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.

Yet more on bugs and cancer

T-cells (red) on the attack

A Research Highlights piece in December’s Nature Reviews Cancer reports on another intriguing aspect of the interplay between our immune systems and the bugs we carry, namely how gut flora might influence the effectiveness of cancer immunotherapy.

Two international research groups set out to determine  whether the composition of the gut microbiome might influence the response to immunotherapy  directed against  PD-1, a so-called “immune checkpoint “ expressed by activated T cells and macrophages and which is exploited by cancer cells to switch off immune attack. Antibody-mediated blockade of the interaction between PD-1 and its ligand, PD-L1 can restore the anti-cancer response. The anti-PD-1 antibodies pembrolizumab and nivolumab (Opdivo® and Keytruda®, respectively) have proved their worth in the treatment of metastatic melanoma and a variety of other solid tumours.

Genetic analysis of faecal bacteria collected from cancer patients before and after anti-PD-1 immunotherapy found a correlation between gut bacteria diversity and the duration of progression-free survival in cancer patient after treatment.

A collaboration between US and French researchers found differences in the abundance of certain gut bacteria, with Faecalibacterium being enriched in melanoma patients responsive to anti‑PD1 therapy: Bacteroidales was enriched in those patients not responsive to immunotherapy. Differences were also found between responders and non-responders in regards to bacterial metabolism and the composition of immune cells found in the tumour microenvironment. Tumour-infiltrating “killer” T cells were more likely to be found in patients carrying an abundance of Faecalibacterium, while  immunosuppresive cells were more common in individuals carrying abundant Bacteroidales.

Another (again, predominantly American and French) research group found that the abundance of the gut bacterium Akkermansia muciniphila in non-small cell lung cancer and renal cancer patients correlated with a positive response to anti-PD-1 immunotherapy.

Both groups looked for possible mechanistic links between gut bacteria abundance and treatment response. When patient-derived gut bacteria were transplanted into germ-free mice, a variety of favourable effects on tumour growth and immune response were observed, including higher numbers of killer T-cells  and other, immune effector cells, along with changes in the expression of  T- cell receptors for key immune signalling molecules (“chemokines”).

The response to immunotherapy is difficult to predict and involves a variety of tumour factors (PD-L1 expression, tumour burden, degree of mutation) and host factors (immune system genetic makeup, T cell infiltration of the tumour). Analysis of the gut microbiome is unlikely to improve prediction of response, but preservation or manipulation of the gut microbiome through avoidance of antibiotic treatment prior to immunotherapy, or probiotic treatment to encourage “good” bacteria could conceivably translate into better and more sustainable response rates for at least some individuals.  

Photo credit : Rita Elena Serda.  National Cancer Institute \ Duncan Comprehensive Cancer Center at Baylor College of Medicine

ASCO 2017 Annual Report again picks immunotherapy as “Advance of the Year “

ASCO, the American Society of Clinical Oncology, is probably best known to followers of the pharma and biotech industries for its high profile annual conference, always the subject of intense sector analyst scrutiny.  ASCO also publishes a highly-readable annual report highlighting clinical advances in cancer therapy and the shape of future research.

Once again, immunotherapy (dubbed “Immunotherapy 2.0” by ASCO) takes the honours as “Advance of the Year”, underscoring the breakthrough nature of this approach to cancer treatment and its expanding role across a growing number of cancer indications.

Put very simply, immunotherapy utilises the patient’s own immune system to combat cancer. Tumours thrive by deploying a variety of countermeasures which are highly effective in subverting the immune response.  A mechanism common to several tumour types is surface expression of proteins that lock onto receptors (“immune checkpoints”) present on T cells,  resulting in their deactivation. By deliberately blocking this interaction, T-cell “seek and destroy” functions can be restored.

Immune checkpoint inhibitors were first approved on the basis of their efficacy in metastatic melanoma, with the first being Yervoy® (ipilimumab: Bristol Myers Squibb) in 2011, followed by Keytruda® (pembrolizumab: Merck) and Opdivo® (nivolumab: Bristol Myers Squibb) in 2014 and,  most recently, Tecentriq® (atezolizumab: Roche) for the treatment of some forms of lung cancer. A number of other biologic immune checkpoint inhibitors are in late stage clinical evaluation.

From the outset, checkpoint inhibitor treatment has been notable for impressive increases in patient survival, although not across the board. Reliable identification of those patients most likely to benefit from checkpoint inhibitor therapy remains a frustration. Optimum duration of therapy also remains to be established. Given the cost of checkpoint inhibitor treatment (around £30,000 before an undisclosed discount in the UK and around $150,000 in the US), patient selection and length of treatment are of key importance to healthcare systems already struggling with soaring cancer therapy expenditure.

Recent checkpoint inhibitor approvals include treatment of head and neck, bladder and renal cancers and Hodgkin’s lymphoma, and evaluation is progressing in liver, breast, gastric and other cancers. The need to attain market dominance is a major driver of clinical trial activity: at the end of 2016, Merck’s Keytruda® was being trialled against 30 tumour type in more than 350 registered studies, of which around 100 studies will evaluate treatment combinations.

Hundreds of micro and mid-cap companies are looking to stake a claim in the immunotherapy (aka “immuno-oncology) space. Some are hopeful that repurposed drugs can modify the tumour microenvironment to favour the immune system, while others believe that combination with checkpoint inhibitors and other agents can boost the so far disappointing efficacy of cancer vaccines.

Tumour immunology remains poorly understood. Potential big winners in next generation immunotherapy are those companies engaged in the unravelling of tumour defence mechanisms to find exploitable vulnerabilities.

Who knows, but given the rate of progress, the 2027 ASCO “Advance of the Year” could well be “Immunotherapy 12.0”.

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ASCO 12^th Annual Report on Progress Against Cancer. 2017 Clinical Advances. Online 1^st February 2017    http://tinyurl.com/zwzv5vg