Oncolytic virotherapy is the use of natural or engineered viruses to combat cancer. Though sounding somewhat esoteric, this strategy actually relies on commonly found human and animal viral pathogens, often times engineered to increase their safety and anti-tumoural efficacy. Recent evidence indicates that in addition to direct killing of cancer cells, oncolytic viruses (OVs) can potently stimulate the immune system to mount an attack against, and promote lasting immunity against the tumour 1. Intriguingly, a similar effect was described by Dr. William Coley over 100 years ago when he injected Streptococcus pyogenes (live or heat-killed) into post-operative lesions of sarcoma patients – ahead of his time, Coley described a “commotion in the blood” leading to flu-like symptoms that in ~40% of patients resulted in an anti-tumour effect 2. Today we know that this commotion in the blood is mediated by cells from the immune system that evolved over tens of millions of years to recognize danger signals.
What makes tumour cells susceptible to OVs? The answer is yet to be completely elucidated, but our research group and others believe that the inability of cancer cells to stop proliferating and synthesizing proteins is at the root of their susceptibility to OVs. Whereas normal cells that are infected with a virus (or an OV) will stimulate a protective pathway known as the Interferon response (IR) – which leads to inhibition of protein synthesis and cell division in an effort to prevent further virus spread 3, 4– most cancer cells are incapable of stimulating this pathway with the consequence that the virus will continue to be produced and infect neighbouring cells 5. Nonetheless, some OVs currently in development have been further engineered to reduce their infectious potential towards normal cells and thus increasing their therapeutic potential. For example, the only currently approved OV is a modified herpes simplex virus -1, Talimogene laherparepvec (Imlygic™, Amgen; approved in the US and Europe for the treatment of melanoma in 2015) which was engineered to remove two pathogenicity genes; one that facilitates evasion of the immune system, and another one that promotes survival of infected cells, resulting in a virus that is incapable of reproducing in normal cells (they either die spontaneously or the immune system removes them)6.
There are myriad of OVs currently in development. Some are derived from animal pathogens, such as Vaccinia, Seneca Valley and Newcastle Disease viruses; some are unmodified human pathogens such as Reovirus, or naturally attenuated human pathogens such as Measles and Coxsackievirus; and yet some have been genetically engineered to increase safety or efficacy such as vesicular stomatitis virus (VSV), Maraba (also derived from VSV), herpes virus simplex-1 (HSV-1), and adenovirus amongst many others 7, 8. The clinical evidence to date suggests that response rates are variable, and that only a subset of patients appear to respond. For instance, a recent report describes that although the Edmonston strain of measles virus was well tolerated, only 1 out of 32 multiple myeloma patients achieved a complete response (and still cancer free, nearly 4 years after the treatment) 9. Similarly, pexastimogene devacirepvec; (JX-594, Sillajen), an OV derived from Vaccinia virus, is reported to be well tolerated in clinical trials for pediatric and adult cancers, but has also shown a disappointing response rate 10-12. Even for Imlygic, emerging data suggests that only ~10% of treated metastatic melanoma patients attain a durable response and benefits in long term survival 13. Though enthusiasm may be tempered by these results, recent advances in immunotherapy are thought to be key to unleash the clinical potential of OVs.
Interestingly, it has been reported that “killed” Maraba and HSV-1 (by UV inactivation) can elicit potent immune-Figure mediated anti-tumour effects 14, 15, suggesting that direct destruction of tumour cells may not be required for therapeutic efficacy – in fact, viruses that have lost the ability to replicate, yet can stimulate potent anti-tumour immunity may indeed be the safest OV therapeutic. Perhaps, as observed by Coley with his heat-killed bacteria, or as proposed by Dr. Polly Matzinger in her danger hypothesis, it is the molecular “shapes”, not the pathogenic function per se of the virus or the bacteria that alert our immune system to fight 16– initially by stimulating our innate immune system (a primordial system evolved to combat dangerous pathogens non-specifically), and subsequently by stimulating our adaptive immune system (exquisitely specific to a particular target). Though the mechanisms remain incompletely understood, they do provide clues as to how best to potentiate OV therapy in a clinically meaningful way.
It is well established that various receptor families expressed in cells of the innate immune system, such as the Toll-like receptors (TLRs), NOD-like receptors, and STING, amongst others, recognize molecular patterns commonly associated with pathogenic organisms, or infected/compromised cells 17, 18. Via these receptor families (collectively known as pattern recognition receptors), OVs likely stimulate a “fight or flight” response in innate immune cells that can promote immediate anti-tumour effects via macrophages/monocytes and natural killer (NK) cells, and subsequent antitumour effects by stimulating priming of T and B cells by antigen presenting cells 19. Fig 1 illustrates some of the mechanisms by which OVs potentiate antitumour immunity. Throughout this mechanistic cascade, there are critical points that can be potentiated with currently available immunotherapeutic strategies. For instance, the priming of T cells by antigen presenting cells can be potentiated anti-CTLA4 checkpoint antibodies, whereas the direct anti-tumour effects of NK or T cells can be further unleashed by anti-PD1 (or anti-PD-L1) checkpoint antibodies. Theoretically, any of these interventions could potentiate OV-mediated anti-tumour immunity.
Currently, several of the above immunotherapy strategies are being explored in clinical trials in combination with a variety of OVs. For example, various HSV-1 based OVs are being tested in combination with Ipilimumab (anti-CTLA-4) 20, 21 and Nivolumab (PD-1 inhibitor) 22, whereas JX-594 is being tested in combination with Ipilimumab 23, Tremelimumab (anti-CTLA-4), and Durvalumab (anti-PD-L1) 24. Moreover, novel OVs engineered to carry and deliver immune stimulator molecules, such as LOAd703 – an adenovirus armed with CD40L and 4-1BBL which potently stimulate innate and adaptive anti-tumour immunity 25– are also entering clinical testing. OVs have also been armed with the immunostimulatory cytokine GM-CSF (such as JX-594, CG0070, and Imlygic among others) 26, though in retrospect this particular cytokine may have the downside of stimulating pro-tumour myeloid cells 27, which may contribute to reduced clinical efficacy.
In addition to immunostimulatory strategies, OVs are also being tested in combination with chemotherapy and radiotherapy 28. Moreover, OVs engineered to deliver suicide genes that convert pro-drugs to toxic metabolites, such as TG6002 29 and Toca-511 30, are also being tested clinically with some encouraging results 31, 32, suggesting that OVs could be well positioned to be combined with various small molecules without increasing the risk of damage to healthy tissues. Similarly, an adenovirus expressing the enzyme thymidylate kinase (TK) is being tested in clinical trials in combination with the anti-viral drug ganciclovir 33, 34 – with the premise that infected tumour cells would express TK and convert ganciclovir to the toxic metabolite ganciclovir triphosphate. Lastly, recent pre-clinical efforts have also identified molecules that may increase OV spread and infectious potential 35-37. Nonetheless, these potentiation strategies carry with them the inherent risk of fomenting OV replication in normal tissues, thus particular attention to safety and tumour selective delivery will be key for their clinical translation.
It is clear that OV therapy has incredible potential, but we are in the early days of testing and implementation. The scientific community eagerly awaits the results of all the above clinical trials, and while some have started showing encouraging efficacy and toxicity, we may have to wait for a few years for all the data to be properly analyzed in sufficient numbers of patients. We believe that identifying the right genetic modifications to OV (i.e. engineering immunostimulatory molecules, suicide genes, etc.), and the proper combinations with small molecules or therapeutic antibodies, will be instrumental to realize the full potential of oncolytic virotherapy.
Ismael Samudio, Ph.D. is the Head of Biologics at The Centre for Drug Research and Development, Vancouver, Canada
Fig 1. Mechanisms by which OV potentiate anti-tumour immunity. In addition to direct oncolysis, various OV (shown are Adenovirus, Vaccinia and herpes simplex virus) can directly stimulate macrophages (Mφ), dendritic cells (DC) and NK cells via various pattern recognition receptors. Activated Mφ and DC can in turn promote further stimulation of NK cells, and by crosspresenting tumour antigens released form tumour cells lysed by the OV, they can also crossprime cytotoxic T cells (CTL). Primed CTL and activated NK cells can then induce direct antitumour effects, and via memory T cell generation establish long lasting antitumour immunity.
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