Written by: Amelia Montemarano
As global cancer incidence is rising at an alarming rate, more attention has been redirected towards cancer immunotherapies. Oncolytic virus (OV) therapy has been recognized as a safe and potentially effective therapeutic approach against multiple malignancies. These naturally occurring or genetically engineered viruses are characterized by their ability to directly infect and lyse tumour cells and induce immune cell infiltration in the tumour microenvironment (TME). Although they have shown promise in combating certain cancers, most notably melanomas, current OV therapies face numerous barriers that limit their feasibility as a cancer treatment in the clinical setting. The objective of this review is to discuss the limitations of OV therapies in suppressing tumour growth and metastasis as well as the challenges that researchers face as they translate these therapies into a clinical setting.
Viruses as cancer treatments
The ability of viruses to infect tumour cells has been known for over a century. Tumour regressions have been continuously observed in patients with cancer following viral infections, which has inspired research on the complex interactions between viruses and malignancies.1,2,3,4 As virology was poorly understood in the early 20th century, the idea of using viruses to facilitate tumour destruction had not emerged in the research setting until the 1950s.2 Early clinical trials involved inoculating cancer patients with virus-infected bodily fluids; however, they provided only modest effects in tumour regression due to antiviral immune attacks.3
Due to the development of murine cancer models and gene editing technologies, OVs have been able to produce clinically significant therapeutic benefits and have garnered more attention in the field of immunotherapy over the last few decades.2 OVs are renowned for their ability to exploit the immunosuppressive effects of the TME to not only replicate in and lyse tumour cells, but also to promote immune cell infiltration and provide antitumor responses.5 Additionally, their appreciable safety profile is evidenced by a lack of significant adverse effects in clinical trials. This renders OVs as a favourable option for the treatment of certain cancers relative to other immunotherapies that have more toxic effects.3,6,7
Currently, there is only one OV therapy approved by the FDA and three approved worldwide. However, multiple viruses are under investigation as oncolytic immunotherapies.5 This review will focus on the development and clinical applications of the first FDA-approved OV, Talimogene Laherparepvec (T-VEC), as well as review the research being done to improve OV treatments.
The first FDA-approved Oncolytic Virus: T-VEC
T-VEC is an intralesional OV that received FDA approval in 2015 to treat unresectable lesions in melanoma patients post-surgical treatment.8It is a first-class recombinant OV developed from a clinical isolate of the herpes simplex-1 virus (HSV). As a normally pathogenic virus, multiple genetic changes are made to the HSV in order to control its functions in the body and prevent it from infecting healthy cells. Deletion of the infected cell protein 47 (ICP47) and infected cell protein 34.5 (ICP34.5) genes inhibit the natural mechanisms used by HSV to promote dissemination and replication in healthy cells.6,8In a normal strain of HSV, ICP47 is responsible for inhibiting CD8+ T cell responses and ICP34.5 blocks the actions of type 1 interferon (IFN) induced antiviral responses These actions promote viral propagation and result in the tissue damage that is associated with HSV infections. Due to the release of immunosuppressive factors, IFN signalling are already inhibited in the TME and a genetically modified HSV is still able to propagate without its natural defence mechanisms, thereby enhancing its selectivity for tumour cells. To improve the immunogenicity of T-VEC, two copies of granulocyte-macrophage colony-stimulating factor (GM-CSF) are inserted into the HSV strain to promote dendritic cell accumulation at sites of inflammation, enhance antigen presentation, and prime T-cell responses.8
Inefficient delivery methods hinder the potential that OVs hold as cancer therapeutics. Intratumoral injections are currently regarded as a more favourable route of administration, given the fact that they have shown greater responses compared to other delivery routes – most notably in the context of melanoma.9 The main advantage of this delivery method is that it offers precise control of the concentration of OV present in the TME, which often leads to better results.10 For instance, in a clinical trial conducted by Andtbacka et al.11, intratumoral delivery of T-VEC treatments in melanoma patients led to complete responses in 46.1% of injected lesions, 30.1% of uninjected non-visceral lesions, and only 9.4% of uninjected visceral lesions.11
The development of a successful systemic delivery method of OV therapies will broaden the range of their clinical applications.2 Although intravenous (IV) OV therapies are being researched, they face major limitations, including significant dilution of the virus in the bloodstream, neutralization of the virus by antiviral antibodies and complement proteins, viral sequestration by liver and spleen cells, and reduced permeability of tumour-associated blood vessels.9In order to increase the efficiency of systematic OV therapy, it is necessary to achieve high and sustained levels of viremia and improve OV tumour selectivity.2 An interesting advancement in systemic OV delivery is the use of cell-based delivery.12 Current methods of systemic delivery involve the injection of a “naked” virion into the patient’s bloodstream, which is susceptible to immune responses. However, cells that are easily infected by viruses and/or
have effective tumour-homing abilities, such as T cells, cytokine-induced killer cells, and mesenchymal progenitor cells, can instead be used to deliver OV therapies to avoid the challenges of systemic delivery routes.12
Another significant obstacle that hinders the efficacy of OVs is the body’s innate immune defence mechanisms. Antiviral immunity induced by natural killer (NK) cells, macrophages, antibodies, and IFNs can reduce a patient’s OV titer and clear the injection site of an OV therapy within hours.13,14 The goal of an effective OV treatment is to strike a balance between immune system activation and suppression in order to induce an antitumor immune response and avoid an antiviral one.14 Many strategies are being explored to mask viral surface proteins from neutralizing antibodies (nAbs) and protect OVs from their own immunogenicity. Recently, Francini et al.15identified a new class of polyvalent diazonium polymers that resulted in complete ablation of a nAb binding on an oncolytic adenovirus while maintaining biological activity in vitro and in vivo.15 Though OV transfection was reduced in the presence of these polymers, this study shows promise in the practice of blocking nAb binding sites to modulate OV activity. Similar protection against nAbs can be achieved through encapsulation of the OV in extracellular vesicles, which demonstrates tumour-selective delivery of oncolytic adenoviruses in models of lung carcinoma, as reported in a study by Garofalo et al.16
Cell-mediated innate immunity may also hinder the effects of OV treatments.14 As NK cells, in particular, contribute to the cytotoxic killing of virus-infected cells and regulating antiviral adaptive immune response, their recruitment leads to premature viral clearance following OV treatment.13,17,18 On the contrary, it is also argued that these seemingly unwanted antiviral responses, specifically immune cell recruitment, may be an essential component of an OVs antitumor effects.19In the TME, the release of immunosuppressive factors reduces the rate of homing into the tumour and therefore downstream cytotoxic effector functions. Immune cells that are recruited to provide an OV-induced adaptive antiviral response can overcome these immune evasion strategies and exert intrinsic anticancer activity.19 The strategic management of these antiviral responses may be critical in advancing OV therapies.13,19 Fu et al.13investigated a strategy to potentiate the antitumor effects of an HSV-based OV by arming it with Protein L-containing chimeric molecules, which diverts the OV from viral clearance. They achieved complete tumour regression in over half of the tumour-bearing mice treated with the armed OV, which emphasizes the importance of improving upon current OV designs.13
Monotherapy vs. Combination Therapy
Though OV therapies such as T-VEC are known to be generally safe, their efficacy as monotherapies is limited.1,6 The OPTiM trial published in 2015 evaluated the effects of T-VEC on 437 patients with unresectable stages IIIB, IIIC, or IV melanoma compared to treatment with subcutaneous recombinant GM-CSF.6 The overall response rate (ORR) and complete response (CR) rate for T-VEC was 26% and 11%, respectively, and 90% of patients who experienced CR were estimated to be alive in 5 years.6 Further analysis of patients with CR revealed that early commencement of this treatment and lower tumour burden were important factors that led to resolution of melanoma and long-term survival.6,7,11 This is further proven by a study published in 2019 by Franke et al.7that investigated the response rates of TVEC on 26 patients with early metastatic melanoma at the Netherlands Cancer Institute. The ORR was reported to be 88.5% after a ≥6-month follow-up, which was hypothesized to be attributed to low tumour burden and early progression of the disease.7 These findings support the fact that T-VEC monotherapies may be most effective within a narrow range of conditions and emphasizes the need for improvement.
Though checkpoint inhibitors are usually preferred over OVs to treat visceral melanoma metastases, the use of T-VEC and other OVs as adjuvants to these systemic immunotherapies may improve their efficacy.20,21 A randomized, open-label phase II trial compared the efficacy of a combination of T-VEC and ipilimumab (a CTLA-4 checkpoint inhibitor) therapies to ipilimumab monotherapy in 198 patients with stages III to IV melanoma.22 The investigators observed an improved ORR of 39% for the combination compared to 18% for the monotherapy, and an 89% durability of response following a mean follow-up of 16 months.22 Additionally, in a phase IB trial, the combination of intralesional injections of T-VEC with the anti-PDL 1 drug, pembrolizumab, resulted in a 62% ORR, which exceeds the ORRs of both T-VEC and pembrolizumab monotherapies in their phase III trials (26% and 33%, respectively).23 The promising results of these studies speak to the potential that T-VEC and other OVs have in enhancing previously developed immunotherapies.
Although clinical trials testing combination therapies of T-VEC and checkpoint inhibitors demonstrate promising results, the cost-effectiveness of these treatments limits their use in clinical settings. Atlmutairi et al.24 conducted an economic evaluation of the T-VEC/ipilimumab combination therapy in comparison to ipilimumab monotherapy and concluded that the price of the combination therapy exceeded the monotherapy by $362 033 (USD). They calculated the incremental cost-effectiveness ratio (the difference in cost between the two interventions divided by their difference in effect) to be approximately $2.2 million per quality-adjusted life-year gained. As insurance programs often cover or partially cover the costs of cancer treatments, manufacturing and administering this expensive therapy to a larger population of patients would
inevitably cause insurance rates to rise, making the cost of healthcare less affordable and accessible to others.25 These concerns must be considered prior to the implementation of novel and expensive immunotherapies into clinical settings, and cutting down costs associated with OV therapies will be a critical step in achieving the widespread use of this immunotherapy.24,25
OV therapies can induce tumour regression and may be used to safely and effectively treat early metastatic melanoma and other cancers. Although three OV therapies are currently available for clinical use worldwide, improving upon their designs is imperative to the future success of OVs as cancer therapeutics. One way of achieving this is to establish an efficient systemic delivery method to broaden the range of their clinical applications. Modulation of OV-induced antiviral responses may also improve the otherwise limited efficacy of this form of immunotherapy. Furthermore, the costs associated with delivering OV therapies to patients are overwhelmingly greater than standard cancer treatments. It is thus currently impractical to introduce OVs into the clinical setting, and its sustainability as a cancer treatment relies on further research to improve its efficacy and cost-effectiveness.
1. EIssa IR, Bustos-Villalobos I, Ichinose T, Matsumura S, Naoe Y, Miyajima N et al. The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Cancers. 2018;10(10):356. Available from doi: 10.3390/cancers10100356.
2. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nature Biotechnology. 2012;30(7):658-670. Available from doi: 10.1038/nbt.2287.
3. Kelly E, Russell SJ. History of Oncolytic Viruses: Genesis to Genetic Engineering. Molecular Therapy.2007;15(4):651-659. Available from: doi: https://doi.org/10.1038/sj.mt.6300108.
4. Dock G. The Influence of Complicating Diseases upon Leukemia. The American Journal of Medical Sciences. 1904;127(4);563
5. Cook M, Chauhan A. Clinical Application of Oncolytic Viruses: A Systematic Review. International Journal of Molecular Sciences. 2020;21(20):7505. Available from: doi: 10.3390/ijms21207505.
6. 6. Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV
melanoma. Journal for Immunotherapy of Cancer. 2019;7:145. Available from: doi: 10.1186/s40425-019-0623-z.
7. Franke V, Berger DMS, Klop WMC, van der Hiel B, van der Wiel BA, ter Meulen S et al. High response rates for T‐VEC in early metastatic melanoma (stage IIIB/C‐IVM1a). International journal of Cancer. 2019;145(4):974-978. Available from: doi: 10.1002/ijc.32172.
8. Corrigan PA, Beaulieu C, Patel RB, Lowe DK. Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma. Annals of Pharmacotherapy. 2017;51(8):675-681. Available from: doi: 10.1177/1060028017702654
9. Russell SJ, Peng KW. Oncolytic Virotherapy: A Contest between Apples and Oranges. Molecular Therapy. 2017;25(5):1107-1116. Available from: doi: 10.1016/j.ymthe.2017.03.026.
10. Ferguson MS, Lemoine NR, Wang Y. Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles. Advances in Virology. 2012;2012:805629. Available from: doi: 10.1155/2012/805629.
11. Andtbacka RHI, Kaufman HL, Colicchio F, Amatruda T, Senzer N, Chesney J et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. Journal of Clinical Oncology. 2015;33(25):2780-2788. Available from: doi: 10.1200/JCO.2014.58.3377.
12. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nature Biotechnology. 2012;30(7):658-670. Available from doi: 10.1038/nbt.2287.
13. Fu X, Tao L, Wu W, Zhang X. Arming HSV-Based Oncolytic Viruses with the Ability to Redirect the Host’s Innate Antiviral Immunity to Attack Tumor Cells. Molecular Therapy – Oncolytics. 2020;19:33-46. Available from: doi: 10.1016/j.omto.2020.09.002.
14. Lemos de Matos A, Franco LS, McFadden G. Oncolytic Viruses and the Immune System: The Dynamic Duo. Molecular Therapy – Methods and Clinical Development. 2020;17:349-358. Available from: doi: 10.1016/j.omtm.2020.01.001.
15. Francini N, Cochrane D, Ilingworth S, Purdie L, Mantovani G, Fisher K et al. Polyvalent Diazonium Polymers Provide Efficient Protection of Oncolytic Adenovirus Enadenotucirev from Neutralizing Antibodies while Maintaining Biological Activity In Vitro and In Vivo. Bioconjugate Chemistry. 2019;30(4):1244-1257. Available from: doi: 10.1021/acs.bioconjchem.9b00189.
16. Garofolo M, Saari H, Somersalo P, Crescenti D, Kuryk L, Aksela L et al. Antitumor effect of oncolytic virus and paclitaxel encapsulated in extracellular vesicles for lung cancer treatment. Journal of Controlled Release. 2018;283:223-234. Available from: doi: 10.1016/j.jconrel.2018.05.015.
17. Alvarez-Breckenridge CA, Yu J, Price R, Wojton J, Pradarelli J, Mao H et al. NK cells impede glioblastoma virotherapy via NKp30 and NKp46 natural cytotoxicity receptors. Nature Medicine. 2012;18(12):1827-1834. Available from doi: 10.1038/nm.3013.
18. Altomonte J, Wu L, Meseck M, Chen L, Ebert O, Sastre-Garcia A, Fallon J et al. Enhanced oncolytic potency of vesicular stomatitis virus through vector-mediated inhibition of NK and NKT cells. Cancer Gene Therapy. 2009;16(3):266-278. Available from: doi: 10.1038/cgt.2008.74.
19. Gujar S, Pol JG, Kim Y, Lee PW, Kroemer G. Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies. Trends in Immunology. 2018;39(3):209-221. Available from: doi: 10.1016/j.it.2017.11.006.
20. Conry RM, Westbrook B, McKee S, Norwood TG. Talimogene laherparepvec: First in class oncolytic virotherapy. Human Vaccines and Immunotherapeutics. 2018;14(4):839-846. Available from: doi: 10.1080/21645515.2017.1412896
21. O’Donoghue C, Doepker MP, Zager JS. Talimogene laherparepvec: overview, combination therapy and current practices. Melanoma Management. 2016;3(4):267-272. Available from: doi: 10.2217/mmt-2016-0021.
22. Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J et al. Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. Journal of Clinical Oncology. 2018;36(17):1658-1667.
23. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109-1119. Available from: doi: 10.1016/j.cell.2017.08.027.
24. Almutairi AR, Alkhatib NS, Oh M, Curiel-Lewandrowski C, Babiker HM, Cranmer LD et al. Economic Evaluation of Talimogene Laherparepvec Plus Ipilimumab Combination Therapy vs Ipilimumab Monotherapy in Patients With Advanced Unresectable Melanoma. JAMA Dermatology. 2019;155(1):22-28. Available from: doi: 10.1001/jamadermatol.2018.3958. 25. DiMagno SSP, Emanuel EJ. Pricing a Year of Progression-Free Survival. When Is the Cost of Cancer Drugs Unreasonable? JAMA Dermatology. 2019;155(1)15-16. Available from: doi: 10.1001/jamadermatol.2018.3753.