key: cord-0072849-qbd8ov7q authors: Kooti, Wesam; Esmaeili Gouvarchin Ghaleh, Hadi; Farzanehpour, Mahdieh; Dorostkar, Ruhollah; Jalali Kondori, Bahman; Bolandian, Masoumeh title: Oncolytic Viruses and Cancer, Do You Know the Main Mechanism? date: 2021-12-22 journal: Front Oncol DOI: 10.3389/fonc.2021.761015 sha: 2c9f72824e0281bdd5511723c44fa25e0c2f0003 doc_id: 72849 cord_uid: qbd8ov7q The global rate of cancer has increased in recent years, and cancer is still a threat to human health. Recent developments in cancer treatment have yielded the understanding that viruses have a high potential in cancer treatment. Using oncolytic viruses (OVs) is a promising approach in the treatment of malignant tumors. OVs can achieve their targeted treatment effects through selective cell death and induction of specific antitumor immunity. Targeting tumors and the mechanism for killing cancer cells are among the critical roles of OVs. Therefore, evaluating OVs and understanding their precise mechanisms of action can be beneficial in cancer therapy. This review study aimed to evaluate OVs and the mechanisms of their effects on cancer cells. that cancer cells are developed to avoid detection and destruction by the host immune system and also to resist apoptosis, which are the critical responses of normal cells in limiting viral infections, OVs can kill cancer cells through a spectrum of actions ranging from direct cytotoxicity to induction of immune-mediated cytotoxicity. OVs can also indirectly destroy cancer cells by destroying tumor vasculature and mediating antitumor responses (7) . Furthermore, in order to augment the therapeutic characteristics, modifications in OVs by genetic engineering such as insertions and deletions in the genome have been employed in many investigations; thus, additional antitumor molecules can be delivered to cancer cells and effectively bypass the widespread resistance of single-target anticancer drugs (8) It should be noted that the use of OVs in cancer therapy was limited due to the pathogenicity and toxicity of these viruses in human cases. Recent advancements in genetic engineering have optimized the function of OVs through genetic modifications and therefore have become the issue of interest in OVT (9) . Each virus tends to a specific tissue, and this tendency determines which host cells are affected by the virus and what type of disease will be generated. For instance, rabies, hepatitis B, human immunodeficiency virus (HIV), and influenza viruses affect neurons, hepatocytes, T lymphocytes, and respiratory tract epithelium, respectively. Several naturally occurring viruses have a preferential but not exclusive tendency towards cancer cells. This issue is more attributed to tumor cell biology compared to the biology of the virus. OVs are generally categorized into two groups. One group is preferentially replicated in cancer cells and is not pathogenic for normal cells due to the increased sensitivity to the innate immune system's antiviral signaling or dependence on the oncogenic signaling pathways. Autonomous parvovirus, myxoma virus (MYXV; poxvirus), Newcastle disease virus (NDV; paramyxovirus), reovirus, and Seneca valley virus (SVV; picornavirus) are categorized in this group. The second group of OVs includes viruses that are either genetically modified for purposes including vaccine vectors such as mumps virus (MV; paramyxovirus), poliovirus (PV; picornavirus), and vaccinia virus (VV; poxvirus), or genetically engineered through mutation/ deletion of genes required for replication in normal cells, including adenovirus (Ad), Herpes simplex virus (HSV), VV, and vesicular stomatitis virus (VSV; rhabdovirus) (10) . Furthermore, the mutation in cancer cells, drug adaptation, resistance, and cell immortality were effective in the initiation and speed of viral dissemination. Today, researchers are trying to discover and identify a new generation of OVs to save more patients' lives from cancer. Evaluation of OVs and identification of the exact mechanism of action of these viruses can be helpful in this way (11) . This review study aimed to evaluate OVs and their mechanism of action against cancer cells. The key terms in the literature search included oncolytic virus, cancer, immunotherapy, innate immunity, adaptive immunity, virotherapy, viral therapy, oncolytic, and virus were searched in international databases, namely, Web of Science, PubMed, and Scopus from 2004 to 2021. The inclusion criterion was the evaluation of viruses using standard in vivo and in vitro laboratory methods. Exclusion criteria were lack of access to full text articles and incomplete description or assessment of diseases other than cancers. The primary search yielded 1,450 articles. Finally, 47 articles were included in the review after eliminating irrelevant and duplicate studies. The characteristics of the 47 included articles are presented in Table 1 , performed from 2004 to 2021. The OV families assessed in the studies included Ad, MV, PV, NDV, SFV, HSV, VV Reovirus, and bovine herpesvirus (BHV). The most commonly assessed virus was adenovirus (Ad) (n = 15), followed by the herpesvirus (HSV) (n = 12) and measles virus (MV) (n = 7). The least assessed viruses were BHV, SFV, and Reovirus (n = 1). According to Table 1 , OVs may employ multifunction against tumor cells; however, the most antitumor actions of OVs were related to cytolysis activity and inducing antitumor immunity (n = 26) in which adenovirus (n = 11) and HSV (n = 9) were the most responsible OVs in their categories, respectively. However, the last action was associated with vascular collapse. The collective data in Table 2 exhibited a summary of clinical trials of OVs implicated in malignancies highlighting the most considerable focus on engineered VV by TK del GMCSF exp (JX-594) on solid tumors supported by Jennerex Biotherapeutics Company. The majority of studies under clinical trials involve a transgene virus encoding an immune-stimulatory or proapoptic gene to boost the oncolytic features of the virus. As Table 2 reveals, granulocyte-macrophage colony-stimulating factor (GM-CSF) and pro-drug-converting enzymes are the most popular transgenes, although many OVs encoding novel therapeutic cargos are in clinical development. Streby et al., in phase I clinical trial, examined the effects of HSV1716 on relapsed/refractory solid tumors. Despite the fact that none of the patients exhibited objective responses, virus replication and inflammatory reactions were seen in patients (58) . In another clinical trial, Desjardins et al. reported a higher survival rate in grade IV malignant glioma patients who received recombinant nonpathogenic polio-rhinovirus chimera (59) . In a phase I clinical trial, Rocio Garcia-Carbonero et al. discovered that enadenotucirev IV infusion was associated with high local CD8+ cell infiltration in 80% of tumor samples evaluated, indicating a possible enadenotucirev-driven immune response (60) . TG4023, a modified vaccinia Ankara viral vector carrying the FCU1 suicide gene, was used in a phase I trial to convert the non-cytotoxic prodrug flucytosine (5-FC) into 5-fluorouracil (5-FU) in the intratumor. Finally, 16 patients with liver tumors were successfully injected; the MTD was not achieved, and a high therapeutic index was demonstrated (61). Dispenzieri et al. examined MV-NIS effects in patients with relapsed, refractory myeloma and reported satisfactory primary results (62) . As a challenge in cancer therapy approaches (1), the exclusive features of oncolytic viruses have attracted plenty of researchers in recent years. OVs have the dramatic capability to selectively infect tumor cells leading to direct or indirect cancer cell death without harming normal cells (7) . This study focused on some mechanisms employed by OVs against tumor cells, which are exactly various from virus to virus (Figure 1) . According to most studies, OVs can target cancer cells and benefit from tumor conditions in favor of replication in infected cells, eventually leading to oncolysis. Indeed, tumor cells tend to resist apoptosis and translational suppression, which are both compatible with the growth of several viruses (7). One of the main actions of OVs is to take advantage of immune-evading properties of cancer cells to escape from recognition and destruction by the immune system. Antiviral processes in normal cells are associated with the interferon pathway in which the secretion of type I interferon (IFN) cytokine can trigger an antiviral response and induce ISGs to block viral replication (69) . This subsequently leads to cell apoptosis, as it is known that the IFN-I signaling regulates the expression of proapoptotic genes such as tumor necrosis factor alpha (TNFa), FAS ligand, and tumor necrosis factor-related apoptosisinducing ligand (TRAIL) (70) . Regarding the IFN-I signaling is defective in most tumor cells, it makes tumor cells susceptible to being infected by some OVs including NDV, VSV, MYXV, and raccoon pox virus (71) (72) (73) . Garcıá-Romero et al. showed that NDV was able to replicate in glioblastoma (GBM) cancer stem cells (CSCs) due to type I IFN gene loss occurring in more than 50% of patients. Infection of GBM with NDV represents oncolytic and immunostimulatory properties through the production of type I IFN in non-tumor cells such as tumor infiltrated macrophages and DC or other cells present at the tumor microenvironment (49) . NDV therapy also declines CSCs self-renewing capacity to improve their differentiation ability and facilitate cancer therapy (49, 74) . OVs can also benefit from the abnormal expression of the proto-oncogene RAS which generally occurs in normal cells but actives in tumor cells (75) . OV infection outcomes can be Oncolytic viruses may interfere with normal physiological process of tumor cells to induce the secretion of proinflammatory mediators or even lead to the exposure of tumor-associated antigens (TAA), pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) following apoptosis or oncolysis. These responses can also result in a change in tumor status from immune desert to inflamed status and further recruit a collection of immune cells such as cytotoxic T lymphocytes, dendritic cells, natural killer cells and phagocytic cells to induce immune cell death along with antiviral responses (86, 87) . Remarkably, most viruses continue their infection by expressing genes responsible for escaping the immune system and disseminating in host cells (88) . Mutation in these genes can probably improve immune induction and thus increase the antitumoral responses regardless these mutations may reduce virus replication further (10) . Thus, oncolytic viruses are often engineered to express various genes aided in the overall antitumor efficacy of the virus. Transgenes mostly include ranging from immune-stimulatory (IL-2, IL-4, IL-12 and GM-CSF) to pro-apoptotic (tumor necrosis factor alpha, p53 and TRAIL genes inserted into oncolytic viruses (87, (89) (90) (91) (92) (93) (94) . Interestingly, bystander effects of OVs through local release of cytokines can potentially cause immune response against nearby tumor cells even without direct antigen expression (95) . Furthermore, OVs can destroy tumor vasculature and impede sufficient intratumoral blood reserve, which is essential for tumor progression and metastasis (96) . Breitbach et al. demonstrated that intravenous injection of JX-594, an engineered vaccine virus with TK deletion and overexpression of human granulocyte-monocyte colony-stimulating factor (hGM-CSF), led to replication of the virus in endothelial cells of the nearby tumor and disrupted tumor blood flow, which ultimately ended in intensive tumor necrosis within 5 days. Consistently, patients with advanced hepatocellular carcinoma, hypervascular and VEGF high tumor type, treated by JX-594 in phase II clinical trials confirmed the efficiency of the JX-594 OV in tumor vasculature disruption without toxicity to normal blood vessels in which inhibition of angiogenesis can passively result in tumor regression (97) . This evidence may open promising technologies toward cancer therapy in a way tumor cells are targeted selectively and bypass the side effects of conventional approaches. Recently, conditionally replication-competent adenoviruses (CRCAs) have been introduced as a successful method for cancer therapy. Sarkar et al. showed that Ad.PEG-E1A-mda-7, a cancer terminator virus (CTV), selectively replicated in cancer cells, inhibits their growth and induces apoptosis (98) . Qian et al. showed that ZD55 expressing melanoma differentiation-associated gene-7/interleukin-24 (ZD55-IL-24) affects B-lymphoblastic leukemia/lymphoma through upregulation of RNA-dependent protein kinase R, enhance phosphorylation of p38 mitogen-activated protein kinase, and induce of endoplasmic reticulum (ER) stress (99) . Azab et al. showed that Ad.5/3-CTV potently suppressed in vivo tumor growth in mouse (100) . Bhoopathi showed that Ad.5/3-CTV induces apoptosis through apoptosis-inducing factor (AIF) translocation into the nucleus, independent of the caspase-3/caspase-9 pathway (101). In an interesting study, Bhoopathi et al. introduced a novel tripartite CTV "theranostic" adenovirus (TCTV) that targets virus replication, cytokine production, and imaging capabilities uniquely in cancer cells. This TCTV permits targeted treatment of tumors while monitoring tumor regression, with the potential to simultaneously detect metastasis due to the cancer-selective activity of reporter gene expression (102) . Greco et al. showed that ultrasound (US) contrast agents guided MB/Ad.mda-7 complexes to DU-145 cells successfully and eradicated not only targeted DU-145/Bcl-xL-therapyresistant tumors but also nontargeted distant tumors (103) . T-VEC, adenovirus, and vaccinia virus are the most popular OVs in clinical trials. Approving T-VEC by FDA for the first time could pave the way for other OVs in the clinic. Oncolytic viruses have a broad therapeutic method; hence, their clinical development requires a multidisciplinary view. It is necessary to understand viral generation and viability in infected cells. To improve clinical trials, important factors such as viral entrance, replication, dissemination, oncolysis, and immune activation should be controlled. These factors can vary between tumor types and OVs. It is also critical to understand the immune composition of diverse cancers and the immunological repercussions of viro-immunotherapy. Cancer is among the most important causes of mortality worldwide, and many chemotherapies and radiotherapy approaches do not have a specific effect on cancer cells and are sometimes accompanied by side effects. Today, a biological war has evolved against cancer by genetically modifying natural pathogens to activate them against neoplastic cells. OVT is a promising therapeutic option in cancer therapy. The mechanisms of action of OVs differ entirely from the mechanism of action of chemotherapy, radiotherapy, surgery, and embolization. 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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.