Oncolytic viruses, an effective tool for cancer therapy
Oncolytic viruses (OVs) replicate and lyse tumor cells in tumor cells through different regulatory mechanisms without affecting normal cell growth [1]. Compared with traditional immunotherapy, oncolytic virus therapy has the advantages of good targeting, less adverse reactions, more ways to kill tumors, and less drug resistance. A number of clinical studies have shown that oncolytic viruses can bring clinical benefits to patients with different types and stages of progression, even metastatic and incurable tumors[2]. More importantly, when it is used in combination with chemotherapy, radiotherapy, immunotherapy, etc., it has a synergistic effect, which can make tumors that have not responded well to immunotherapy drugs such as immune checkpoint inhibitors become sensitive[3].
Today, the oncolytic viruses used for clinical treatment can be roughly divided into the following two categories: one is a naturally occurring virus without gene editing, mainly including reovirus, newcastle disease virus , NDV), natural coxsackie virus A21 (eoxsaekie virus A21, CVA21), etc. The other is genetically modified viruses, mainly including adenovirus, vaccinia virus, herpes simplex virus, vesicular stomatitis virus, etc. [4]. Most OVs are genetically modified to increase the tropism of the virus to tumor cells, improve the selective replication and lytic potential of the virus, and enhance the host's anti-tumor immunity.
Figure 1: Types of Oncolytic Viruses
The anti-viral mechanisms of oncolytic viruses
According to the definition of oncolytic virus, oncolytic virus selectively replicates in tumor tissue and has no killing effect on normal cells. However, there are many types of oncolytic viruses, and their tumor-specific killing mechanisms are different. Oncolytic viruses selectively infect tumor cells and self-replicate in tumor cells to destroy tumor cells by releasing pathogen-associated molecular pattern molecules (PAMP), tumor-associated antigen (tumor-associated antigen, TAA), inflammation sex factor, substances such as molecules and chemokines activate the body's immune system, directly or indirectly kill tumor cells, and transform cold tumors into hot tumors, as shown in Figure 2.
Figure 2: Oncolytic virus mechanism of action
The anti-tumor mechanism of oncolytic virus is mainly manifested in the following aspects:
(1) Lying tumor cells directly: The virus replicates in large numbers in tumor cells and lyses the cells. When the tumor cells rupture and die under the infection of the virus, the released virus particles further infect the surrounding tumor cells.
(2) In situ vaccines and distant effects: the lysis of tumor cells leads to the release of a large amount of tumor-associated antigen (TAA), and then recruits more immune cells such as dendritic cells (DC) to infiltrate the tumor , activate the anti-tumor immune response and play the role of "in situ vaccine". Oncolytic viruses can also use "in situ vaccines" to promote the regression of distant uninfected metastases through cross-presentation, resulting in a "distal effect".
(3) Induction of innate immunity: there are receptors (such as Toll-like receptors) in the cells or on the surface, which can recognize the nucleic acid or protein of the virus, induce the expression of cytokines, and the expressed cytokines bind to receptors on other cells, resulting in Expression of antiviral genes and recruitment of immune cells.
(4) Stimulate adaptive immune response: After the virus lyses tumor cells, the released tumor-specific antigens are presented by DCs, and DCs recruit and activate CD8+ and CD4+ T cells, thereby inducing antigen-specific T cell killing.
(5) Destruction of tumor vasculature: Tumor growth depends on tumor vascular system to provide nutrients. Therefore, if tumor vascular system can be destroyed, tumor growth can be effectively inhibited. Compared with other therapeutic methods, oncolytic virus has the characteristic of destroying tumor blood vessels, which makes it have obvious advantages in tumor treatment. Studies have shown that intravenous administration of Vesicular Stomatitis Virus (VSV) can directly infect and destroy tumor blood vessels in vivo without affecting normal blood vessels.
(6) Improving the suppressive microenvironment: Under the pressure of the immune system, the tumor gradually forms a highly complex tumor microenvironment, which contains a large number of immunosuppressive cells such as immune regulatory T cells (Treg) and myeloid-derived suppressor cells ( MDSC), immunosuppressive cytokines such as IL-10, and immunosuppressive molecules such as PD-L1, etc. These factors can maintain a tumor suppressive microenvironment to promote tumor growth and help tumor escape. Oncolytic viruses can not only break the existing anatomical structure of the tumor microenvironment, but also break the tumor suppressive tumor microenvironment, creating favorable microenvironmental conditions for other immunotherapies. Oncolytic viruses expressing specific cytokines can not only achieve the purpose of lysing tumor cells, but also improve anti-tumor immunity, which has dual curative effects.
Current status of anticancer therapy
In anti-tumor therapy, there are currently three oncolytic virus drugs approved for clinical use:
(1) Recombinant human adenovirus type 5 (Ankerui, H101) is a genetically modified oncolytic adenovirus developed by Sanwei Bio, which was approved by the China Food and Drug Administration (CFDA) in 2005 for joint use Chemotherapy for the treatment of nasopharyngeal carcinoma is the earliest oncolytic virus in the world.
(2) T-VEC (talimogene laherparepvec), a genetically modified product based on HSV-1 (herpes simplex type 1) virus, approved by the U.S. Food and Drug Administration (U.S. Food and Drug Administration) for listing on the market in the United States ( It was subsequently approved for marketing by the European Union), which is the first oncolytic virus approved for clinical application in the treatment of melanoma solid tumors.
(3) In 2021, the oncolytic virus therapy Delytact (teserpaturev/G47∆) developed by Daiichi Sankyo has received a conditional time-limited approval from the Japanese Ministry of Health, Labor and Welfare (MHLW) for the treatment of malignant glioma. This is the world's first oncolytic virus therapy approved for the treatment of primary brain tumors.
Among all clinical trials in 2017, 78 were intervention trials of oncolytic viruses in various malignant solid tumors, which indicated that oncolytic viruses have good prospects for anti-tumor research.
Oncolytic virus is a multifunctional anticancer drug that selectively infects, replicates, and kills tumor cells. This process depends on surface receptors, the tumor cell's permission for virus replication. Oncolytic viruses have shown variable therapeutic efficacy in multiple clinical trials, but rarely induce complete tumor regression in vivo over the long term. Moreover, the selective pressure of heterogeneous tumors results in resistance to oncolytic viruses. In order to overcome these shortcomings, many novel oncolytic virus combination therapies have been established clinically to enhance the lethality of tumors.
Oncolytic virus combined with chemotherapy or targeted therapy
Chemotherapy directly kills malignant cells, enhances the immunogenicity of tumor cells, and enhances the cytotoxicity of oncolytic viruses; oncolytic viruses combined with chemotherapy have a synergistic effect and promote anti-tumor immune responses [5]. Mechanisms of combination chemotherapy with oncolytic viruses include:
(1) Evade anti-viral immune response, enhance viral oncolysis, and improve anti-tumor efficacy of HSV, AD, measles virus and reovirus;
(2) Resistance to immunosuppressive tumor microenvironment. The main components of TME are regulatory T cells (regulatory cells, Treg) and myeloid-derived suppressor cells (MDSC), both of which effectively reduce tumor immunity. Studies have shown that the accumulation of MDSCs in the TME inhibits anti-tumor effector T cells and promotes tumor growth; many chemical drugs such as gemcitabine, sunitinib, and 5-Fu clear MDSCs and improve survival [6, 7].
(3) Regulating the immunogenicity of tumor cells. Doxorubicin and Ara-C reduce the expression of immune checkpoint molecules, blocking their suppression of infiltrating T cells. Chemotherapeutic drugs affect multiple biological processes, such as rapamycin and its analogs alter mTOR signaling, increase oncolytic virus targeting, and induce autophagy.
Targeted therapy works on the same principle as combination chemotherapy, and it also inhibits abnormal signaling pathways in cancer cells[8].
Oncolytic virus combined with radiotherapy
Oncolytic viruses and radiotherapy are two distinct areas of cancer therapy with non-overlapping cytotoxicity profiles. Radiation enhances the oncolytic effect of the virus, and the virus increases the radiosensitivity of cells, and the two have a synergistic effect [5, 9]. Oncolytic virus is a potential tumor treatment strategy. It was initially thought that the cytotoxicity of oncolytic viruses was to increase virus replication, enhance tumor cell infection and oncolysis, but many research data on oncolytic viruses do not support this hypothesis; most of them believed that oncolytic viruses prevent DNA repair and make tumor cells Radiation-sensitizing, induces apoptosis.
Oncolytic virus combined with immunotherapy
Although oncolytic viruses can quickly reduce the size of local tumors, they are not easy to generate a sustained anti-tumor immune response. The immune response is a key component of OV therapy, with strong initial induction followed by suppression of effector cell antitumor activity by various immunomodulators such as CTLA-4 and PD-L1. In a mouse model of malignant melanoma, oncolytic measles virus delivered anti-CTLA-4 and anti-PD-L1 antibodies to the TME, induced a strong specific anti-tumor immune response, and no immune-related toxicity was found[10] . In another mouse model of melanoma, intratumoral injection of NDV combined with anti-CTLA-4 antibody resulted in tumor regression and prolonged survival [12]. PDL1 is produced by overexpression of tumor cells and infiltrating tumor cells, binds to PD-1 on T cells, induces T cell apoptosis [10, 11], and allows tumor cells to escape; while blocking PD-1 improves T cell function. OV infection enhances the expression of immunomodulators, enhances the sensitivity of tumor cells to PD-1 or PD-L1 blockade, and induces anti-tumor immune responses. Therefore, combined immunization with oncolytic virus has therapeutic value.
Combination therapy of oncolytic virus and nanomaterials
In recent years, with the rapid development of the field of nanotechnology, the application of bionanomaterials in tumor therapy has received extensive attention [12]. They have good drug loading capacity. Integrating biological imaging, activating tumor immunity and other functions, it can specifically target tumor cells after certain modifications. Both in tumor diagnosis and treatment have shown high potential application prospects. Therefore, biomaterials can be used to load oncolytic viruses to achieve the purpose of blocking viral immunogenicity and achieving tumor-targeted delivery. Currently, liposomes, cells or exosomes are mainly used to carry oncolytic viruses [13, 14], as well as some non-biological material carriers, such as polymers [15].
In the field of drug efficacy and pharmacological evaluation related to nervous system diseases, we can provide you with a one-stop platform for evaluating the behavior of animals from the gene molecular level to the cell tissue level, to the neural circuit, and finally to the animal as a whole.
If you are interested in the application of oncolytic viruses and would like to customize personalized oncolytic and evaluation plans, feel free to contact us at BD@ebraincase.com
literature citation [1] GUJAR S, BELL J, DIALLO J S. SnapShot: cancer immunotherapy with oncolytic uses [J] . Cell, 2019, 176(5):1240-1240. el.
[2] ANDTBACKA R H, KAUFMAN H L, COLLICHIO F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma［J］. J Clin Oncol, 2015,33(25): 2780-2788.
[3] HARRINGTON K J, KONG A, MACH N, et al. Talimogene laherparepvec and pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (MASTERKEY-232): a multicenter, phase 1b study [J] . Clin Cancer Res, 2020, 26(19): 5153-5161.
[4] CAO G D, HE X B, SUN Q, et al. The oncolytic virus in cancer diagnosis and treatment [J] . Front Oncol, 2020, 10: 1786.
[5] Choi AH, O'leary MP, Fong Y, et al. From Benchtop to Bedside: A Review of Oncolytic Virotherapy[J]. Biomedicines, 2016, 4(3):18.
[6] Ko JS, Rayman P, Ireland J, et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained[J]. Cancer Res, 2010, 70(9):3526-3536.
[7] Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity[J]. Cancer Res, 2010,70(8):3052-3061.
[8] Roulstone V, Pedersen M, Kyula J, et al. BRAF- and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress[J]. Mol Ther, 2015, 23(5):931-942.
[9] Kyula JN, Khan AA, Mansfield D, et al. Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in (V600D/E)BRAF mutant melanoma depends on JNK and TNF-alpha signaling[J]. Oncogene,2014, 33(13):1700-1712.
[10] Engeland CE, Grossardt C, Veinalde R, et al. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy[J]. Mol Ther, 2014, 22(11):1949-1959.
[11] Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy[J]. Sci Transl Med, 2014,6(226):226ra32.
[12] 115. Kyle MP, William RM, Kyle PC, et al. The evolution and future of targeted cancer therapy: from nanoparticles, oncolytic viruses, and oncolytic bacteria to the treatment of solid tumors. Nanomaterials (Basel) 2021;11(11):3018. doi: 10.3390/nano11113018.
[13] 116. Tong M, Xiyu L, Yiqun L, et al. Aptamer-based biosensors and application in tumor theranostics. Cancer Sci. 2022;113(1):7–16. doi: 10.1111/cas.15194.
[14] 117. Briolay T, Petithomme T, Fouet M, et al. Delivery of cancer therapies by synthetic and bio-inspired nanovectors. Mol Cancer. 2021;20(1):1–24. doi: 10.1186/s12943-021-01346-2.
[15] 118. Robles-Planells C, Sánchez-Guerrero G, Barrera-Avalos C, et al. Chitosan-based nanoparticles for intracellular delivery of ISAV fusion protein cDNA into melanoma cells: a path to develop oncolytic anticancer therapies. Mediators Inflamm. 2020;2020.
