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.

Safety concerns put the brakes on checkpoint inhibitor studies in multiple myeloma

While CAR-T therapy development has regularly been in the spotlight due to an association with lethal adverse events (AEs), immune checkpoint inhibitor therapies, with the exception of some combinations, have so far proved to be comparatively benign.

Severe AEs do occur with current PD-1/PD-L1 antibodies, most commonly with the CTLA-4 antibody ipilimumab (Yervoy®). Immune checkpoint inhibitors act by restoring the immune system’s ability to identify tumours as being “not self”: since the same mechanisms also serve to prevent unwanted immune responses to normal tissue, it’s not surprising that checkpoint inhibitor therapy can result in autoimmune-disease like effects involving the gut, liver, skin and thyroid gland. Severe immune related AEs can require intensive management with steroid and/or other anti-inflammatories, but fortunately occur in a minority of patients.

Studies leading to the approval of checkpoint inhibitors in melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer and bladder cancer progressed without the red flag of safety concerns, so it’s all the more surprising that a slew of multiple myeloma studies involving checkpoint inhibitor combinations have been brought to a halt by the FDA.

Three Merck studies involving anti-PD-L1 (Keytruda®: pembrolizumab) in combination with drugs already used in multiple myeloma treatment (pomalidomide or lenalidomide with dexamethasone) were placed on clinical hold as of early July following a higher number of deaths in the treatment arms. The FDA have since halted enrolment (although not dosing of enrolled subjects in similar studies involving combination with Bristol Myer Squibb’s anti-PD-1 checkpoint inhibitor, Opdivo® (nivolumab) plus either of two antibodies approved for multiple myeloma treatment.

The FDA’s caution also extend to six combination studies sponsored by Celgene, all involving AstraZeneca’s anti-PD-L1 antibody, Infinzi® (durvalumab),with one study being placed on full hold.

Lenalidomide (Revlimid®) and pomalidomide (Pomalyst®), chemical descendant of thalidomide, are approved for the treatment of multiple myeloma.  Lenalidomide and pomalidomide are potent immunomodulators but also act through a variety of other, non-immune mechanisms. It’s tempting to consider excessive up (or down) regulation of cytokines as a likely  smoking gun, but the combination of effects on tumour/immune system interaction with PD-1/PD-L1 may prove hard to unravel.

No approved cancer treatment is effective (or necessarily safe) for all tumour types: clinical experience with checkpoint inhibitors is still at a early stage, so perhaps safety (or efficacy) issues arising with one or more form of malignancy and/or with a number of the various checkpoint inhibitor combinations under study should perhaps not be unexpected and will not derail the advance of immuno-oncology.

The current generation of checkpoint inhibitors might never make for better multiple myeloma treatment but each setback represents an opportunity to gain better insight into what might work, and what’s to be avoided in the ongoing development and deployment of cancer immunotherapy.

Image courtesy of sheelamohan at FreeDigitalPhotos.net

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First flagged in:  UPDATED: Safety fears spur FDA to pause checkpoint combo studies by Bristol-Myers, Celgene. John Carroll. Endpoints News, online 7^th September 2017. http://tinyurl.com/ybekxrzl

Bristol-Myers Squibb Provides an Update on Three Opdivo-based Combination Clinical Studies in Multiple Myeloma. Company press release online 6^th September 2017. http://tinyurl.com/y9wv3h3g

Merck Provides Further Update on Three Multiple Myeloma Studies Evaluating KEYTRUDA® (pembrolizumab) in Combination with Pomalidomide or Lenalidomide. Company press release online 5^th July 2017. http://tinyurl.com/ya9z2tfs

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