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종양 용해성 바이러스-암 치료에서의 새 시대

Oncolytic Viruses - A New Era for Cancer Therapy

  • Ngabire, Daniel (Gene and Cell Therapy Research Center for Vessel-Associated Diseases, School of Medicine, Pusan National University) ;
  • Niyonizigiye, Irvine (Department of Microbiology, College of Natural Sciences, Pukyong National University) ;
  • Kang, Min-jae (Department of Microbiology, College of Natural Sciences, Pukyong National University) ;
  • Kim, Gun-Do (Department of Microbiology, College of Natural Sciences, Pukyong National University)
  • 투고 : 2019.07.23
  • 심사 : 2019.07.26
  • 발행 : 2019.07.30

초록

최근 수십 년 간 종양 용해성 바이러스(Oncolytic viruses; OV)는 암 치료제로서의 잠재성에 의해 광범위하게 연구되어왔다. 종양 용해성 바이러스는 두 가지의 독특한 장점을 가지고 있는데, 첫째로 암세포만을 특이적으로 감염시키고 사멸시킬 수 있다는 것이고, 두 번째로는 암이 진행되는 초기 단계에 숨어서 인식되지 않는 상태인 종양 관련 항원들을 인식하는 특정한 적응 면역을 활성화 시키는 것이다. 2015년에는 유전자 변형 종양 용해성 바이러스인 Talminogene laherparepvec (T-VEC)이 미국 식약청(FDA)의 승인을 받았으며, 현재는 다양한 종양 용해성 바이러스들이 단일로 사용되거나 기존의 암 치료 방법인 면역 치료법, 방사선 치료법, 화학 치료법과 함께 사용되어 임상 시험에서 활성이 연구되고 있다. 종양 용해성 바이러스 치료법의 효능은 항 종양 면역 활성과 항바이러스 반응의 균형이 어느 정도인가에 의해 조절되기 때문에, 획기적인 성과에도 불구하고 암 치료를 위한 종양 용해성 바이러스의 개발은 전달 방법, 바이러스를 인식하는 신체 내 항체 및 종양의 복잡성, 가변성, 반응성에 따른 항바이러스의 면역 유도와 같은 다양한 장애물을 극복하여야 하는 문제가 있다. 종양 내에 직접 종양 용해성 바이러스를 투여하는 방법은 눈에 띄는 부작용이 없이 고형 종양을 줄이는 것에 성공하였으나, 아쉽게도 뇌종양 같은 일부 종양에는 사용할 수 없고 전신 투여가 필요한 단점이 존재한다. 이러한 장애물들을 극복하기 위해서 종양 용해성 바이러스의 효능을 높이기 위한 형질 전환 유전자의 삽입 혹은 면역 조절 물질과 바이러스를 조합하는 등의 다양한 전략들이 개발되고 있다.

In recent decades, oncolytic viruses (OVs) have extensively been investigated as a potential cancer drug. Oncolytic viruses have primarily the unique advantage in the fact that they can only infect and destroy cancer cells. Secondary, oncolytic viruses induce the activation of specific adaptive immunity which targets tumor-associated antigens that were hidden during the initial cancer progression. In 2015, one genetically modified oncolytic virus, talimogene laherparepvec (T-VEC), was approved by the American Food and Drug Administration (FDA) for the treatment of melanoma. Currently, various oncolytic viruses are being investigated in clinical trials as monotherapy or in combination with preexistent cancer therapies like immunotherapy, radiotherapy or chemotherapy. The efficacy of oncolytic virotherapy relies on the balance between the induced anti-tumor immunity and the anti-viral response. Despite the revolutionary outcome, the development of oncolytic viruses for the treatment of cancer faces a number of obstacles such as delivery method, neutralizing antibodies and induction of antiviral immunity due to the complexity, variability and reactivity of tumors. Intratumoral administration has been successful reducing considerably solid tumors with no notable side effects unfortunately some tumors are not accessible (brain) and require a systemic administration of the oncolytic viruses. In order to overcome these hurdles, various strategies to enhance the efficacy of oncolytic viruses have been developed which include the insertion of transgenes or combination with immune-modulatory substances.

키워드

SMGHBM_2019_v29n7_824_f0001.png 이미지

Fig. 1. Principle of oncolytic virotherapy. Oncolytic viruses are natural or programmed cancer-killing viruses. The infection of normal leads to the activation of antiviral pathway such as Type 1 interferons which will block the virus replication. In cancer cells, antiviral and cell proliferation pathways are altered and oncolytic viruses utilize these disruptions to specifically target and infect only cancer cells which lead to the lysis of infected cancer cells and the expansion of oncolytic viruses to other tumor cells.

SMGHBM_2019_v29n7_824_f0002.png 이미지

Fig. 2. Mechanisms of oncolytic viruses. Oncolytic viruses enter the cell through the interaction with cell receptors that are usually overexpressed in cancer. Some viruses utilize more than one specific receptor but different viruses can also share one receptor. Other viruses enter the cell via endocytosis through fusion of membranes. Once in the cell, viruses take advantage of aberrant pathways to replicate. CD, Cluster of differentiation; CAR, Coxsackievirus-adenovirus receptor; ICAM-1, Intracellular adhesion molecule 1; LDLR, Low density lipoprotein receptor; HSV, Herpes simplex virus; HVEM, Herpesvirus entry mediator; SARs, Sialic acid receptors; SLAM, Signaling lymphocyte activation molecule; JAK, Janus kinase; STAT, Signal transducer and activator of transcription; Rb, Retinoblastoma; PKR, Protein kinase R; RIG-Ⅰ, Retinoic acid-inducible gene Ⅰ; TK, Thymidine kinase.

SMGHBM_2019_v29n7_824_f0003.png 이미지

Fig. 3. The induction of immune response by oncolytic viruses. The cell lysis of cancer cells by oncolytic viruses is followed by the release of neo-oncolytic viruses, tumor-associated antigens (TAAs), danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). The new oncolytic viruses can infect other existing cancer cells and continue the cycle of cancer cells elimination. TAAs, DAMPs and PAMPs are processed by antigen presenting cells (APCs) and initiate adaptive immune response by CD8+T lymphocytes against cancer cells.

Table 1 Clinical trials of oncolytic virus

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참고문헌

  1. Alemany, R. 2013. Viruses in cancer treatment. Clin. Transl. Oncol. 15, 182-188. https://doi.org/10.1007/s12094-012-0951-7
  2. Andtbacka, R. H. I., Curti, B. D., Kaufman, H., Daniels, G. A., Nemunaitis, J. J., Spitler, L. E., Hallmeyer, S., Lutzky, J., Schultz, S. M., Whitman, E. D., Zhou, K., Karpathy, R., Weisberg, J. I., Grose, M. and Shafren, D. 2015. Final data from CALM: A phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma. J. Clin. Oncol. 33, doi:10.1200/jco.2015_suppl.9030.9030-9030.
  3. Andtbacka, R. H., Kaufman, H. L., Collichio, F., Amatruda, T., Senzer, N., Chesney, J., Delman, K. A., Spitler, L. E., Puzanov, I., Agarwala, S. S., Milhem, M., Cranmer, L., Curti, B., Lewis, K., Ross, M., Guthrie, T., Linette, G. P., Daniels, G. A., Harrington, K., Middleton, M. R., Miller, W. H. Jr, Zager, J. S., Ye, Y., Yao, B., Li, A., Doleman, S., Vander Walde, A., Gansert, J. and Coffin, R. S. 2015. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780-2788. https://doi.org/10.1200/JCO.2014.58.3377
  4. Annels, N. E., Arif, M., Simpson, G. R., Denyer, M., Moller-Levet, C., Mansfield, D. and Harrington, K. 2018. Oncolytic immunotherapy for bladder cancer using Coxsackie A21 virus. Mol. Ther. Oncolytics 9, 1-12. https://doi.org/10.1016/j.omto.2018.02.001
  5. Aref, S., Bailey, K. and Fielding, A. 2016. Measles to the rescue: A review of oncolytic measles virus. Viruses 8, doi: 10.3390/v8100294.
  6. Barber, G. N. 2004. Vesicular stomatitis virus as an oncolytic vector. Viral Immunol. 17, 516-527. https://doi.org/10.1089/vim.2004.17.516
  7. Buijs, P. R., Verhagen, J. H., van Eijck, C. H. and van den Hoogen, B. G. 2015. Oncolytic viruses: from bench to bedside with a focus on safety. Hum. Vaccin. Immunother. 11, 1573-1584. https://doi.org/10.1080/21645515.2015.1037058
  8. Carew, J. S., Espitia, C. M., Zhao, W., Kelly, K. R., Coffey, M., Freeman, J. W., Nawrocki, S. T. 2013. Reolysin is a novel reovirus-based agent that induces endoplasmic reticular stress-mediated apoptosis in pancreatic cancer. Cell Death Dis. 4, doi: 10.1038/cddis.2013.259.
  9. Carpenter, A. B. 2019. Recombinant oncolytic poliovirus for glioblastoma: A current review of PVS (RIPO). Georgetown Med. Review 3, https://gmr.scholasticahq.com/article/7789.
  10. Chang, K. J., Senzer, N. N., Binmoeller, K., Goldsweig, H. and Coffin, R. 2012. Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer(ca). J. Clin. Oncol. 30, doi:10.1200/jco.2012.30.15_suppl.e14546.
  11. Cheng, X., Wang, W., Xu, Q., Harper, J., Carroll, D., Galinski, M. S. and Jin, H. 2016. Genetic modification of oncolytic Newcastle disease virus for cancer therapy. J. Virol. 90, 5343-5352. https://doi.org/10.1128/JVI.00136-16
  12. Chon, H. and Kim, C. 2018. Combination of oncolytic vaccinia virus and immune checkpoint blockade overcomes resistance to immunotherapy in renal cell carcinoma. Proceeding of the American Association for Cancer Research Annual 10. Meeting. April 14-18. Chicago. U. S. A.
  13. Chon, H. J., Lee, W. S., Yang, H., Kong, S. J., Lee, N. K., Moon, E. S. and Kim, J. H. 2019. Tumor microenvironment remodeling by intratumoral oncolytic vaccinia virus enhances the efficacy of immune-checkpoint blockade. Clin. Cancer Res. 25, 1612-1623.
  14. Chu, R. L., Post, D. E., Khuri, F. R. and Van Meir, E. G. 2004. Use of replicating oncolytic adenoviruses in combination therapy for cancer. Clin. Cancer Res. 10, 5299-5312. https://doi.org/10.1158/1078-0432.CCR-0349-03
  15. Cockle, J. V., Ilett, E., Scott, K., Bruning-Richardson, A., Picton, S., Short, S. C. and Melcher, A. 2014. Evaluating the effects of oncolytic Herpes Simplex Virus (SEPREHVIR) on paediatric high grade glioma viability, migration and invasion: Potential for clinical application. Hum. Gene Ther. 25, https://doi.org/10.1089/hum.2014.2538.abstracts.
  16. Cohn, D. E., Sill, M. W., Walker, J. L., O'Malley, D., Nagel, C. I., Rutledge, T. L., Bradley, W., Richardson, D. L., Moxley, K. M. and Aghajanian, C. 2017. Randomized phase IIB evaluation of weekly paclitaxel versus weekly paclitaxel with oncolytic reovirus (Reolysin(R))n recurrent ovarian, tubal, or peritoneal cancer: An NRG oncology/gynecologic oncology group study. Gynecol. Oncol. 146, 477-483. https://doi.org/10.1016/j.ygyno.2017.07.135
  17. Cui, C., Lian, B., Chi, Z., Si, L., Sheng, X., Li, D., Li, S. M., Tang, B., Mao, L. L., Wang, X., Zhou, L., Yan, X., Bai, X. and Guo, J. 2017. OrienX010 oncolytic viral therapy in phase Ic trial of intralesional injection in liver metastases among patients with stage IV melanoma after standard treatment. J. Clin. Oncol. 35, doi:10.1200/jco.2017.35.15_suppl.e21013.
  18. De Gruijl, T. D., Janssen, A. B. and van Beusechem, V. W. 2015. Arming oncolytic viruses to leverage antitumor immunity. Expert Opin. Biol. Ther. 15, 959-971. https://doi.org/10.1517/14712598.2015.1044433
  19. Desjardins, A., Gromeier, M., Herndon, J. E. 2nd., Beaubier, N., Bolognesi, D. P., Friedman, A. H., Friedman, H. S., McSherry, F., Muscat, A. M., Nair, S., Peters, K. B., Randazzo, D., Sampson, J. H., Vlahovic, G., Harrison, W. T., Mc Lendon, R. E., Ashley, D. and Bigner, D. D. 2018. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379, 150-161. https://doi.org/10.1056/NEJMoa1716435
  20. Desjardins, A., Vlahovic, G. and Friedman, H. S. 2016. Vaccine therapy, oncolytic viruses, and gliomas. Oncology 30, 211-218.
  21. Farkona, S., Diamandis, E. P. and Blasutig, I. M. 2016. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 14, 73. doi: 10.1186/s12916-016-0623-5.
  22. Ferguson, M. S., Lemoine, N. R. and Wang, Y. 2012. Systemic delivery of oncolytic viruses: Hopes and hurdles. Adv. Virol. 2012, 1-14. https://doi.org/10.1155/2012/805629
  23. Foloppe, J., Kempf, J., Futin, N., Kintz, J., Cordier, P., Pichon, C. and Erbs, P. 2019. The enhanced tumor specificity of TG6002, an armed-oncolytic vaccinia virus deleted in two genes involved in nucleotide metabolism. Mol. Ther. Oncolytics 27, 1-14.
  24. Fonteneau, J. 2016. Oncolytic viruses and immune checkpoint inhibitors. Immunother. Open Acc. 2, doi: 10.4172/2471-9552.1000e105.
  25. Forsyth, P., Roldan, G., George, D., Wallace, C., Palmer, C. A., Morris, D., Cairncross, G., Matthews, M. V., Markert, J., Gillespie, Y., Coffey, M., Thompson, B. and Hamilton, M. 2008. A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol. Ther. 16, 627-632. https://doi.org/10.1038/sj.mt.6300403
  26. Fukuhara, H., Ino, Y. and Todo, T. 2016. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci. 107, 1373-1379. https://doi.org/10.1111/cas.13027
  27. Fulci, G., Breymann, L., Gianni, D., Kurozomi, K., Rhee, S. S., Yu, J. and Chiocca, E. A. 2006. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proc. Natl. Acad. Sci. USA. 103, 12873-12878. https://doi.org/10.1073/pnas.0605496103
  28. Galanis, E., Atherton, P. J., Maurer, M. J., Knutson, K. L., Dowdy, S. C., Cliby, W. A. and Block, M. S. 2015. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res. 75, 22-30. https://doi.org/10.1158/0008-5472.CAN-14-2533
  29. Galanis, E., Markovic, S. N., Suman, V. J., Nuovo, G. J., Vile, R. G., Kottke, T. J., Nevala, W. K., Thompson, M. A., Lewis, J. E., Rumilla, K. M., Roulstone, V., Harrington, K., Linette, G. P., Maples, W. J., Coffey, M., Zwiebel, J. and Kendra, K. 2012. Phase II trial of intravenous administration of Reolysin(R) (Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. Mol. Ther. 20, 1998-2003. https://doi.org/10.1038/mt.2012.146
  30. Gattiker, H. H., Wiltshaw, E. and Galton, D. A. G. 1980. Spontaneous regression in non-Hodgkin's lymphoma. Cancer 45, 2627-2632. https://doi.org/10.1002/1097-0142(19800515)45:10<2627::AID-CNCR2820451023>3.0.CO;2-0
  31. Geoerger, B., Grill, J., Opolon, P., Morizet, J., Aubert, G., Lecluse, Y., van Beusechem, V. W., Gerritsen, W. R., Kirn, D. H. and Vassal, G. 2003. Potentiation of radiation therapy by the oncolytic adenovirus dl1520 (ONYX-015) in human malignant glioma xenografts. Br. J. Cancer 89, 577-584. https://doi.org/10.1038/sj.bjc.6601102
  32. Gesundheit, B. and Rosenzweig, J. P. 2017. Oncolytic viruses-Genetically engineering the future of cancer therapy. Front. Oncol. 7, 271. doi: 10.3389/fonc.2017.00271.
  33. Gollamudi, R., Ghalib, M. H., Desai, K. K., Chaudhary, I., Won,g B., Einstein, M., Coffey, M., Gill, G. M., Mettinger, K., Mariadason, J. M., Mani, S. and Goel, S. 2010. Intravenous administration of Reolysin, a live replication competent RNA virus is safe in patients with advanced solid tumors. Invest. New Drugs 28, 641-649. https://doi.org/10.1007/s10637-009-9279-8
  34. Hansen, R. M. and Libnoch, J. A. 1978. Remission of chronic lymphocytic leukemia after smallpox vaccination. Arch. Intern. Med. (Chicago) 138, 1137-1138. https://doi.org/10.1001/archinte.1978.03630320073024
  35. Hecht, J., Bedford, R., Abbruzzese, J. L., Lahoti, S., Reid, T. R., Soetikno, R. M., Kirn, D. H. and Freeman, S. M. 2003. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin. Cancer Res. 9, 555-561.
  36. Heo, J., Breitbach, C. J., Moon, A., Kim, C. W., Patt, R., Kim, M. K., Lee, Y. K., Oh, S. Y., Woo, H. Y., Parato, K., Rintoul, J., Falls, T., Hickman, T., Rhee, B. G., Bell, J. C., Kirn, D. H. and Hwang, T. H. 2011. Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy. Mol. Ther. 19, 1170-1179. https://doi.org/10.1038/mt.2011.39
  37. Hingorani, P., Zhang, W., Lin, J., Liu, L., Guha, C. and Kolb, E. A. 2011. Systemic administration of reovirus (Reolysin) inhibits growth of human sarcoma xenografts. Cancer 117, 1764-1774. https://doi.org/10.1002/cncr.25741
  38. Hirooka, Y., Kasuya, H., Ishikawa, T., Kawashima, H., Ohno, E., Villalobos, I. B. and Kodera, Y. 2018. A phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer 18, 596. https://doi.org/10.1186/s12885-018-4453-z
  39. Howells, A., Marelli, G., Lemoine, N. R. and Wang, Y. 2017. Oncolytic viruses-interaction of virus and tumor cells in the battle to eliminate cancer. Front. Oncol. 7, doi:10.3389/fonc.2017.00195.
  40. Hwang, T. H., Moon, A., Burke, J., Ribas, A., Stephenson, J., Breitbach, C. J., Daneshmand, M., De Silva, N., Parato, K., Diallo, J. S., Lee, Y. S., Liu, T. C., Bell, J. C. and Kirn, D. H. 2011. A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol. Ther. 19, 1913-1922. https://doi.org/10.1038/mt.2011.132
  41. Jaime-Ramirez, A. C., Yu, J. G., Caserta, E., Yoo, J. Y., Zhang, J., Lee, T. J., Hofmeister, C., Lee, J. H., Kumar, B., Pan, Q., Kumar, P., Baiocchi, R., Teknos, T., Pichiorri, F., Kaur, B. and Old, M. 2017. Reolysin and histone deacetylase inhibition in the treatment of head and neck squamous cell carcinoma. Mol. Ther. Oncol. 5, 87-96. https://doi.org/10.1016/j.omto.2017.05.002
  42. Johnson, D. B., Puzanov, I. and Kelley, M. C. 2015. Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. Immunotheraphy 7, 611-619. https://doi.org/10.2217/imt.15.35
  43. Jolly, D. J., Robbins, J. M., Ostertag, D., Ibanez, C., Kasahara, N., Gruber, H. and Chu, A. 2016. Ascending dose trials of a retroviral replicating vector (Toca 511) in patients with recurrent high-grade glioma: Clinical update, molecular analyses, and proposed mechanism of action. Mol. Ther. 24, S27.
  44. Kaufman, H. L., Kohlhapp, F. J. and Zloza, A. 2015. Oncolytic viruses: a new class of immunotherapy drugs. Nat. Rev. Drug Discov. 14, 642-662. https://doi.org/10.1038/nrd4663
  45. Kelly, E. and Russell, S. J. 2007. History of oncolytic viruses: genesis to genetic engineering. Mol. Ther. 15, 651-659. https://doi.org/10.1038/sj.mt.6300108
  46. Kirn, D. H. and McCormick, F. 1996. Replicating viruses as selective cancer therapeutics. Mol. Med. Today 2, 519-527. https://doi.org/10.1016/S1357-4310(97)81456-6
  47. Kirn, D., Hermiston, T. and McCormick, F. 1998. ONXY-015: clinical data are encouraging. Nat. Med. 4, 1341-1342. https://doi.org/10.1038/3902
  48. Kowalsky, S. J., Liu, Z., Feist, M., Berkey, S. E., Ma, C., Ravindranathan, R. and Bartlett, D. L. 2018. Superagonist IL-15-armed oncolytic virus elicits potent antitumor immunity and therapy that are enhanced with PD-1 blockade. Mol. Ther. 26, 2476-2486. https://doi.org/10.1016/j.ymthe.2018.07.013
  49. Krug, L. M., Zauderer, M. G., Adusumili, P. S., McGee, E., Sepkowitz, K., Klang, M., Yu, Y. A., Scigalla, P. and Rusch, V. W. 2015. Phase I study of intra-pleural administration of GL-ONC1, an oncolytic vaccinia virus, in patients with malignant pleural effusion. J. Clin. Oncol. 33, 7559-7559. https://doi.org/10.1200/jco.2015.33.15_suppl.7559
  50. Lang, F. F., Conrad, C., Gomez-Manzano, C., Yung, W. K. A., Sawaya, R., Weinberg, J. S., Prabhu, S. S., Rao, G., Fuller, G. N., Aldape, K. D., Gumin, J., Vence, L. M., Wistuba, I., Rodriguez-Canales, J., Villalobos, P. A., Dirven, C. M. F., Tejada, S., Valle, R. D., Alonso, M. M., Ewald, B., Peterkin, J. J., Tufaro, F. and Fueyo, J. 2018. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J. Clin. Oncol. 36, 1419-1427. https://doi.org/10.1200/JCO.2017.75.8219
  51. LaRocca, C. J. and Warner, S. G. 2018. Oncolytic viruses and checkpoint inhibitors: Combination therapy in clinical trials. Clin. Transl. Med. 7, 35, doi: 10.1186/s40169-018-0214-5.
  52. Lauer, U. M., Schell, M., Beil, J., Berchtold, S., Koppenhofer, U., Glatzle, J., Alfred Konigsrainer, A., Mohle, R., Nann, D., Fend, F., Pfannenberg, C., Bitzer, M. and Malek, N. P. 2018. Phase I study of oncolytic vaccinia virus GL-ONC1 in patients with peritoneal carcinomatosis. Clin. Cancer Res. 24, 4388-4398. https://doi.org/10.1158/1078-0432.CCR-18-0244
  53. Lawler, S. E., Speranza, M. C., Cho, C. F. and Chiocca, E. A. 2017. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 3, 841-849. https://doi.org/10.1001/jamaoncol.2016.2064
  54. Learmonth, K., Braidwood, L., Woll, P. and Conner, J. 2015. Immune responses following intrapleural administration of oncolytic SEPREHVIR in patients with malignant pleural mesothelioma. J. Immunother. Cancer 3, 335. https://doi.org/10.1186/2051-1426-3-S2-P335
  55. Liu, B. L., Robinson, M., Han, Z. Q., Branston, R. H., English, C., Reay, P. and Love, C. A. 2003. ICP34. 5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 10, 292-303. https://doi.org/10.1038/sj.gt.3301885
  56. Liu, H., Yuan, S. J., Chen, Y. T., Xie, Y. B., Cui, L., Yang, W. Z. and Tian, Y. T. 2013. Preclinical evaluation of herpes simplex virus armed with granulocyte-macrophage colony-stimulating factor in pancreatic carcinoma. World J. Gastroenterol. 19, 5138-5143. https://doi.org/10.3748/wjg.v19.i31.5138
  57. Mahalingam, D., Fountzilas, C., Moseley, J., Noronha, N., Tran, H., Chakrabarty, R. and Sarantopoulos, J. 2017. A phase II study of REOLYSIN(R) (pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma. Cancer Chemother. Pharmacol. 79, 697-703. https://doi.org/10.1007/s00280-017-3260-6
  58. Mahalingam, D., Goel, S., Aparo, S., Patel Arora, S., Noronha, N., Tran, H. Chakrabarty, R., Selvaggi, G., Gutierrez, A., Coffey, M., Nawrocki, S. T., Nuovo, G. and Mita, M. M. 2018. A phase II study of pelareorep (REOLYSIN(R)) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers 10, doi: 10.3390/cancers10060160.
  59. Makower, D., Rozenblit, A., Kaufman, H., Edelman, M., Lane, M. E., Zwiebel, J., Haynes, H. and Wadler, S. 2003. Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin. Cancer Res. 9, 693-702.
  60. Mantovani, A., Romero, P., Palucka, A. K. and Marincola, F. M. 2008. Tumour immunity: Effector response to tumour and role of the microenvironment. Lancet 371, 771-783. https://doi.org/10.1016/S0140-6736(08)60241-X
  61. Markert, J. M., Medlock, M. D., Rabkin, S. D., Gillespie, G. Y., Todo, T., Hunter, W. D. and Martuza, R. L. 2000. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 7, 867-874. https://doi.org/10.1038/sj.gt.3301205
  62. Markert, J. M., Liechty, P. G., Wang, W., Gaston, S., Braz, E., Karrasch, M., Nabors, L. B., Markiewicz, M., Lakeman, A. D., Palmer, C. A., Parker, J. N., Whitley, R. J., and Gillespie, G. Y. 2009. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol. Ther. 17, 199-207. https://doi.org/10.1038/mt.2008.228
  63. Mell, L. K., Brumund, K. T., Daniels, G. A., Advani, S. J., Zakeri, K., Wright, M. E. and Szalay, A. A. 2017. Phase I trial of intravenous oncolytic vaccinia virus (GL-ONC1) with cisplatin and radiotherapy in patients with locoregionally advanced head and neck carcinoma. Clin. Cancer Res. 23, 5696-5702. https://doi.org/10.1158/1078-0432.CCR-16-3232
  64. Nakao, A., Kasuya, H., Sahin, T. T., Nomura, N., Kanzaki, A., Misawa, M., Shirota, T., Yamada, S., Fujii, T., Sugimoto, H., Shikano, T., Nomoto, S., Takeda, S., Kodera, Y. and Nishiyama, Y. 2011. A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer. Cancer Gene Ther. 18, 167-175. https://doi.org/10.1038/cgt.2010.65
  65. Nakao, A., Kimata, H., Imai, T., Kikumori, T., Teshigahara, O., Nagasaka, T., Goshima, F. and Nishiyama, Y. 2004. Intratumoral injection of herpes simplex virus HF10 in recurrent breast cancer. Ann. Oncol. 15, 988-989. https://doi.org/10.1093/annonc/mdh225
  66. Packiriswamy, N., Upreti, D., Zhou, Y., Dispenzieri, A., Peng, K. W. and Russell, S. J. 2017. T cell responses to tumor associated antigens in multiple myeloma patients treated with MV-NIS, an oncolytic measles virus. Blood 130, 3793.
  67. Pandha, H., Harrington, K., Ralph, C., Melcher, A., Grose, M. and Shafren, D. 2015. Phase I/II storm study: Intravenous delivery of a novel oncolytic immunotherapy agent, Coxsackievirus A21, in advanced cancer patients. J. Immunother. Cancer 3, doi: 10.1186/2051-1426-3-S2-P341.
  68. Park, B. H., Hwang, T., Liu, T. C., Sze, D. Y., Kim, J. S., Kwon, H. C., Oh, S. Y., Han, S. Y., Yoon, J. H., Hong, S. H., Moon, A., Speth, K., Park, C., Ahn, Y. J., Daneshmand, M., Rhee, B. G., Pinedo, H. M., Bell, J. C. and Kirn, D. H. 2008. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 9, 533-542. https://doi.org/10.1016/S1470-2045(08)70107-4
  69. Park, S. H., Breitbach, C. J., Lee, J., Park, J. O., Lim, H. Y., Kang, W. K. and Patt, R. 2015. Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer. Mol. Ther. 23, 1532-1540. https://doi.org/10.1038/mt.2015.109
  70. Parviainen, S., Ahonen, M., Diaconu, I., Kipar, A., Siurala, M., Vaha-Koskela, M. and Hemminki, A. 2015. GMCSFarmed vaccinia virus induces an antitumor immune response. Int. J. Cancer 136, 1065-1072. https://doi.org/10.1002/ijc.29068
  71. Patel, M. R., Jacobson, B. A., Ji, Y., Drees, J., Tang, S., Xiong, K. and Mesev, E. 2015. Vesicular stomatitis virus expressing interferon-${\beta}$ is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer. Oncotarget 6, 33165-33177. https://doi.org/10.18632/oncotarget.5320
  72. Philbrick, B. D. and Adamson, D. C. 2019. Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma. Expert Opin. Investig. Drugs 28, 207-216. https://doi.org/10.1080/13543784.2019.1572112
  73. Pol, J., Kroemer, G. and Galluzzi, L. 2016. First oncolytic virus approved for melanoma immunotherapy. Oncoimmunol. 5, doi: 10.1080/2162402X.2015.1115641.
  74. Ramesh, N., Ge, Y., Ennist, D. L., Zhu, M., Mina, M., Ganesh, S., Reddy, P. S. and Yu, D. C. 2006. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor-armed oncolytic adenovirus for the treatment of bladder cancer. Clin. Cancer Res. 12, 305-313. https://doi.org/10.1158/1078-0432.CCR-05-1059
  75. Rampling, R., Cruickshank, G., Papanastassiou, V., Nicoll, J., Hadley, D., Brennan, D., Petty, R., MacLean, A., Harland, J., McKie, E., Mabbs, R. and Brown, M. 2000. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther. 7, 859-866. https://doi.org/10.1038/sj.gt.3301184
  76. Ranki, T., Pesonen, S., Hemminki, A., Partanen, K., Kairemo, K., Alanko, T., Lundin, J., Linder, N., Turkki, R., Jager, E., Karbach, J., Wahle, C., Kankainen, M., Backman, C., Euler, M. E., Haavisto, E., Hakonen, T., Heiskanen, R., Jaderberg, M., Juhila, J., Priha, P., Suoranta, L., Vassilev, L., Vuolanto, A. and Joensuu, T. 2016. Phase I study with ONCOS-102 for the treatment of solid tumors-an evaluation of clinical response and exploratory analyses of immune markers. J. Immunoth. Cancer 4, doi: 10.1186/s40425-016-0121-5.
  77. Reid, T., Galanis, E., Abbruzzese, J., Sze, D., Andrews, J., Romel, L., Hatfield, M., Rubin, J. and Kirn, D. 2001. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Ther. 8, 1618-1626. https://doi.org/10.1038/sj.gt.3301512
  78. Sborov, D. W., Nuovo, G. J., Stiff, A., Mace, T., Lesinski, G. B., Benson, D. M., Efebera, Y. A., Rosko, A. E., Pichiorri, F., Grever, M. R. and Hofmeister, C. C. 2014. A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma. Clin. Cancer Res. 20, 5946-5955. https://doi.org/10.1158/1078-0432.CCR-14-1404
  79. Scott, E. M., Duffy, M. R., Freedman, J. D., Fisher, K. D. and Seymour, L. W. 2018. Solid tumor immunotherapy with T cell Engager-armed oncolytic viruses. Macromol. Biosci. 18, doi: 10.1002/mabi.201700187.
  80. Shah, A. C., Benos, D., Gillespie, G. Y. and Markert, J. M. 2003. Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas. J. Neurooncol. 65, 203-226. https://doi.org/10.1023/B:NEON.0000003651.97832.6c
  81. Sivanandam, V., LaRocca, C. J., Chen, N. G., Fong, Y. and Warner, S. G. 2019. Oncolytic viruses and immune checkpoint inhibition: The best of both worlds. Mol. Ther. Oncolytics 13, 93-106. https://doi.org/10.1016/j.omto.2019.04.003
  82. Van Tellingen, O., Yetkin-Arik, B., De Gooijer, M. C., Wesseling, P., Wurdinger, T. and De Vries, H. E. 2015. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist. Updat. 19, 1-12. https://doi.org/10.1016/j.drup.2015.02.002
  83. Vasey, P. A., Shulman, L. N., Campos, S., Davis, J., Gore, M., Johnston, S., Kirn, D. H., O'Neill, V., Siddiqui, N., Seiden, M. V. and Kaye, S. B. 2002. Phase I Trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J. Clin. Oncol. 20, 1562-1569. https://doi.org/10.1200/jco.2002.20.6.1562
  84. Vesely, M. D., Kershaw, M. H., Schreiber, R. D. and Smyth, M. J. 2011. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235-271. https://doi.org/10.1146/annurev-immunol-031210-101324
  85. Walton, R. W., Brown, M. C., Sacco, M. T. and Gromeier, M. 2018. Engineered oncolytic poliovirus PVSRIPO subverts MDA5-dependent innate immune responses in cancer cells. J. Virol. 92, doi: 10.1128/JVI.00879-18.
  86. Watanabe, D., Goshima, F., Mori, I., Tamada, Y., Matsumoto, Y. and Nishiyama, Y. 2008. Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10. J. Dermatol. Sci. 50, 185-196. https://doi.org/10.1016/j.jdermsci.2007.12.001
  87. Wiernik, P. H. 1976. Spontaneous regression of hematologic cancers. Nat. Cancer Inst. Monogr. 44, 35-38.
  88. Wing, A., Fajardo, C. A., Posey, A. D., Shaw, C., Da, T., Young, R. M. and Guedan, S. 2018. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol. Res. 6, 605-616. https://doi.org/10.1158/2326-6066.CIR-17-0314
  89. Wong, H. H., Lemoine, N. and Wang, Y. 2010. Oncolytic viruses for cancer therapy: Overcoming the obstacles. Viruses 2, 78-106. https://doi.org/10.3390/v2010078
  90. Xia, Z. J., Chang, J. H., Zhang, L., Jiang, W. Q., Guan, Z. Z., Liu, J. W., Zhang, Y., Hu, X. H., Wu, G. H., Wang, H. Q., Chen, Z. C., Chen, J. C., Zhou, Q. H., Lu, J. W., Fan, Q. X., Huang, J. J. and Zheng, X. 2004. 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 23, 1666-1670.
  91. Yamamoto, M. and Curiel, D. T. 2010. Current issues and future directions of oncolytic adenoviruses. Mol. Ther. 18, 243-250. https://doi.org/10.1038/mt.2009.266
  92. You, L., Yang, C. T. and Jablons, D. M. 2000. ONYX-015 works synergistically with chemotherapy in lung cancer cell lines and primary cultures freshly made from lung cancer patients. Cancer Res. 60, 1009-1013.
  93. Zhang, L., Steele, M. B., Jenks, N., Grell, J., Suksanpaisan, L., Naik, S. and Peng, K. W. 2016. Safety studies in tumor and non-tumor-bearing mice in support of clinical trials using oncolytic VSV-${IFN\beta}$-NIS. Hum. Gene Ther. Clin. Dev. 27, 111-122. https://doi.org/10.1089/humc.2016.061