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| False colour image of herpes virus. |
That certain viruses cause or promote cancer has been known for decades, prompting the development of effective vaccination against human papilloma virus and hepatitis B and curative drug treatments for hepatitis C to protect against or eliminate these cancer-causing (“oncogenic”) viruses. Conversely, viruses also have the potential to be useful allies in cancer treatment.
Destruction of
tumour cells as a consequence of viral infection was first observed in the
1950s, leading to empirical, and largely unsuccessful, clinical
experimentation. In the last 20 years, the capability to genetically modify
viruses and culture them consistently in quantity has allowed the practical exploitation
of tumour-destroying viruses to be revisited.
A variety of common
viruses (including herpes, measles, and polio viruses) are “oncolytic”, that is
they can selectively infect and rupture cancer cells and, in doing so, usefully
redirect the innate and adaptive immune responses towards the tumour. Lysis is also
believed to reveal tumour antigens normally hidden from immune system
recognition and can disrupt blood vessels essential for tumour survival.
The other side
of immune recognition (and memory) is that prior encounters with the
myriad of viruses that we are naturally
exposed to serves to blunt the effectiveness of oncolytic viruses, by either thwarting
their spread within the tumour, or through neutralization before the virus
reaches the tumour. The latter can be circumvented by administering the virus
directly into the tumour, albeit not a convenient way of dosing, while substantial
ingenuity has been applied to improving the effectiveness of virotherapy through
chemically masking viruses from immune recognition or using viral strains not normally
encountered by humans, permitting systemic rather than local administration.
Other enhancements
aimed at improving the safety and effectiveness of virotherapy have included genetic
modification to more efficiently target molecules expressed only by tumours, to
promote viral replication within cancer cells, and to express proteins that
boost anti-tumour immunity. Despite numerous clinical studies across a range of
tumour types, including combination with chemotherapy or radiotherapy, consistent
and compelling efficacy data has largely eluded virotherapy.
This might be
set to change. Virotherapy has the very useful side effect of upregulating
immune checkpoint inhibitor expression, opening up prospects for improving
clinical response rates in combination immunotherapy.
This week saw
Merck take a plunge into virotherapy with the acquisition of Viralytics, an
Australian biotech that has successfully taken a therapy exploiting a common
cold virus into the clinic. Merck have gambled $394 million on the Viralytics
candidate being synergistic with their blockbuster PD-1 immune checkpoint inhibitor,
Keytruda®.
Amgen, the
first global biopharmaceutical company to venture into virotherapy in 2011 with
the acquisition of BioVex and its lead development candidate, since rebranded
as Imlygic™ (talimogene laherparepvec or “T-Vec”) has shown that the
combination of Imlygic™ and the CTl4-A checkpoint inhibitor Yervoy® resulted in
a doubling in clinical response rates over Yervoy® alone in melanoma patients. Amgen
and Merck are co-sponsors of an ongoing Phase II clinical study evaluating T-Vec
in combination with Keytruda® in sarcoma patients.
While the
Merck deal offers encouragement for the raft of small and mid-cap biotechs
pursuing virotherapy development, it remains to be seen whether these “living
drugs” can hold their own against the multitude of more easily manufactured and
administered biologic and small molecule immunotherapies also under evaluation
in immune checkpoint combination studies.
That said, further tweaking could eventually establish virotherapy as a potent
means of triggering innate and adaptive immune responses across a spectrum of solid
tumours, irrespective of checkpoint inhibitor expression, immune infiltration
or degree of tumour mutation.
Photo credit: Credit:
NIH Image gallery. Bernard Heymann, Ph.D., NIAMS Laboratory of Structural
Biology Research.
