Clinical trials on oncolytic viruses

Oncolytic viruses (OVs) are a new class of targeted anticancer drugs with unique mechanisms of action. Oncolytic virotherapy has evolved from the use of in vitro-passaged strains (first generation) to genetically engineered viruses with increased selectivity (second generation) and, ultimately, to recombinant OVs expressing a transgene (third generation).

The aim of the review was to analyze and summarize data on the current state of clinical research on OVs.

A PubMed search identified 182 articles from 1997 to 2024 with 154 studies reporting data on 4,850 patients. We found that adenovirus (n = 44) is the most common OV in clinical trials with more than two-thirds (n = 108) using modified or recombinant viral backbones, and granulocyte-macrophage colony-stimulating factor (GM-CSF; n = 40) was the most common transgene. The most common tumors targeted were melanoma (n = 1,997) and gastrointestinal (GI; n = 916) cancers with the most common monotherapy received by intratumoral (n = 3,003) or intravenous (n = 1,318) delivery routes. The most common combination included chemotherapy (n = 54).

Treatment-related adverse events included low-grade constitutional symptoms and local injection site reactions. Measurements of virus shedding were frequently performed, but many studies were limited to blood and tumor tissue analysis, using only polymerase chain reaction (PCR). Although most studies reported antiviral antibody titers (n = 101), only a few reported virus-specific T-cell responses (n = 23). Objective responses were recorded in 458 (9.4%) patients and disease control was achieved in 1,141 (23.5%) patients, although standard reporting criteria were used in only 60.4% of cases.

These data provide an insight into the current state of clinical research on OVs and highlight potential areas requiring further investigation to better define the role of OVs in cancer treatment.

1. Debela D.T., Muzazu S.G., Heraro K.D., Ndalama M.T., Mesele B.W., Haile D.C. et al. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med. 2021;9:1–10. DOI: 10.1177/20503121211034366.

2. Кит О.И., Харагезов Д.А., Лазутин Ю.Н., Мирзоян Э.А., Милакин А.Г., Статешный О.Н. и др. Иммунотерапия эпителиальных опухолей вилочковой железы. Южно-Российский онкологический журнал. 2023;4(3):56–67. DOI: 10.37748/2686-9039-2023-4-3-7.

3. Santos Apolonio J., Lima de Souza Gonçalves V., Cordeiro Santos M.L., Silva Luz M., Silva Souza J.V., Rocha Pinheiro S.L. et al. Oncolytic virus therapy in cancer: A current review. World J. Virol. 2021;10(5):229–255. DOI: 10.5501/wjv.v10. i5.229.

4. Hemminki O., Dos Santos J.M., Hemminki A. Oncolytic viruses for cancer immunotherapy. J. Hematol. Oncol. 2020;13(1):84. DOI: 10.1186/s13045-020-00922-1.

5. Heidbuechel J.P.W., Engeland C.E. Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies. J. Hematol. Oncol. 2021;14(1):63. DOI: 10.1186/s13045-021-01075-5.

6. Cristi F., Gutiérrez T., Hitt M.M., Shmulevitz M. Genetic modifications that expand oncolytic virus potency. Front. Mol. Biosci. 2022;9:831091. DOI: 10.3389/fmolb.2022.831091.

7. Silva Lima B., Videira M.A. Toxicology and biodistribution: the clinical value of animal biodistribution studies. Mol. Ther. Methods Clin. Dev. 2018;8:183–197. DOI: 10.1016/j.omtm.2018.01.003.

8. Yamaguchi T., Uchida E. Oncolytic virus: regulatory aspects from quality control to clinical studies. Curr. Cancer Drug Targets. 2018;18(2):202–208. DOI: 10.2174/1568009617666170222142650.

9. Russell S.J., Peng K.W. Oncolytic virotherapy: a contest between apples and oranges. Mol. Ther. 2017;25(5):1107–1116. DOI: 10.1016/j.ymthe.2017.03.026.

10. Li K., Zhao Y., Hu X., Jiao J., Wang W., Yao H. Advances in the clinical development of oncolytic viruses. Am. J. Transl. Res. 2022;14(6):4192–4206.

11. Кит О.И., Игнатов С.Н., Златник Е.Ю., Солдаткина Н.В., Росторгуев Э.Е., Сагакянц А.Б., Бондаренко Е.С. и др. Онколитическая виротерапия в лечении глиобластомы: достижения и проблемы клинических исследований (обзор литературы). Сибирский онкологический журнал. 2020;19(6):133–140. DOI: 10.21294/1814-4861-2020-19-6-133-140.

12. Abou-Alfa G.K., Galle P.R., Chao Y., Erinjeri J., Heo J., Borad M.J. et al. PHOCUS: A Phase 3, Randomized, Open-Label Study of Sequential Treatment with Pexa-Vec (JX-594) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer. 2023;1–17. DOI: 10.1159/000533650.

13. Rahman M.M., McFadden G. Oncolytic viruses: newest frontier for cancer immunotherapy. Cancers (Basel). 2021;13(21):5452. DOI: 10.3390/cancers13215452.

14. Aiuti A., Cossu G., de Felipe P., Galli M.C., Narayanan G., Renner M. et al. The committee for advanced therapies’ of the European Medicines Agency reflection paper on management of clinical risks deriving from insertional mutagenesis. Hum. Gene Ther. Clin. Dev. 2013;24(2):47–54. DOI: 10.1089/humc.2013.119.

15. Kaufman H.L., Kohlhapp F.J., Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat. Rev. Drug Discov. 2015;14(9):642–662. DOI: 10.1038/nrd4663.

16. Appaiahgari M.B., Vrati S. Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. Expert Opin. Biol. Ther. 2015;15(3):337–351. DOI: 10.1517/14712598.2015.993374.

17. Sena-Esteves M., Gao G. Introducing genes into mammalian cells: viral vectors. Cold Spring Harb. Protoc. 2020;2020(8):095513. DOI: 10.1101/pdb.top095513.

18. Kumar A., Taghi Khani A., Sanchez Ortiz A., Swaminathan S. GM-CSF: a double-edged sword in cancer immunotherapy. Front. Immunol. 2022;13:901277. DOI: 10.3389/fimmu.2022.901277.

19. Zhao Y., Liu Z., Li L., Wu J., Zhang H., Zhang H. et al. Oncolytic adenovirus: prospects for cancer immunotherapy. Front. Microbiol. 2021;12:707290. DOI: 10.3389/fmicb.2021.707290.

20. Woo S.R., Fuertes M.B., Corrales L., Spranger S., Furdyna M.J., Leung M.Y. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–842. DOI: 10.1016/j.immuni.2014.10.017.

21. Iurescia S., Fioretti D., Rinaldi M. Targeting cytosolic nucleic acid-sensing pathways for cancer immunotherapies. Front. Immunol. 2018;9:711. DOI: 10.3389/fimmu.2018.00711.

22. Andtbacka R.H.I., Collichio F., Harrington K.J., Middleton M.R., 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. J. Immunother. Cancer. 2019;7(1):145. DOI: 10.1186/s40425-019-0623-z.

23. Zhang B., Cheng P. Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol. Cancer. 2020;19(1):158. DOI: 10.1186/s12943-020-01275-6.

24. Soliman H., Hogue D., Han H., Mooney B., Costa R., Lee M.C. et al. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial. Nat. Med. 2023;29(2):450–457. DOI: 10.1038/s41591-023-02210-0.

25. Ren Y., Miao J.M., Wang Y.Y., Fan Z., Kong X.B., Yang L. et al. Oncolytic viruses combined with immune checkpoint therapy for colorectal cancer is a promising treatment option. Front. Immunol. 2022;13:961796. DOI: 10.3389/fimmu.2022.961796.

26. Monge C., Xie C., Myojin Y., Coffman K., Hrones D.M., Wang S. et al. Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer. J. Immunother. Cancer. 2023;11(2):e005640. DOI: 10.1136/jitc-2022-005640.

27. Liu X., Zhang J., Feng K., Wang S., Chen L., Niu S. et al. Efficacy and safety of oncolytic virus combined with chemotherapy or immune checkpoint inhibitors in solid tumor patients: A meta-analysis. Front. Pharmacol. 2022;13:1023533. DOI: 10.3389/fphar.2022.1023533.

28. Zhang B., Cheng P. Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol. Cancer. 2020;19(1):158. DOI: 10.1186/s12943-020-01275-6.

29. Passaro C., Alayo Q., De Laura I., McNulty J., Grauwet K., Ito H. et al. Arming an oncolytic herpes simplex virus type 1 with a single-chain fragment variable antibody against PD-1 for experimental glioblastoma therapy. Clin. Cancer Res. 2019;25(1):290–299. DOI: 10.1158/1078-0432.CCR-18-2311.

30. Zhu X., Fan C., Xiong Z., Chen M., Li Z., Tao T. et al. Development and application of oncolytic viruses as the nemesis of tumor cells. Front. Microbiol. 2023;14:1188526. DOI: 10.3389/fmicb.2023.1188526.

31. Ji W., Li L., Zhou S., Qiu L., Qian Z., Zhang H. et al. Combination immunotherapy of oncolytic virus nanovesicles and PD-1 blockade effectively enhances therapeutic effects and boosts antitumour immune response. J. Drug Target. 2020;28(9):982– 990. DOI: 10.1080/1061186X.2020.1766473.

32. Chen L., Ma Z., Xu C., Xie Y., Ouyang D., Song S., Zhao X. et al. Progress in oncolytic viruses modified with nanomaterials for intravenous application. Cancer Biol. Med. 2023;20(11):830– 855. DOI: 10.20892/j.issn.2095-3941.2023.0275.

33. Ban W., Guan J., Huang H., He Z., Sun M., Liu F. et al. Emerging systemic delivery strategies of oncolytic viruses: A key step toward cancer immunotherapy. Nano Res. 2022;15(5):4137–4153. DOI: 10.1007/s12274-021-4031-6.

34. Fares J., Ahmed A.U., Ulasov I.V., Sonabend A.M., Miska J., Lee-Chang C., Balyasnikova I.V. et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malig nant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 2021;22(8):1103–1114. DOI: 10.1016/S1470-2045(21)00245-X.

35. Fujita K., Kato T., Hatano K., Kawashima A., Ujike T., Uemura M. et al. Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer. Cancer Sci. 2020;111(5):1692–1698. DOI: 10.1111/cas.14366.

36. Silk A.W., O’Day S.J., Kaufman H.L., Bryan J., Norrell J.T., Imbergamo C. et al. A phase 1b single-arm trial of intratumoral oncolytic virus V937 in combination with pembrolizumab in patients with advanced melanoma: results from the CAPRA study. Cancer Immunol. Immunother. 2023;72(6):1405–1415. DOI: 10.1007/s00262-022-03314-1.

37. Nawrocki S.T., Olea J., Villa Celi C., Dadrastoussi H., Wu K., Tsao-Wei D. et al. Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial. Clin. Cancer Res. 2023;29(24):5087–5103. DOI: 10.1158/1078-0432.CCR-23-0229.

38. Hill C., Carlisle R. Achieving systemic delivery of oncolytic viruses. Expert Opin. Drug Deliv. 2019;16(6):607–620. DOI: 10.1080/17425247.2019.1617269.

39. Naumenko V., Van S., Dastidar H., Kim D.S., Kim S.J., Zeng Z. Visualizing oncolytic virus-host interactions in live mice using intravital microscopy. Mol. Ther. Oncolytics. 2018;10:14–27. DOI: 10.1016/j.omto.2018.06.001.

40. Bulcha J.T., Wang Y., Ma H., Tai P.W.L., Gao G. Viral vector platforms within the gene therapy landscape. Signal Transduct. Target Ther. 2021;6(1):53. DOI: 10.1038/s41392-021-00487-6.

41. Bubela T., Boch R., Viswanathan S. Recommendations for regulating the environmental risk of shedding for gene therapy and oncolytic viruses in Canada. Front. Med. (Lausanne). 2019;6:58. DOI: 10.3389/fmed.2019.00058.

42. Onnockx S., Baldo A., Pauwels K. Oncolytic viruses: an inventory of shedding data from clinical trials and elements for the environmental risk assessment. Vaccines (Basel). 2023;11(9):1448. DOI: 10.3390/vaccines11091448.

43. Berkeley R.A., Steele L.P., Mulder A.A., van den Wollenberg D.J.M., Kottke T.J., Thompson J. et al. Antibody-neutralized reovirus is effective in oncolytic virotherapy. Cancer Immunol. Res. 2018;6(10):1161–1173. DOI: 10.1158/2326-6066.CIR-18-0309.

44. Alberts P., Tilgase A., Rasa A., Bandere K., Venskus D. The advent of oncolytic virotherapy in oncology: The Rigvir® story. Eur. J. Pharmacol. 2018;837:117–126. DOI: 10.1016/j.ejphar.2018.08.042.

45. Xia Z.J., Chang J.H., Zhang L., Jiang W.Q., Guan Z.Z., Liu J.W. et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng. 2004;23(12):1666–1670.

46. Andtbacka R.H., Kaufman H.L., Collichio F., Amatruda T., Senzer N., Chesney J. et al. talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 2015;33(25):2780–2788. DOI: 10.1200/JCO.2014.58.3377.

47. Frampton J.E. Teserpaturev/G47Δ: first approval. BioDrugs. 2022;36(5):667–672. DOI: 10.1007/s40259-022-00553-7.

48. Forbes N.S., Coffin R.S., Deng L., Evgin L., Fiering S., Giacalone M. et al. White paper on microbial anti-cancer therapy and prevention. J. Immunother. Cancer. 2018;6(1):78. DOI: 10.1186/s40425-018-0381-3.

49. Lawler S.E., Speranza M.C., Cho C.F., Chiocca E.A. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3(6):841–849. DOI: 10.1001/jamaoncol.2016.2064.

50. Omole R.K., Oluwatola O., Akere M.T., Eniafe J., Agboluaje E.O., Daramola O.B. et al. Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy. Front. Pharmacol. 2022;13:1082797. DOI: 10.3389/fphar.2022.1082797.