But in spite of the impressive results, there are still challenges to be faced with the therapies. Only two CAR-T’s have received FDA approval to date and checkpoint inhibitors, targeting proteins such as PD-1 and PD-L1, are only effective in about 20% of cancers. As an industry, it’s our responsibility to challenge ourselves to address the needs of the remaining 80% of patientsCar who’ve been unable to harness the potential of immunotherapies.
The answer may rest in an old immunotherapeutic approach that is finally getting its due and experiencing a renaissance of late – the oncolytic virus.
Commenting on this approach, Padmanee Sharma, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center said: “Oncolytic virus therapy is a priority on the list of new immuno-oncology therapies. It’s a therapy that is very effective at activating an adaptive immune response by generating a strong innate immune response.”
Checkpoint inhibitors’ lack of efficacy is largely due to their inability to create an inflamed tumour phenotype – a trait that severely limits their potential in targeting and destroying cancerous tissue. An inflamed phenotype allows the immune system to recognise cancerous tissue from healthy tissue; without it, the immune system has a difficult time discerning which cells to destroy and which cells to leave unharmed. This process of inflaming tumours is commonly referred to as turning ‘cold’ tumours ‘hot’, as it serves as a signal to our immune system’s natural killer cells and T cells to destroy them – potentially increasing the number of patients who could be impacted by checkpoint inhibitors.
This is where oncolytic viruses come in. Having been investigated since the late 1800s, oncolytic viruses are hardly a novel approach to treating cancers, but the science backing their potential has only recently begun to be recognised. Initially, oncolytic viruses were evaluated solely for their ability to directly kill cancerous cells, which yielded mixed results. Decades later, scientists are now beginning to understand the ways oncolytic viruses help to not just destroy tumours, but to also elicit from the body an immune response against them.
Evidence of increased PD-L1 expression pre (left) and post (right) treatment
When an oncolytic virus invades a tumour, it recruits both the innate and adaptive immune systems to the tissue. Specifically, the cancerous cells lyse upon viral invasion, triggering the body’s innate immune response and activating natural killer cells to destroy the cancerous tissue. The adaptive immune system then kicks in, recruiting B cells and T cells to recognise and target the rest of the tumour, ultimately inducing PD-1 and PDL-1 expression – making oncolytic viruses an ideal candidate to pair with checkpoint inhibitors.
The newfound potential for oncolytic viruses has not gone unnoticed, either – the landscape is gaining serious traction in the biopharma world, capturing the attention of high-profile investors and pharmaceutical giants alike.
Thanks to this emerging recognition, the oncolytic virus market is growing rapidly. In May Janssen acquired BeneVir BioPharm – a private biotech developing a proprietary oncolytic virus platform to be used in combination with checkpoint inhibitors – for just over $1 billion. Just a few months prior to that deal Merck purchased Australian-based Viralytics for just under $400 million, giving them rights to develop and test Keytruda (pembrolizumab) with Viralytics’ oncolytic virus. It’s also important to note a recent trend in collaborations between pharma and oncolytic virus companies, as both seek to validate the potential of oncolytic viruses and immunotherapies when administered simultaneously.
The one FDA-approved oncolytic virus so far has been Amgen’s Imlygic (talimogene laherparepvec), otherwise known as T-VEC. Imlygic is a genetically modified herpes virus indicated for the treatment of recurrent melanoma. But there’s a number of oncolytic viruses being investigated in research labs and clinical trials across the world – 164 in preclinical and clinical development in total – working from sources such as adenovirus, reovirus, measles and herpes. Some, like adenovirus, are engineered for tumour selectivity, and others, such as reovirus, occur naturally.
A number of oncolytic viruses currently being investigated in combination with immuno-oncology agents have shown promise in the clinic. TargoVax’s adenovirus-based immunotherapy ONCOS-102 is in phase I clinical studies in combination with either chemotherapy or a checkpoint inhibitor across multiple tumour types. TurnStone Biologics is developing a therapy engineered from the Maraba virus and is running a phase I/II clinical trial of it with Keytruda in lung cancer patients. Oncolytics Biotech is developing a reovirus-based immunotherapy – pelareorep – in combination with Celgene’s Imnovid (pomalidomide) and Revlimid (lenalidomide) in patients with myeloma, as well as with Merck’s Keytruda in patients with second-line pancreatic cancer and is preparing for a phase III study in metastatic breast cancer.
Among the oncolytic viruses currently in development, factors such as virus type, engineering and administration differentiate them from one another. Arming viruses – engineering them to have immune modulators to further activate the immune system against cancerous tissue – is one such differentiation. However, while armed viruses have shown success and may be valuable in future development of immuno-oncology agents, they are not necessary in creating the inflamed tumour phenotype. Unarmed, naturally-occurring viruses are capable of turning tumours from ‘cold’ to ‘hot’, so arming them with additional, extraneous enhancements in not necessary for potential work with checkpoint inhibitors.
A final clinical development consideration with oncolytic viruses is whether they should be administered intratumourally or intravenously. Delivering intratumourally can reduce the toxicity of armed viruses and could potentially be more targeted, but this delivery often leads to problems in the clinic due to leakage from injection, and genetic engineering of a virus may result in additional handling and administrative challenges in the clinic. Intravenous delivery of oncolytic viruses is a safer, less time intensive administration and a better method of targeting systemic or metastatic disease. An unarmed intravenous delivery may be the safest oncolytic virus. There is also human experience of unarmed viruses that doesn’t exist with armed viruses – consequently the unarmed intravenous delivery of a virus is considered a BioSafety Level 2 agent – the equivalent of a blood product – that can be delivered in a standard outpatient setting, as is typical of a chemotherapy agent.
While it has taken our industry some time to fully understand the potential of oncolytic viruses as effective immunotherapy agents, recent research and clinical developments have revealed the ways we can utilise them to all that they’re capable of. This renaissance of sorts has shown what is currently lacking in approved immunotherapies – the lack of the inflamed tumour type, as well as how we can improve their efficacy by combining them with agents like oncolytic viruses.
As showcased by acquisitions and significant clinical advancements, oncolytic viruses hold the potential to reach much of the remaining 80% of cancer patients for whom checkpoint inhibitors are ineffective. The breadth of oncolytic viruses and their delivery – engineered versus naturally occurring, armed versus unarmed, intravenous versus intratumoural delivery – reflects the breadth not only of cancer types’ indications, but more importantly, of patients in need.