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Cancer Treatment Using Oncolytic Viruses
Oncolytic viruses can activate innate and adaptive immune mechanisms that are capable of targeting both cancer cells and viruses, it is very important to keep a balance between viral immunogenicity and anticancer immunity.
Despite the long history of cancer being treated mainly by the “cut, poison and burn” principle, immunotherapeutics allowed to outsmart the tumor using the intrinsic potential of the immune system. The immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1) have been the first kind of drugs that gave patients hope and revolutionized the treatment of cancers previously thought to be incurable . Since the establishment of immunotherapy approaches, dozens of immune checkpoint inhibitors were studied for the treatment of different cancers with various degrees of success . The breakthroughs of immunotherapy had an avalanche effect and stimulated the research of multiple combinatorial approaches for cancer treatment .
The modern arsenal of immunotherapeutics is impressively rich and includes diverse drugs and approaches such as pro-inflammatory cytokines , cancer vaccines , adoptive T-cell therapies , antibody-based immunotherapies (bispecific T cell engagers, checkpoint inhibitors, antibody-drug conjugates)  and oncolytic viruses (OV) . The latest is of particular interest because of the recent encouraging clinical results and extreme flexibility of virus development platforms.
The oncolytic potential of several viruses has been known for quite a while, however, its clinical application for cancer therapy has been hampered by a lack of knowledge in virus molecular biology and immune pathways . Most OV show selective replication in tumor cells (have enhanced tumor tropism) and affect several key steps in cancer–immunity cycle . (IFN type I response genes, tumor suppressor proteins, etc.) are dysfunctional in tumor cells, enabling preferential replication of OVs . Although some viruses exhibit inherent tropism for tumor cells, genetic engineering also helps to precisely tune up the virus life cycle to become the most potent cancer killer .
The therapeutic effect of OVs in cancer therapy is mediated by several main mechanisms that eventually lead to immunogenic cell death (ICD), a form of regulated cell death (RCD) . Firstly, OV infection of cancer cells initiates direct cell lysis . OVs can induce anti-angiogenesis through reduction of VEGF concentration, resulting in a loss of tumor perfusion that leads to apoptotic and necrotic tumor cell death . In particular, the lysis of tumor cells caused by oncolytic viruses leads to the release of danger-associated molecular patterns (DAMPs) such as uric acid, secreted adenosine triphosphate (ATP), high mobility group protein B1 (HMGB1), surface-exposed calreticulin (ecto-CRT), heat shock proteins as well as pathogen-associated molecular patterns (PAMPs) including viral components (nucleic acids, proteins and capsid components).
2. Combination Therapies and Future Perspectives
|Pembrolizumab||14||Targets and blocks a PD-1 protein on the surface of T-cells. Blocking PD-1 triggers the T-cells activation towards finding and killing cancer cells. Pemrolizumab known under brand name Keytruda.|
|Nivolumab||8||An anti-PD-1 monoclonal antibody (brand name Opdivo).|
|Ipililumab||5||Humanized immune checkpoint inhibitor which blocks CTLA-4 receptor and upregulates cytotoxic T–lymphocytes (brand name Yervoy).|
|Avelumab||3||An anti-PD-1 monoclonal antibody (brand name Bavencio).|
|Durvalumab||3||An anti-PD-L1 specific human IgG1 kappa monoclonal antibody.|
|Cemiplimab||3||An anti-PD-1 monoclonal antibody (brand name Libtayo).|
|Atezolizumab||2||An anti-PDL-1 monoclonal antibody (brand name Tecentriq).|
|Socazolimab||1||Anti-PD-L1 monoclonal antibody (ZKAB001).|
|HX008||1||Anti-PD-L1 monoclonal antibody.|
|Vibostolimab||1||Vibostolimab is a monoclonal antibody against T-cell immunoreceptor with Ig and ITIM domains (TIGIT). Vibostolimab blocks the interaction between TIGIT and its ligands (CD112 and CD155) thereby activating T cells.|
|Bevacizumab||1||Bevacizumab (Avastin) targets cellular vascular endothelial growth factor (VEGF), a protein that is essential for blood vessel growth.|
|Trasuzumab||1||Trasuzumab (Herceptin) is an anti-HER2 monoclonal antibody targeting breast cancer and stomach cancer cells expressing HER2 receptors.|
|Tremelimumab||1||An anti- CTLA-4 monoclonal antibody.|
|Interleukine-2 (IL-2)||3||Stimulates cytotoxic T cells (CD8+) and NK cells, controls both the primary and secondary expansion of antigen-specific CD8+ T cell populations.|
|Interferon-α||3||Cytokine activates immune cells (NK cells and T-cells) and suppresses tumor cell division by inhibiting protein and hormone synthesis. It also reduces angiogenesis through inhibition of angiogenic factors b-FGF and VEGF.|
|Granulocyte-macrophage colony-stimulating factor (GM-CSF)||3||GM-CSF enhances the number of circulating white blood cells and increases neutrophil and monocyte function. It also actively shapes the dendritic cell profile leading to an enhanced anti-tumor effect.|
|Autologous tumor cells||14||Therapeutic agent produced from patient tumor cells. Processed and treated tumor cells are a great source of cancer antigens that, after administration, boost the immune system of the individual that they have been isolated.|
|Melanoma-associated antigen 3(MAGE-A3)||3||MAGE-A3 is a tumor-specific shared antigen often expressed in lung cancer and melanoma. Immunization with MAGE-A3 tends to stimulate the immune response to cancer, which has been traditionally considered as poorly immunogenic.|
|ag-E6E7||1||Human papillomavirus oncoproteins E6 and E7. Immunization with E6 and E7 antigens improves antitumor immunity against HPV-related tumors and enhances the immunogenicity of dendritic cells.|
|Bacillus Calmette-Guerin (BCG)||1||Nontumor antigen was initially used as a tuberculosis vaccine. High immunogenic BCG mounts an overall immune response that potentially decreases the reoccurrence of cancer.|
|Radiotherapy/Chemotherapy/Surgery||80||Various drugs, radiotherapy regimes accompanied by tumor resection (where possible) are in use in combination with virotherapy. The reader may find specific details in decent reviews and supplementary materials.|
|Single-agent virotherapy||88||Wild-type viruses attenuated or genetically engineered variants armored with immunomodulatory molecules are frequently used as a monotherapy. Variants of the used genetic modifications of oncolytics (mainly for stimulating the immune system) are shown in Table 2.|
|Payload and Modifications||n||Function|
|GM-CSF (CSF2)||49||GM-CSF is a growth factor that stimulates differentiation, proliferation and migration of myeloid cells.|
|Thymidine kinase (TK)||24||HSV-1 TK is a virulence factor deletion of which attenuates virus but is not essential for virus replication. In addition, TK is being used as a suicide gene to specifically target tumor cells.|
|Human sodium iodide symporter (hNIS)||14||NIS mediates a transport process of iodide uptake. Overexpression of NIS in cancer cells increases iodide concentration within the cells that benefit from radioiodine therapy.|
|p53 (TP53)||10||Tumor protein is a major tumor suppressor factor that acts through the regulation of the cell cycle. p53 often malfunctions in tumor cells.|
|Interferon β (IFN-beta)||8||IFN-beta is a cytokine, which has an antiviral and anti-proliferative effect. IFN-beta stimulates innate and adaptive immunity and has confirmed antitumor activity.|
|MAGE-A3||3||Tumor-specific antigen. MAGE-A3 immunization elicits an antigen-specific immune response.|
|PSA-TRICOM (B7.1, ICAM-1, LFA-3)||2||Prostate-specific antigen (PSA). B7.1, ICAM-1, LFA-3 are T-cell costimulatory molecules.|
|Carcinoembryonic antigen (CEA)||2||CEA is a glycoprotein, which rarely found in the blood of adults. Expression of CEA serves as a marker for noninvasive monitoring of virus dissemination in vivo.|
|Interleukine-12 (IL-12)||1||IL-12 plays a central role in T-cell and natural killer cell responses, induces the production of interferon-γ (IFN-γ).|
|Fas-c and PPE-1 promoter||1||Chimeric death receptor Fas and TNF receptor 1 and modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter delivered by virus vector may trigger apoptosis of endothelial cells and reduce tumor angiogenesis.|
|HPV E6/HPV E7||1||Human papillomavirus oncoproteins.|
|TERT promoter||1||Telomerase reverse transcriptase promoter (TERT) is used to attenuate virus replication.|
|Interferon-gamma (IFN-ɣ)||1||IFN-ɣ is a cytokine molecule with pronounced cytostatic, pro-apoptotic and immune-stimulating effects.|
|Tyrosinase-related protein (TYRP1)||1||TYRP1 is expressed in melanomas and on the surface of melanocytes and is an immunoreactive protein.|
|Anti-CTLA4||1||blocks CTLA-4 receptor and upregulate cytotoxic T –lymphocytes|
|None||109||Many wild-type viruses have an oncolytic potential and are frequently used without payload. Attenuated or evolutionary selected viruses also demonstrate a strong antitumor effect.|
The entry is from 10.3390/v13071271
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