Going viral

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.

Merck and Viralytics announce acquisition agreement, expanding Merck’s leading immuno-oncology pipeline. Company press release online 21st February 2018. http://tinyurl.com/yckoq5o8

Combination strategies harness the power of the oncolytic virus talimogene laherparepvec. Helwick, C. The ASCO Post online 10th November 2016. http://tinyurl.com/ybt73aha.

Review: Oncolytic virotherapy, updates and future directions. Fountzilas, C et al. Oncotarget. 2017; 8:102617-102639. http://tinyurl.com/y8wbc3mv

Added 25th February 2018:

A publication in Science Translational Medicine suggests that an intravenously administered oncolytic rheovirus can cross the blood-brain barrier to infect  high grade gliomas and brain metastases.  Investigation of excised tumours from nine subjects indicated that viral infection resulted in interferon production and cytotoxic T cell recruitment in the tumour microenvironment, along with upregulation of the PD-1/PD-L1 immune checkpoints. 

Whether combination with an immune checkpoint inhibitor results in meaningful tumour regression (or in the case of glioma, significant reduction in the rate of recurrence after surgery) awaits further clinical studies. Treatment with the PD-1 immune checkpoint inhibitor Opdivo failed to increase survival over best standard of care in glioblastoma patients in a Phase III study concluded last year (April 2017). 

Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Samson, A et al. Sci. Transl. Med. 10, eaam7577 (2018) 3 January 2018