to achieve this, says 
Antonio Chiocca (Massachusetts General  Hospital, Charlestown, MA, USA), “but 
the one that has been most commonly and  successfully used experimentally is to 
remove genes from the virus or to put new  genes in so that viral replication 
can occur only in tumour cells”. 
About ten different types of virus are  being investigated as potential 
oncolytic therapies, but adenovirus, herpes  simplex virus (HSV), and reovirus are 
the clear favourites. Of these, most  clinical work has been done with 
adenoviruses, in particular with Onyx-015. “To  date, we have treated around 250 
patients with Onyx-015”, explains Kirn.  Wild-type adenovirus will replicate in 
normal cells. In Onyx-015 a gene has been  deleted which is essential for viral 
replication in normal cells but not in  tumour cells that have lost p53 tumour 
 suppressor function. Thus, Onyx-015 replicates preferentially in tumour  
cells. 
Data from published phase I and II  trials show that Onyx-015 is safe, that 
it replicates only in tumour tissue, and  that although it has minimal 
antitumour activity on its own, in combination with  chemotherapy its efficacy is much 
greater. A phase III trial is now underway in  which patients with recurrent 
neck and head cancer will be given standard  chemotherapy or chemotherapy plus 
intratumoral injection of Onyx-015. “This  trial started last September”, 
says oncologist John Nemuniatis (US Oncology,  Dallas, TX, USA), but it will 
take some time to accrue all the patients. And,  adds Kirn, although the results 
with Onyx-015 in patients with head and neck  cancer are encouraging, “this 
first-generation virus is not a home run. We have  now made a more potent virus 
with a targeted deletion in another gene needed for  viral replication in 
normal but not tumour cells. We hope to get viruses such as  this into phase I 
trials early this year.” Oncolytic viruses based on HSV also  look promising. 
Indeed, says Kirn, it was work in the early 1990s by Robert  Martuza 
(Massachusetts General Hospital, Charlestown, MA, USA) that re-ignited  interest in 
oncolytic virus therapy. The approach taken by Martuza, Chiocca, and  others to 
achieve selective replication of HSV in tumour cells has been to  delete viral 
genes needed for nucleotide synthesis. Normal cells do not make  sufficient 
nucleotides to support viral replication and so HSV carries genes  encoding 
nucleotide synthesis enzymes. HSV mutants with deletions in these genes  cannot 
replicate in normal cells but can do so in tumour cells where nucleotide  pools are 
much higher. 
Moira Brown (University of Glasgow, UK),  meanwhile, is concentrating on 
another aspect of HSV replication. “We found that  HSV1716, a mutant in which a 
protein called ICP34·5 was deleted, could only grow  in rapidly dividing cells”, 
she explains. Brown's working hypothesis is that for  viral replication to 
occur in normal cells, ICP34·5 has to recruit a specific  DNA replication 
factor. Because tumour cells contain much more of this factor  than normal cells, 
ICP34·5 is not needed for viral replication in tumour cells.  HSV1716 grows in 
all the cancer cell types that Brown has tested but she is  concentrating on 
its effects in glioma cells. “We have completed two phase I  trials of direct 
viral injection into gliomas and although we cannot say  anything definite about 
anti-tumour effects, three out of nine patients in our  first trial are still 
alive, including one who was treated in October, 1997.  This is very 
encouraging and we plan to start a phase II trial of HSV1716 in  patients with glioma 
in February.” 
Reovirus, the final front runner,  differs from adenovirus and HSV in that 
replication of wild-type virus is  already tumour selective, no engineering is 
needed. “Reovirus causes mild  respiratory and enteric symptoms”, explains 
Patrick Lee (University of Calgary,  Alberta, Canada), “and we have discovered 
that only cells with an activated ras  pathway support reoviral growth. These 
cells include the rapidly dividing cells  of the respiratory and 
gastrointestinal tract that reovirus normally infects and  many tumour cells.” Interactions 
between the host cell and the virus mean that  viral proteins necessary for 
replication are produced in only cells with an  activated ras pathway. 
Consequently, wild-type reovirus will kill tumour cells  but not normal cells. “We 
started a phase I study last June”, continues Lee, in  which we are injecting 
reovirus directly into the tumours of patients with head  and neck cancer. This 
trial should be completed next summer.” 
The future, then, looks good for  oncolytic therapy but can 
replication-competent viruses be safely injected into  people? “When the results of all our 
trials on Onyx-015 are published, which  include intratumoural, intraperitoneal, 
intra-arterial, and intravenous  administration, I feel sure that people will 
realise how safe adenoviruses are”,  says Kirn. Nemunaitis concurs, noting 
that “we have not found any evidence for  Onyx-015 growing in normal cells even 
when it was given intravenously”. Lee is  also reasonably confident that there 
will be no major safety problem with  reovirus. “Most of us have been infected 
by reovirus as children without even  knowing about it”, he comments. Brown, 
however, is more cautious. “I would be a  fool to say there is absolutely no 
possibility of our mutated HSV replicating in  normal rapidly dividing cells”, 
she comments, “but to date there has been zero  toxicity in our trials”. 
And what about efficacy? Is oncolytic  therapy the elusive, magic anti-cancer 
bullet? Unlikely, says Chiocca, “but we  are getting indications that 
oncolytic virus therapy works well in combination  with other therapies. So, maybe 
putting this bullet together with other bullets  will turn out to be magic.”





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