Oncolytic Virotherapy in Solid Tumors: History
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Subjects: Immunology
Contributor:
Xiao-Zhou Mou

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens.

  • oncolytic virus
  • tumor microenvironment
  • antitumor immune response
  • delivery
  • genetic modification

1. Introduction

The first hints of the possible anticancer effects of viruses occurred during the early 20th century, with evidence of tumor regression in patients with simultaneous viral infections [1]. Such reports persisted until the 1950s, when the primary clinical studies on the tumor-killing ability of viruses that form the cornerstone of today’s achievements were carried-out [2]. Since then, various preclinical and clinical studies have attempted to optimize the viruses for increasing specificity, efficiency, and reducing adverse events (AEs), which led to the introduction of oncolytic virotherapy (OVT) as emerging immunotherapy of cancers [3]. Oncolytic virus (OVs) or cancer-killing viruses are defined as natural or genetically modified viruses that are able to selectively proliferate in tumor cells without damaging normal cells [4]. This natural tropism of some viruses to tumors is due to an increase in some receptors (such as CD54) on the surfaces of tumor cells or defects of tumor cells to induce innate immunity against viruses [5]. So far, various DNA and RNA OVs have been used to treat cancer [6]. The majority of DNA viruses are double-stranded, while RNA viruses are predominantly single-stranded. The advantages of double-stranded DNA viruses are their large genomes which enable them to carry large eukaryotic transgenes and high fidelity DNA polymerase, maintaining the virus genome integrity during replication [7]. Regarding their relatively small size, RNA viruses cannot encode large transgenes. However, they are better candidates in the delivery system due to less induction of immune responses [8]. Several RNA viruses and DNA viruses, including reovirus (RV), Seneca Valley virus (SVV), poliovirus (PoV), parvovirus (PV), vaccinia virus (VACV), and herpes simplex virus (HSV) have the ability to cross the blood-brain barrier (BBB) enabling their use in brain tumors [9][10][11][12][13][14]. OVT started with wild-type viruses such as Newcastle disease virus (NDV), myxoma virus (MYXV), SVV, PV, coxsackievirus (CV), and RV [3]. However, genetic modification was a revolutionary achievement in the OVT providing greater specificity and efficacy against tumors with higher safety for healthy cells [15]. Genetically modified OVs (GMOVs) mainly include PoV, measles virus (MeV), adenovirus (AdV), VACV, HSV, and vesicular stomatitis virus (VSV) [3]. The first GMOV was HSV-1, introduced in 1991 [16]. So far, three OV-based drugs have been approved for cancer treatment, the first of which was an unmodified ECHO-7 virus called Rigavirus which was approved in 2004 in Lativa under the brand name Rigvir for melanoma [17]. However, the approval was withdrawn in 2019 due to its low efficacy. The two other approved OVs are GMOVs include Oncorine (H101 adenovirus), which obtained approval for head and neck cancer in China in 2005 [3], and T-VEC or Imlygic (HSV-1), which was approved in 2015 in the United States and Europe for non-surgical melanoma [18]. The efficacy of OVs on many cancers, such as melanoma, glioblastoma, triple-negative breast cancer (TNBC), head and neck cancers, and colorectal cancers has been elucidated [19][20][21][22][23], and a large number of clinical trials are currently evaluating the wild-type and GMOVs efficiency and safety in various cancers which are listed in Table 1. Along with the therapeutic approaches, GMOVs expressing reporter genes can be applied in the diagnosis of various cancers by positron emission tomography or single-photon emission computed tomography [24].

Table 1. Oncolytic viruses that reached the clinical phase.

Oncolytic Virus Modification Combination Therapy Cancer Type (Clinical Trial Phase) Ref.
HSV-1 Virulence gene ICP34.5 and ICP47 are deleted and human GM-CSF gene is inserted ICIs (anti-PD1, anti-CTLA4 Melanoma (I, II), Sarcoma (I, II) [25][26][27]
- Breast cancer (I), Head and neck cancer (I, I/II), Gastrointestinal cancers (I), Melanoma (I, II, III) [28][29][30][31][32]
Virulence gene ICP34.5 is deleted - Oral SCC (I), Pediatric extracranial cancers (I) [33][34]
Chemotherapy Chemo-resistant metastatic colon cancer (I, I/II) [35][36]
Virulence gene ICP34.5 is deleted and ICP6 gene is inactivated Radiotherapy Glioblastoma (I) [37]
Naturally mutated - Pancreatic cancer (I) [38]
NDV Autologous tumor lysate and IL-2 is added - Stage III of Melanoma (I) [39]
Naturally attenuated - Advanced solid tumors (I) [40]
One-cycle replicating cytopathogenic NDV - Glioblastoma (I/II) [41]
CVA21 - ICIs (anti-PD1) NSCLC (Ib), Bladder cancer (Ib) [42]
- Bladder cancer (II), Advanced melanoma (II) [43][44]
RV - - Advanced solid tumors (I), Recurrent glioma (I), Extracranial solid tumors (I), Melanoma (II), Pancreatic adenocarcinoma (II) [45][46][47][48][49]
Chemotherapy Advanced solid tumors (I), Ovarian cancer (IIb), Peritoneal cancer (IIb), Melanoma (II), Metastatic breast cancer (II), Advanced head and neck cancer (I/II) Pancreatic adenocarcinoma (II) [50][51][52][53][54]
Radiotherapy Advanced solid tumors (I) [55]
PoV Recombinant oral PoV Sabin-1:
the internal ribosome entry site (IRES) is replaced with the IRES from human rhinovirus-2: nonpathogenic		 - Recurrent glioblastoma (I) [56]
AdV AdV3 fiber knob is inserted into the backbone of AdV5,
A 24-base pair in the E1 gene is deleted: CRAd
GM-CSF gene is inserted		 - Ovarian Cancer (I), Gynecologic malignancies (I), Advanced solid tumors (I) [57][58][59]
Chemotherapy Chemo-resistant advanced solid tumors (I) [57]
RGD motif is inserted into the AdV5 fiber knob: Integrin targeted instead of CAR dependence
GM-CSF gene is inserted		 - Chemo-resistant advanced solid tumors (I) [60]
Prostate-specific antigen (PSA)-selective Radiotherapy Metastatic prostate cancer (I) [61]
Conditionally replicating GM-CSF expressing AdV - Bladder Cancer (I, II), Head and neck cancers (I) [62][63]
Human telomerase reverse transcriptase (hTERT) is inserted: tumor selective replication - Advanced solid tumors (I) [64]
E1B-deleted AdV: selective replication in P53-deficient cells Chemotherapy Advanced solid tumors (I), Malignant glioma (I), Recurrent head and neck cancer (I, II), Gastrointestinal cancers (II), Colorectal cancer (II), Advanced sarcoma (I/II), [65][66][67][68]
Chimeric AdV:
Ad11p/Ad3,
AdV5- cytosine deaminase/HSV-1 thymidine kinase: suicide gene for safety		 - RCC (I), NSCLC (I), Colorectal cancer (I), Urothelial cancer (I),Prostate cancer (I, II), Glioma (II) [69][70][71][72]
VACV GM-CSF gene is inserted
Thymidine kinase gene is deleted		 Chemotherapy Metastatic melanoma (I), HCC (I, II), Colorectal cancer (I), Ewing sarcoma (I), neuroblastoma (I), [73][74][75][76]
FCU1 transgene is inserted: metabolize 5-FC to 5-FU-monophosphate Chemotherapy Chemo-resistant liver tumors (I) [77]
Thymidine kinase gene and hemagglutinin gene and F14.5 gene are deleted
Luciferase gene, beta-galactosidase, and beta-glucuronidase are inserted		 Chemotherapy and radiotherapy Head and neck cancer (I), Colorectal cancer (I)
Advanced solid tumors (I)		 [78][79][80]
MeV Genetically modified to
express carcinoembryonic antigen		 - Ovarian cancer (I) [81]
SVV - - Neuroblstoma (I), rhabdomyosarcoma (I), Neuroendocrine malignancies (I) [82][83]
Poxvirus Genetically modified expressing costimulatory and adhesion molecules such as B7-1, LFA-3, ICAM-1 - Colorectal cancer (I), Melanoma (I) [84]
PV - - Glioblastoma (I/II) [85]

HSV-1. Herpes simplex virus-1; ICP. Infected cell protein; GM-CSF. Granulocyte-macrophage colony-stimulating factor; ICI. Immune-checkpoint inhibitor; PD1. Programmed cell death protein 1; CTLA4. cytotoxic T-lymphocyte-associated protein 4; SCC. Squamous cell carcinoma; NDV. Newcastle disease virus; CVA21. Coxsackievirus A21; NSCLC. Nonsmall-cell lung carcinoma; RV. Reovirus; PoV. Poliovirus; AdV. Adenovirus; CRAd. Conditionally replicative adenoviruses; RGD. Arginine-Glycine-Aspartate; CAR. Coxsackievirus and adenovirus receptor; RCC. Renal cell carcinoma; VACV. Vaccinia virus; HCC. Hepatocellular carcinoma; FCU1. Fusion suicide gene; 5-FC. 5-fluorocytosine; 5-FU.5-Fluorouracil; MeV. Measles virus; SVV. Seneca Valley virus; LFA-3. Lymphocyte function-associated antigen-3; ICAM-1. Intercellular adhesion molecule-1; PV. Parvovirus.

OVs can kill the tumor cells in the following main ways: 1. OVs infect and replicate specifically in tumor cells leading to direct lysis of tumor cells. Malignant cells have defects in antiviral responses allowing OVs to replicate and lyse malignant cells [7]; 2. OVs can induce different types of immunogenic cell death (ICD), including necrosis, necroptosis, immunologic apoptosis, pyroptosis, and autophagy. Tumor cell death or lysis causes the release of tumor-associated antigens (TAA) and neoantigens (TAN) and damage-associated molecular patterns (DAMPs), which increase inflammation and improve the efficacy of immunotherapy [25,26]; 3. OVs, especially GMOVs, can enhance tumor antigen presentation and prime the immune response in the tumor microenvironment (TME) by induction of antiviral responses, inflammation, cytokine production, and expression of costimulatory molecules [86][87]; 4. The infection of vascular endothelial cells (vECs) by OVs destroys tumor vasculature, resulting in tumor necrosis and the infiltration of immune cells into the TME [88].

Accordingly, a considerable part of OVT effects on tumors is achieved by changing the TME from an immunosuppressive to the immunostimulatory microenvironment and affecting the tumor vasculature and matrix. Moreover, the success of OVT in solid tumors largely depends on the OV access to the tumor.

2. Oncolytic Virus Effects on TME

The long-term effects of immunotherapy in solid tumors are mostly unsatisfactory, partly due to the immunosuppressive condition of TME and low infiltration of immune cells. TME consists of tumor cells, tumor-associated fibroblasts (TAF), vEC, mesenchymal cells, myeloid-derived suppressor cells (MDSCs), and tumor-infiltrating leukocytes (TILs), such as T cells, B cells, dendritic cells (DCs), natural killer (NK) cells, macrophages, and neutrophils [89]. The presence of exhausted cytotoxic T lymphocytes (CTLs), helper T-cells (THs), and NK cells, as well as a large number of regulatory T-cells (Tregs), tolerogenic DCs, MDSC, and M2-macrophages, induce immunosuppressive milieu in the TME through inhibitory ligands and secretion of inhibitory cytokines such as interleukin (IL)-10, tumor growth factor (TGF)-β, IL-35, and IL-27 [90]. OVs can change the paradigm in the TME and convert cold tumors to hot ones by various mechanisms.

2.1. OV-Mediated Lysis of Tumor

Direct oncolysis activity of OVs is the first stimulus of the immune response in the TME [91]. Overexpression of surface receptors such as CD46, CD54, CD155, CD55, and integrins enhances OVs’ preferable entry to tumor cells [92][93][94][95][96]. In normal cells, viral components known as pathogen-associated molecular patterns (PAMPs) are sensed by pattern recognition receptors (PRRs) and induce the production of interferon (IFN)-I through the Janus kinase signal transducer and activator of transcription (JAK-STAT) and Nuclear Factor (NF)-kB signaling pathways. IFN-I activates the protein kinase RNA-activated (PKR) signaling pathway leading to protein synthesis blockade and viral clearance [97]. Tumor cells have defects in antiviral pathways such as IFN-I, PKR, and JAK-STAT, resulting in the survival and proliferation of OVs, specifically in tumor cells [98][99][100]. Lysis of OV-infected cells releases a very diverse TAAs that prime immune cells to induce a local and systemic vaccination against the released TAAs [91]. While many cancer immunotherapies depend on identifying and targeting TAAs (one or several limited TAAs), OVT can vaccinate patients against the entire TAA and TAN treasure of cancer through a phenomenon called antigen/epitope spreading. Hence, OVT could be considered a kind of personalized immunotherapy. Interestingly enough, recent studies have reported the increase of TAA- and TAN-specific T cells in the blood of patients with melanoma and ovarian cancer treated with OVs, suggesting that the in situ OV injection might enhance the systemic antitumor response [101][102][103]. This finding raises hopes for the anti-metastatic effects of OVT. TANs are assumed to be derived from high mutational burden of tumor cells [104][105]. These immunogenic TANs are capable of eliciting tumor-specific immune responses and serve as ideal targets in immunotherapy [104][105][106]. However, TAN-specific T cells are not activated enough in cancer patients due to the poor presentation of TANs, lack of costimulatory signals, and abundance of inhibitory immune checkpoints in the TME [106]. OVs, especially armed OVs, have been shown to activate the TANs-specific T cells by increasing the access of APCs to the TANs (epitope spreading), enhancing the TANs processing and presentation by APCs, and providing costimulatory signals [106][107][108]. Accordingly, Wang et al. demonstrated that VACV armed with PD-L1 inhibitor and GM-CSF enhanced TANs presentation and activated systemic T cell responses against dominant and subdominant (cryptic) neoantigens [106], so OVT could potentiate the antitumor immune responses by activating the TANs-specific T cells.

2.2. Induction of Immunologic Cell Death

Apart from the direct lysis of cancer cells, OVs can induce various ICDs in virus-infected cells through induction of endoplasmic reticulum (ER) stress [109]. Infection of tumor cells with AdV, CV-B3, MeV, VACV, HSV, and H1-PV has been shown to induce ICD and autophagy in cancer cells [110][111]. ICD is characterized by the expression and release of DAMPs such as ATP, uric acid, heat shock proteins, ecto-calreticulin, and HMGB1, as well as extracellular proinflammatory cytokines [112]. Extracellular ATP acts as a danger signal which attracts and activates DCs [113]. HMGB1 and calreticulin can activate DCs via toll-like receptor (TLR)-4 signaling [114]. In addition, calreticulin neutralizes CD47 receptors on the tumor cell surface, and thereby, increases the tumor cell engulfment by macrophages [115]. OV-mediated ICD, along with other ICD-inducing methods such as chemotherapy and radiotherapy, break immune tolerance against the tumor and increase lymphocyte and neutrophil infiltration, leading to antitumor response and more survival in preclinical models [110].

2.3. Stimulation of Antitumor Immune Response

Besides the release of DAMPs, cancer cell death also causes the release of viral PAMPs in the TME. These PAMPs mainly include DNA, ssRNA, dsRNA, proteins, and capsid contents that activate innate immune cells through stimulating PRRs such as retinoic acid-inducible gene (RIG)-1, cyclic GMP-AMP synthase (cGAS), and stimulator of interferon genes (STING) [112]. DCs, as a bridge between the innate and adaptive immune systems, play a critical role in generating the antitumor response. DCs elicit a specific response against TAA-expressing tumor cells by engulfing OV-infected cells and cross-presentation of TAAs to CD8+ T and CD4+ T cells [116]. On the other hand, the OVs-derived PAMPs cause maturation of myeloid and plasmacytoid DCs, leading to the production of proinflammatory cytokines such as IFN-α, IFN-γ, IL-12, IL-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α [89][117][118]. These functional DCs, mainly CD103+ and BATF3+, prime CD8+ T cells against tumors [119]. Innate immune signaling, such as the cGAS-STING pathway, plays a pivotal role in the recruitment of lymphocytes to the TME through the expression of CXCL9 and CXCL10 [120]. Parallel to DCs, innate lymphoid cells (ILCs) also respond to the released PAMPs leading to higher inflammation and antitumor responses [18]. As an example, arenavirus-infected melanoma cells produce a high level of CCL5, leading to recruitment of NK cells and melanoma regression [121]. Interestingly, in situ antitumor responses following OVT are mainly mediated by IFN-I, whereas OVT-mediated systemic antitumor responses appear to be mediated by IFN-II excreted from TILs [122]. In general, the innate immune response to OVs increases lymphocyte infiltration, antigen presentation, and activation of the antitumor adaptive immune response through an IFN-mediated mechanism [18]. T cell activation requires at least three consecutive signals (peptide-MHC, CD28-B7, and stimulatory cytokines), all of which are defected in TME to escape adaptive immune responses. OVs, as potent immunogens, induce all three signals needed to activate T cells [18]. OVT increases the expression of B7-1/2 and CD40 on the surface of DCs and induces the expression of MHC-peptide on the surface of tumor cells leading to optimal activation of T cells [123]. Conversion of the TME phenotype from immunologically inert to immunologically active status can augment the effectiveness of the immunotherapeutic modalities.

2.4. Effect of OV on Tumor Vasculature

Some OVs, such as HSVs and VACVs, can target tumor stromal cells, such as TAFs, vECs, and pericytes, thereby destroy the tumor’s complex structure [86]. TGF-β secreted by tumor cells makes TAFs susceptible to OV infection [124]. OVs also reduce the fibrosis in the TME. VSV has been shown to infect hepatic stellate cells (HSCs), leading to tumor fibrosis reduction [125]. OVs affect the tumors vasculature by replicating in the tumor vECs. Vascular endothelial growth factor (VEGF) secreted from tumor vECs suppresses the antiviral response and allows the replication of OVs in endothelial cells through ERK1/2 and STAT3 pathways [126]. Following infection and replication, the OVs reduce VEGF production from the infected cell resulting in angiogenesis prevention in the tumor. OVs’ antiangiogenic properties further limit tumor growth by decreasing the oxygen and nutrition supplies [6]. VACV is shown to replicate in the tumor vEC and cause vascular destruction and ischemia [88]. Neutrophil infiltration into the TME seems essential for OVT-mediated ischemia through the induction of thrombosis in small tumor vessels [88]. It has been shown that the administration of JX-594 in hepatocellular carcinoma destroyed tumor vasculature without affecting patients’ normal vessels [88]. Thus, targeting of stromal cells by OVs increases the infiltration of immune cells into the TME, and converts immuno-deserted or immune-excluded tumors (with low TILs) into immune-infiltrated tumors [18]. OVT-mediated changes in the TME, including lymphocyte infiltration into the tumor, enhancement of TAAs/TANs presentation, and heating the TME can improve other immunotherapies such as adoptive cell therapy (ACT) and immune checkpoint inhibitors (ICIs) [89].

This entry is adapted from the peer-reviewed paper 10.3390/cancers13040588

References

  1. Dock, G. The influence of complicating diseases upon leukaemia. Am. J. Med. Sci. (1827–1924) 1904, 127, 563.
  2. Kelly, E.; Russell, S.J. History of oncolytic viruses: Genesis to genetic engineering. Mol. Ther. 2007, 15, 651–659.
  3. Russell, S.J.; Peng, K.-W.; Bell, J.C. Oncolytic virotherapy. Nat. Biotechnol. 2012, 30, 658.
  4. Chiocca, E.A.; Rabkin, S.D. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol. Res. 2014, 2, 295–300.
  5. Annels, N.E.; Mansfield, D.; Arif, M.; Ballesteros-Merino, C.; Simpson, G.R.; Denyer, M.; Sandhu, S.S.; Melcher, A.A.; Harrington, K.J.; Davies, B. Phase I trial of an ICAM-1-targeted immunotherapeutic-coxsackievirus A21 (CVA21) as an oncolytic agent against non muscle-invasive bladder cancer. Clin. Cancer Res. 2019, 25, 5818–5831.
  6. Lan, Q.; Xia, S.; Wang, Q.; Xu, W.; Huang, H.; Jiang, S.; Lu, L. Development of oncolytic virotherapy: From genetic modification to combination therapy. Front. Med. 2020, 14, 1–25.
  7. Kaufman, H.L.; Kohlhapp, F.J.; Zloza, A. Oncolytic viruses: A new class of immunotherapy drugs. Nat. Rev. Drug Discov. 2015, 14, 642–662.
  8. Bommareddy, P.K.; Patel, A.; Hossain, S.; Kaufman, H.L. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am. J. Clin. Dermatol. 2017, 18, 1–15.
  9. Samson, A.; Scott, K.J.; Taggart, D.; West, E.J.; Wilson, E.; Nuovo, G.J.; Thomson, S.; Corns, R.; Mathew, R.K.; Fuller, M.J. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl. Med. 2018, 10, eaam7577.
  10. Geletneky, K.; Hajda, J.; Angelova, A.L.; Leuchs, B.; Capper, D.; Bartsch, A.J.; Neumann, J.-O.; Schöning, T.; Hüsing, J.; Beelte, B. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol. Ther. 2017, 25, 2620–2634.
  11. Yu, L.; Baxter, P.A.; Zhao, X.; Liu, Z.; Wadhwa, L.; Zhang, Y.; Su, J.M.; Tan, X.; Yang, J.; Adesina, A. A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models. Neuro Oncol. 2010, 13, 14–27.
  12. Ohka, S.; Nihei, C.-I.; Yamazaki, M.; Nomoto, A. Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and-independent pathway. Front. Microbiol. 2012, 3, 147.
  13. Garcel, A.; Fauquette, W.; Dehouck, M.-P.; Crance, J.-M.; Favier, A.-L. Vaccinia virus-induced smallpox postvaccinal encephalitis in case of blood–brain barrier damage. Vaccine 2012, 30, 1397–1405.
  14. Liu, H.; Qiu, K.; He, Q.; Lei, Q.; Lu, W. Mechanisms of blood-brain barrier disruption in herpes simplex encephalitis. J. Neuroimmune Pharmacol. 2019, 14, 157–172.
  15. Yu, F.; Wang, X.; Guo, Z.S.; Bartlett, D.L.; Gottschalk, S.M.; Song, X.-T. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol. Ther. 2014, 22, 102–111.
  16. Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991, 252, 854–856.
  17. 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.
  18. Bommareddy, P.K.; Shettigar, M.; Kaufman, H.L. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 2018, 18, 498.
  19. Bourgeois-Daigneault, M.-C.; Roy, D.G.; Aitken, A.S.; El Sayes, N.; Martin, N.T.; Varette, O.; Falls, T.; St-Germain, L.E.; Pelin, A.; Lichty, B.D. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci. Transl. Med. 2018, 10, 1641–1650.
  20. Delwar, Z.M.; Kuo, Y.; Wen, Y.H.; Rennie, P.S.; Jia, W. Oncolytic virotherapy blockade by microglia and macrophages requires STAT1/3. Cancer Res. 2018, 78, 718–730.
  21. Garcia-Carbonero, R.; Salazar, R.; Duran, I.; Osman-Garcia, I.; Paz-Ares, L.; Bozada, J.M.; Boni, V.; Blanc, C.; Seymour, L.; Beadle, J. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J. Immunother. Cancer 2017, 5, 1–13.
  22. Lawler, S.E.; Speranza, M.-C.; Cho, C.-F.; Chiocca, E.A. Oncolytic viruses in cancer treatment: A review. JAMA Oncol. 2017, 3, 841–849.
  23. Martikainen, M.; Essand, M. Virus-based immunotherapy of glioblastoma. Cancers 2019, 11, 186.
  24. Haddad, D. Genetically engineered vaccinia viruses as agents for cancer treatment, imaging, and transgene delivery. Front. Oncol. 2017, 7, 96.
  25. Chesney, J.; Puzanov, I.; Collichio, F.; Singh, P.; Milhem, M.M.; Glaspy, J.; Hamid, O.; Ross, M.; Friedlander, P.; Garbe, C. 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. J. Clin. Oncol. 2018, 36, 1658.
  26. Kelly, C.M.; Antonescu, C.R.; Bowler, T.; Munhoz, R.; Chi, P.; Dickson, M.A.; Gounder, M.M.; Keohan, M.L.; Movva, S.; Dholakia, R. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab: A phase 2 clinical trial. JAMA Oncol. 2020, 6, 402–408.
  27. Ribas, A.; Dummer, R.; Puzanov, I.; VanderWalde, A.; Andtbacka, R.H.; Michielin, O.; Olszanski, A.J.; Malvehy, J.; Cebon, J.; Fernandez, E. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017, 170, 1109–1119. e1110.
  28. Chesney, J.; Awasthi, S.; Curti, B.; Hutchins, L.; Linette, G.; Triozzi, P.; Tan, M.C.; Brown, R.E.; Nemunaitis, J.; Whitman, E. Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB–IVM1c melanoma. Melanoma Res. 2018, 28, 44–51.
  29. Andtbacka, R.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 2015, 33, 2780–2788.
  30. Harrington, K.J.; Hingorani, M.; Tanay, M.A.; Hickey, J.; Bhide, S.A.; Clarke, P.M.; Renouf, L.C.; Thway, K.; Sibtain, A.; McNeish, I.A. Phase I/II study of oncolytic HSVGM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin. Cancer Res. 2010, 16, 4005–4015.
  31. Senzer, N.N.; Kaufman, H.L.; Amatruda, T.; Nemunaitis, M.; Reid, T.; Daniels, G.; Gonzalez, R.; Glaspy, J.; Whitman, E.; Harrington, K. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 2009, 27, 5763.
  32. Hu, J.C.; Coffin, R.S.; Davis, C.J.; Graham, N.J.; Groves, N.; Guest, P.J.; Harrington, K.J.; James, N.D.; Love, C.A.; McNeish, I. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin. Cancer Res. 2006, 12, 6737–6747.
  33. Streby, K.A.; Geller, J.I.; Currier, M.A.; Warren, P.S.; Racadio, J.M.; Towbin, A.J.; Vaughan, M.R.; Triplet, M.; Ott-Napier, K.; Dishman, D.J. Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin. Cancer Res. 2017, 23, 3566–3574.
  34. Mace, A.T.; Ganly, I.; Soutar, D.S.; Brown, S.M. Potential for efficacy of the oncolytic Herpes simplex virus 1716 in patients with oral squamous cell carcinoma. Head Neck J. Sci. Spec. Head Neck 2008, 30, 1045–1051.
  35. Geevarghese, S.K.; Geller, D.A.; de Haan, H.A.; Hörer, M.; Knoll, A.E.; Mescheder, A.; Nemunaitis, J.; Reid, T.R.; Sze, D.Y.; Tanabe, K.K. Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver. Hum. Gene Ther. 2010, 21, 1119–1128.
  36. Fong, Y.; Kim, T.; Bhargava, A.; Schwartz, L.; Brown, K.; Brody, L.; Covey, A.; Karrasch, M.; Getrajdman, G.; Mescheder, A. A herpes oncolytic virus can be delivered via the vasculature to produce biologic changes in human colorectal cancer. Mol. Ther. 2009, 17, 389–394.
  37. Markert, J.M.; Razdan, S.N.; Kuo, H.-C.; Cantor, A.; Knoll, A.; Karrasch, M.; Nabors, L.B.; Markiewicz, M.; Agee, B.S.; Coleman, J.M. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol. Ther. 2014, 22, 1048–1055.
  38. Hirooka, Y.; Kasuya, H.; Ishikawa, T.; Kawashima, H.; Ohno, E.; Villalobos, I.B.; Naoe, Y.; Ichinose, T.; Koyama, N.; Tanaka, M. A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer 2018, 18, 1–9.
  39. Voit, C.; Kron, M.; Schwürzer-Voit, M.; Sterry, W. Intradermal injection of Newcastle disease virus-modified autologous melanoma cell lysate and interleukin-2 for adjuvant treatment of melanoma patients with resectable stage III disease: Adjuvante Therapie von Melanompatienten im Stadium III mit einer Kombination aus Newcastle-disease-Virus-modifiziertem Tumorzelllysat und Interleukin-2. JDDG J. Der Dtsch. Dermatol. Ges. 2003, 1, 120–125.
  40. Pecora, A.L.; Rizvi, N.; Cohen, G.I.; Meropol, N.J.; Sterman, D.; Marshall, J.L.; Goldberg, S.; Gross, P.; O’Neil, J.D.; Groene, W.S. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J. Clin. Oncol. 2002, 20, 2251–2266.
  41. Freeman, A.I.; Zakay-Rones, Z.; Gomori, J.M.; Linetsky, E.; Rasooly, L.; Greenbaum, E.; Rozenman-Yair, S.; Panet, A.; Libson, E.; Irving, C.S. Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol. Ther. 2006, 13, 221–228.
  42. Rudin, C.; Pandha, H.; Gupta, S.; Zibelman, M.; Akerley, W.; Day, D.; Hill, A.; Sanborn, R.; O’Day, S.; Clay, T. Phase Ib KEYNOTE-200: A study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced NSCLC and bladder cancer patients. Ann. Oncol. 2018, 29, viii732.
  43. Cook, M.; Chauhan, A. Clinical Application of Oncolytic Viruses: A Systematic Review. Int. J. Mol. Sci. 2020, 21, 7505.
  44. A Study of Intratumoral CAVATAK in Patients with Stage IIIc and Stage IV Malignant Melanoma (VLA-007 CALM) (CALM). Available online: (accessed on 23 January 2021).
  45. Morris, D.G.; Feng, X.; DiFrancesco, L.M.; Fonseca, K.; Forsyth, P.A.; Paterson, A.H.; Coffey, M.C.; Thompson, B. REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors. Investig. New Drugs 2013, 31, 696–706.
  46. Kicielinski, K.P.; Chiocca, E.A.; John, S.Y.; Gill, G.M.; Coffey, M.; Markert, J.M. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol. Ther. 2014, 22, 1056–1062.
  47. Kolb, E.A.; Sampson, V.; Stabley, D.; Walter, A.; Sol-Church, K.; Cripe, T.; Hingorani, P.; Ahern, C.H.; Weigel, B.J.; Zwiebel, J. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children’s Oncology Group Phase I Consortium report. Pediatr. Blood Cancer 2015, 62, 751–758.
  48. Noonan, A.M.; Farren, M.R.; Geyer, S.M.; Huang, Y.; Tahiri, S.; Ahn, D.; Mikhail, S.; Ciombor, K.K.; Pant, S.; Aparo, S. Randomized phase 2 trial of the oncolytic virus pelareorep (Reolysin) in upfront treatment of metastatic pancreatic adenocarcinoma. Mol. Ther. 2016, 24, 1150–1158.
  49. 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. Phase II trial of intravenous administration of Reolysin®(Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. Mol. Ther. 2012, 20, 1998–2003.
  50. Bernstein, V.; Ellard, S.; Dent, S.; Tu, D.; Mates, M.; Dhesy-Thind, S.; Panasci, L.; Gelmon, K.; Salim, M.; Song, X. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: Final analysis of Canadian Cancer Trials Group IND. 213. Breast Cancer Res. Treat. 2018, 167, 485–493.
  51. Mahalingam, D.; Goel, S.; Aparo, S.; Patel Arora, S.; Noronha, N.; Tran, H.; Chakrabarty, R.; Selvaggi, G.; Gutierrez, A.; Coffey, M. A phase II study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers 2018, 10, 160.
  52. Mahalingam, D.; Fountzilas, C.; Moseley, J.; Noronha, N.; Tran, H.; Chakrabarty, R.; Selvaggi, G.; Coffey, M.; Thompson, B.; Sarantopoulos, J. A phase II study of REOLYSIN®(pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma. Cancer Chemother. Pharmacol. 2017, 79, 697–703.
  53. 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.; Aghajanian, C. Randomized phase IIB evaluation of weekly paclitaxel versus weekly paclitaxel with oncolytic reovirus (Reolysin®) in recurrent ovarian, tubal, or peritoneal cancer: An nrg oncology/gynecologic oncology group study. Gynecol. Oncol. 2017, 146, 477–483.
  54. Roulstone, V.; Khan, K.; Pandha, H.S.; Rudman, S.; Coffey, M.; Gill, G.M.; Melcher, A.A.; Vile, R.; Harrington, K.J.; De Bono, J. Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. Clin. Cancer Res. 2015, 21, 1305–1312.
  55. Harrington, K.J.; Karapanagiotou, E.M.; Roulstone, V.; Twigger, K.R.; White, C.L.; Vidal, L.; Beirne, D.; Prestwich, R.; Newbold, K.; Ahmed, M. Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers. Clin. Cancer Res. 2010, 16, 3067–3077.
  56. Desjardins, A.; Gromeier, M.; Herndon, J.E.; Beaubier, N.; Bolognesi, D.P.; Friedman, A.H.; Friedman, H.S.; McSherry, F.; Muscat, A.M.; Nair, S. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 2018, 379, 150–161.
  57. Nokisalmi, P.; Pesonen, S.; Escutenaire, S.; Särkioja, M.; Raki, M.; Cerullo, V.; Laasonen, L.; Alemany, R.; Rojas, J.; Cascallo, M. Oncolytic adenovirus ICOVIR-7 in patients with advanced and refractory solid tumors. Clin. Cancer Res. 2010, 16, 3035–3043.
  58. Kimball, K.J.; Preuss, M.A.; Barnes, M.N.; Wang, M.; Siegal, G.P.; Wan, W.; Kuo, H.; Saddekni, S.; Stockard, C.R.; Grizzle, W.E. A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases. Clin. Cancer Res. 2010, 16, 5277–5287.
  59. Kim, K.H.; Dmitriev, I.P.; Saddekni, S.; Kashentseva, E.A.; Harris, R.D.; Aurigemma, R.; Bae, S.; Singh, K.P.; Siegal, G.P.; Curiel, D.T. A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer. Gynecol. Oncol. 2013, 130, 518–524.
  60. Pesonen, S.; Diaconu, I.; Cerullo, V.; Escutenaire, S.; Raki, M.; Kangasniemi, L.; Nokisalmi, P.; Dotti, G.; Guse, K.; Laasonen, L. Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors. Int. J. Cancer 2012, 130, 1937–1947.
  61. DeWeese, T.L.; van der Poel, H.; Li, S.; Mikhak, B.; Drew, R.; Goemann, M.; Hamper, U.; DeJong, R.; Detorie, N.; Rodriguez, R. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res. 2001, 61, 7464–7472.
  62. Chang, J.; Zhao, X.; Wu, X.; Guo, Y.; Guo, H.; Cao, J.; Guo, Y.; Lou, D.; Yu, D.; Li, J. A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor: Armed oncolytic adenovirus for the treatment of head and neck cancers. Cancer Biol. Ther. 2009, 8, 676–682.
  63. Packiam, V.T.; Lamm, D.L.; Barocas, D.A.; Trainer, A.; Fand, B.; Davis III, R.L.; Clark, W.; Kroeger, M.; Dumbadze, I.; Chamie, K. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results. Urol. Oncol. Semin. Ori. 2018, 36, 440–447.
  64. Nemunaitis, J.; Tong, A.W.; Nemunaitis, M.; Senzer, N.; Phadke, A.P.; Bedell, C.; Adams, N.; Zhang, Y.-A.; Maples, P.B.; Chen, S. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol. Ther. 2010, 18, 429–434.
  65. Nemunaitis, J.; Ganly, I.; Khuri, F.; Arseneau, J.; Kuhn, J.; McCarty, T.; Landers, S.; Maples, P.; Romel, L.; Randlev, B. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: A phase II trial. Cancer Res. 2000, 60, 6359–6366.
  66. Galanis, E.; Okuno, S.H.; Nascimento, A.; Lewis, B.; Lee, R.; Oliveira, A.; Sloan, J.A.; Atherton, P.; Edmonson, J.; Erlichman, C. Phase I–II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther. 2005, 12, 437–445.
  67. Reid, T.R.; Freeman, S.; Post, L.; McCormick, F.; Sze, D.Y. Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin. Cancer Gene Ther. 2005, 12, 673–681.
  68. Nemunaitis, J.; Senzer, N.; Sarmiento, S.; Zhang, Y.; Arzaga, R.; Sands, B.; Maples, P.; Tong, A. A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. Cancer Gene Ther. 2007, 14, 885–893.
  69. Wheeler, L.A.; Manzanera, A.G.; Bell, S.D.; Cavaliere, R.; McGregor, J.M.; Grecula, J.C.; Newton, H.B.; Lo, S.S.; Badie, B.; Portnow, J. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro Oncol. 2016, 18, 1137–1145.
  70. Freytag, S.O.; Stricker, H.; Lu, M.; Elshaikh, M.; Aref, I.; Pradhan, D.; Levin, K.; Kim, J.H.; Peabody, J.; Siddiqui, F. Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2014, 89, 268–276.
  71. Freytag, S.O.; Movsas, B.; Aref, I.; Stricker, H.; Peabody, J.; Pegg, J.; Zhang, Y.; Barton, K.N.; Brown, S.L.; Lu, M. Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol. Ther. 2007, 15, 1016–1023.
  72. Machiels, J.-P.; Salazar, R.; Rottey, S.; Duran, I.; Dirix, L.; Geboes, K.; Wilkinson-Blanc, C.; Pover, G.; Alvis, S.; Champion, B. A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE). J. Immunother. Cancer 2019, 7, 1–15.
  73. Cripe, T.P.; Ngo, M.C.; Geller, J.I.; Louis, C.U.; Currier, M.A.; Racadio, J.M.; Towbin, A.J.; Rooney, C.M.; Pelusio, A.; Moon, A. Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. Mol. Ther. 2015, 23, 602–608.
  74. Heo, J.; Breitbach, C.; Cho, M.; Hwang, T.-H.; Kim, C.W.; Jeon, U.B.; Woo, H.Y.; Yoon, K.T.; Lee, J.W.; Burke, J. Phase II Trial of Pexa-Vec (Pexastimogene Devacirepvec; JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus, Followed by Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC); American Society of Clinical Oncology: Alexandria, VA, USA, 2013.
  75. Park, S.H.; Breitbach, C.J.; Lee, J.; Park, J.O.; Lim, H.Y.; Kang, W.K.; Moon, A.; Mun, J.-H.; Sommermann, E.M.; Avidal, L.M. Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer. Mol. Ther. 2015, 23, 1532–1540.
  76. Hwang, T.-H.; Moon, A.; Burke, J.; Ribas, A.; Stephenson, J.; Breitbach, C.J.; Daneshmand, M.; De Silva, N.; Parato, K.; Diallo, J.-S. A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol. Ther. 2011, 19, 1913–1922.
  77. Husseini, F.; Delord, J.-P.; Fournel-Federico, C.; Guitton, J.; Erbs, P.; Homerin, M.; Halluard, C.; Jemming, C.; Orange, C.; Limacher, J.-M. Vectorized gene therapy of liver tumors: Proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine. Ann. Oncol. 2017, 28, 169–174.
  78. Downs-Canner, S.; Guo, Z.S.; Ravindranathan, R.; Breitbach, C.J.; O’malley, M.E.; Jones, H.L.; Moon, A.; McCart, J.A.; Shuai, Y.; Zeh, H.J. Phase 1 study of intravenous oncolytic poxvirus (vvDD) in patients with advanced solid cancers. Mol. Ther. 2016, 24, 1492–1501.
  79. Zeh, H.J.; Downs-Canner, S.; McCart, J.A.; Guo, Z.S.; Rao, U.N.; Ramalingam, L.; Thorne, S.H.; Jones, H.L.; Kalinski, P.; Wieckowski, E. First-in-man study of western reserve strain oncolytic vaccinia virus: Safety, systemic spread, and antitumor activity. Mol. Ther. 2015, 23, 202–214.
  80. Mell, L.K.; Brumund, K.T.; Daniels, G.A.; Advani, S.J.; Zakeri, K.; Wright, M.E.; Onyeama, S.-J.; Weisman, R.A.; Sanghvi, P.R.; Martin, P.J. 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. 2017, 23, 5696–5702.
  81. Galanis, E.; Hartmann, L.C.; Cliby, W.A.; Long, H.J.; Peethambaram, P.P.; Barrette, B.A.; Kaur, J.S.; Haluska, P.J.; Aderca, I.; Zollman, P.J. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res. 2010, 70, 875–882.
  82. Rudin, C.M.; Poirier, J.T.; Senzer, N.N.; Stephenson, J.; Loesch, D.; Burroughs, K.D.; Reddy, P.S.; Hann, C.L.; Hallenbeck, P.L. Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. Clin. Cancer Res. 2011, 17, 888–895.
  83. Burke, M.J.; Ahern, C.; Weigel, B.J.; Poirier, J.T.; Rudin, C.M.; Chen, Y.; Cripe, T.P.; Bernhardt, M.B.; Blaney, S.M. Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: A report of the Children’s Oncology Group. Pediatr. Blood Cancer 2015, 62, 743–750.
  84. Kaufman, H.L.; Kim, D.W.; Kim-Schulze, S.; DeRaffele, G.; Jagoda, M.C.; Broucek, J.R.; Zloza, A. Results of a randomized phase I gene therapy clinical trial of nononcolytic fowlpox viruses encoding T cell costimulatory molecules. Hum. Gene Ther. 2014, 25, 452–460.
  85. Angelova, A.L.; Barf, M.; Geletneky, K.; Unterberg, A.; Rommelaere, J. Immunotherapeutic potential of oncolytic H-1 parvovirus: Hints of glioblastoma microenvironment conversion towards immunogenicity. Viruses 2017, 9, 382.
  86. Ylösmäki, E.; Cerullo, V. Design and application of oncolytic viruses for cancer immunotherapy. Curr. Opin. Biotechnol. 2020, 65, 25–36.
  87. De Graaf, J.F.; de Vor, L.; Fouchier, R.A.M.; Van Den Hoogen, B.G. Armed oncolytic viruses: A kick-start for anti-tumor immunity. Cytokine Growth Factor Rev. 2018, 41, 28–39.
  88. Breitbach, C.J.; Arulanandam, R.; De Silva, N.; Thorne, S.H.; Patt, R.; Daneshmand, M.; Moon, A.; Ilkow, C.; Burke, J.; Hwang, T.-H. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 2013, 73, 1265–1275.
  89. Achard, C.; Surendran, A.; Wedge, M.-E.; Ungerechts, G.; Bell, J.; Ilkow, C.S. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine 2018, 31, 17–24.
  90. Allegrezza, M.J.; Conejo-Garcia, J.R. Targeted therapy and immunosuppression in the tumor microenvironment. Trends Cancer 2017, 3, 19–27.
  91. Pol, J.G.; Bridle, B.W.; Lichty, B.D. Detection of Tumor Antigen-Specific T-Cell Responses after Oncolytic Vaccination. In Oncolytic Viruses; Springer: Humana, NY, USA, 2020; pp. 191–211.
  92. Bakhshaei, P.; Kazemi, M.H.; Golara, M.; Abdolmaleki, S.; Khosravi-Eghbal, R.; Khoshnoodi, J.; Judaki, M.A.; Salimi, V.; Douraghi, M.; Jeddi-Tehrani, M.; et al. Investigation of the Cellular Immune Response to Recombinant Fragments of Filamentous Hemagglutinin and Pertactin of Bordetella pertussis in BALB/c Mice. J. Interferon Cytokine Res. 2018, 38.
  93. Kuryk, L.; Møller, A.S.W. Chimeric oncolytic Ad5/3 virus replicates and lyses ovarian cancer cells through desmoglein-2 cell entry receptor. J. Med. Virol. 2020, 92, 1309–1315.
  94. Wang, M.; Liu, W.; Zhang, Y.; Dang, M.; Zhang, Y.; Tao, J.; Chen, K.; Peng, X.; Teng, Z. Intercellular adhesion molecule 1 antibody-mediated mesoporous drug delivery system for targeted treatment of triple-negative breast cancer. J. Colloid Interface Sci. 2019, 538, 630–637.
  95. Wenthe, J.; Naseri, S.; Hellström, A.-C.; Wiklund, H.J.; Eriksson, E.; Loskog, A. Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40. Cancer Gene Ther. 2020, 27, 948–959.
  96. Zhang, Y.; Ye, M.; Huang, F.; Wang, S.; Wang, H.; Mou, X.; Wang, Y. Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma. Hum. Gene Ther. 2020, 31, 15–16.
  97. Heiniö, C.; Havunen, R.; Santos, J.; Lint, K.D.; Cervera-Carrascon, V.; Kanerva, A.; Hemminki, A. TNFa and IL2 encoding oncolytic adenovirus activates pathogen and danger-associated immunological signaling. Cells 2020, 9, 798.
  98. Delaunay, T.; Achard, C.; Boisgerault, N.; Grard, M.; Petithomme, T.; Chatelain, C.; Dutoit, S.; Blanquart, C.; Royer, P.-J.; Minvielle, S. Frequent homozygous deletions of type I interferon genes in pleural mesothelioma confer sensitivity to oncolytic measles virus. J. Thorac. Oncol. 2020, 15, 827–842.
  99. Hindupur, S.V.; Schmid, S.C.; Koch, J.A.; Youssef, A.; Baur, E.-M.; Wang, D.; Horn, T.; Slotta-Huspenina, J.; Gschwend, J.E.; Holm, P.S. STAT3/5 inhibitors suppress proliferation in bladder cancer and enhance oncolytic adenovirus therapy. Int. J. Mol. Sci. 2020, 21, 1106.
  100. McLaughlin, M.; Pedersen, M.; Roulstone, V.; Bergerhoff, K.F.; Smith, H.G.; Whittock, H.; Kyula, J.N.; Dillon, M.T.; Pandha, H.S.; Vile, R. The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism. Mol. Ther. Oncolytics 2020, 16, 238–249.
  101. Kaufman, H.L.; Kim, D.W.; DeRaffele, G.; Mitcham, J.; Coffin, R.S.; Kim-Schulze, S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 2010, 17, 718–730.
  102. Moesta, A.K.; Cooke, K.; Piasecki, J.; Mitchell, P.; Rottman, J.B.; Fitzgerald, K.; Zhan, J.; Yang, B.; Le, T.; Belmontes, B. Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte–Associated Protein Blockade. Clin. Cancer Res. 2017, 23, 6190–6202.
  103. Galanis, E.; Atherton, P.J.; Maurer, M.J.; Knutson, K.L.; Dowdy, S.C.; Cliby, W.A.; Haluska, P.; Long, H.J.; Oberg, A.; Aderca, I. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res. 2015, 75, 22–30.
  104. DuPage, M.; Mazumdar, C.; Schmidt, L.M.; Cheung, A.F.; Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 2012, 482, 405–409.
  105. Segal, N.H.; Parsons, D.W.; Peggs, K.S.; Velculescu, V.; Kinzler, K.W.; Vogelstein, B.; Allison, J.P. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008, 68, 889–892.
  106. Wang, G.; Kang, X.; Chen, K.S.; Jehng, T.; Jones, L.; Chen, J.; Huang, X.F.; Chen, S.-Y. An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses. Nat. Commun. 2020, 11, 1–14.
  107. Kanerva, A.; Nokisalmi, P.; Diaconu, I.; Koski, A.; Cerullo, V.; Liikanen, I.; Tähtinen, S.; Oksanen, M.; Heiskanen, R.; Pesonen, S. Antiviral and antitumor T-cell immunity in patients treated with GM-CSF–coding oncolytic adenovirus. Clin. Cancer Res. 2013, 19, 2734–2744.
  108. Woller, N.; Gürlevik, E.; Fleischmann-Mundt, B.; Schumacher, A.; Knocke, S.; Kloos, A.M.; Saborowski, M.; Geffers, R.; Manns, M.P.; Wirth, T.C. Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses. Mol. Ther. 2015, 23, 1630–1640.
  109. Wang, X.; Shao, X.; Gu, L.; Jiang, K.; Wang, S.; Chen, J.; Fang, J.; Guo, X.; Yuan, M.; Shi, J. Targeting STAT3 enhances NDV-induced immunogenic cell death in prostate cancer cells. J. Cell. Mol. Med. 2020, 24, 4286–4297.
  110. Ma, J.; Ramachandran, M.; Jin, C.; Quijano-Rubio, C.; Martikainen, M.; Yu, D.; Essand, M. Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer. Cell Death Dis. 2020, 11, 1–15.
  111. van Vloten, J.P.; Workenhe, S.T.; Wootton, S.K.; Mossman, K.L.; Bridle, B.W. Critical interactions between immunogenic cancer cell death, oncolytic viruses, and the immune system define the rational design of combination immunotherapies. J. Immunol. 2018, 200, 450–458.
  112. Guo, Z.S.; Liu, Z.; Bartlett, D.L. Oncolytic immunotherapy: Dying the right way is a key to eliciting potent antitumor immunity. Front. Oncol. 2014, 4, 74.
  113. Hajifathali, A.; Parkhideh, S.; Kazemi, M.H.; Chegeni, R.; Roshandel, E.; Gholizadeh, M. Immune checkpoints in hematologic malignancies: What made the immune cells and clinicians exhausted! J. Cell. Physiol. 2020, 235, 9080–9097.
  114. Kepp, O.; Senovilla, L.; Vitale, I.; Vacchelli, E.; Adjemian, S.; Agostinis, P.; Apetoh, L.; Aranda, F.; Barnaba, V.; Bloy, N. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 2014, 3, e955691.
  115. Lin, H.D.; Fong, C.-Y.; Biswas, A.; Bongso, A. Hypoxic Wharton’s Jelly Stem Cell Conditioned Medium Induces Immunogenic Cell Death in Lymphoma Cells. Stem Cells Int. 2020, 20, 1–14.
  116. Burke, S.; Shergold, A.; Elder, M.J.; Whitworth, J.; Cheng, X.; Jin, H.; Wilkinson, R.W.; Harper, J.; Carroll, D.K. Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro. Cancer Immunol. Immunother. 2020, 69, 1015–1027.
  117. Ghasemi, K.; Parkhideh, S.; Kazemi, M.H.; Salimi, M.; Salari, S.; Nalini, R.; Hajifathali, A. The role of serum uric acid in the prediction of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. J. Clin. Lab. Anal. 2020, 34, e23271.
  118. Schuster, P.; Lindner, G.; Thomann, S.; Haferkamp, S.; Schmidt, B. Prospect of plasmacytoid dendritic cells in enhancing anti-tumor immunity of oncolytic herpes viruses. Cancers 2019, 11, 651.
  119. Dai, P.; Wang, W.; Yang, N.; Serna-Tamayo, C.; Ricca, J.M.; Zamarin, D.; Shuman, S.; Merghoub, T.; Wolchok, J.D.; Deng, L. Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci. Immunol. 2017, 2, 1713–1725.
  120. Woo, S.-R.; Fuertes, M.B.; Corrales, L.; Spranger, S.; Furdyna, M.J.; Leung, M.Y.K.; Duggan, R.; Wang, Y.; Barber, G.N.; Fitzgerald, K.A. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014, 41, 830–842.
  121. Bhat, H.; Zaun, G.; Hamdan, T.A.; Lang, J.; Adomati, T.; Schmitz, R.; Friedrich, S.-K.; Bergerhausen, M.; Cham, L.B.; Li, F. Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression. Front. Immunol. 2020, 11, 1849.
  122. Zamarin, D.; Ricca, J.M.; Sadekova, S.; Oseledchyk, A.; Yu, Y.; Blumenschein, W.M.; Wong, J.; Gigoux, M.; Merghoub, T.; Wolchok, J.D. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J. Clin. Investig. 2018, 128, 1413–1428.
  123. Gujar, S.A.; Lee, P.W.K. Oncolytic virus-mediated reversal of impaired tumor antigen presentation. Front. Oncol. 2014, 4, 77.
  124. Ilkow, C.S.; Marguerie, M.; Batenchuk, C.; Mayer, J.; Neriah, D.B.; Cousineau, S.; Falls, T.; Jennings, V.A.; Boileau, M.; Bellamy, D. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat. Med. 2015, 21, 530.
  125. Altomonte, J.; Marozin, S.; De Toni, E.N.; Rizzani, A.; Esposito, I.; Steiger, K.; Feuchtinger, A.; Hellerbrand, C.; Schmid, R.M.; Ebert, O. Antifibrotic properties of transarterial oncolytic VSV therapy for hepatocellular carcinoma in rats with thioacetamide-induced liver fibrosis. Mol. Ther. 2013, 21, 2032–2042.
  126. Arulanandam, R.; Batenchuk, C.; Angarita, F.A.; Ottolino-Perry, K.; Cousineau, S.; Mottashed, A.; Burgess, E.; Falls, T.J.; De Silva, N.; Tsang, J. VEGF-mediated induction of PRD1-BF1/Blimp1 expression sensitizes tumor vasculature to oncolytic virus infection. Cancer Cell 2015, 28, 210–224.
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