Advance in herpes simplex viruses for cancer therapy
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Virotherapy
Virotherapy
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Virotherapy
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Treating tumors with viruses, that is, oncolytic viruses, was originally suggested by the clinicians who witnessed tumor regression after spontaneous viral infections. An increased understanding of virology, as well as experience using viruses in cancer gene therapy, has prompted a new wave of oncolytic virotherapy. The use of virotherapy against neuroblastoma (NB) is an emerging field. The use of oncolytic adenoviruses in the clinic has been recently reported in sporadic cases of children with metastatic NB. Oncolytic adenovirus (ICOVIR-5) is used for treating four children with refractory metastatic NB, using mesenchymal stem cells (MSCs) as the carrier for our oncolytic adenovirus. In the cases of oncolytic viruses, carrier cells can also protect the virus from inactivation by immune defense mechanisms. Cells can also serve as production factories to produce and correctly process these agents in their most physiological form.
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Destruction of the tumor (cancerous) cells may be caused by live viruses, which have replicative ability and replicate selectively in tumor cells, known as oncolytic virotherapy. In comparison of conservative cancer therapy, tumor-selective replicating viruses have more advantages. These viruses have introduced new methodologies for the human cancer treatment. Numerous strategies are used in development of virotherapeutics. Virotherapy is not unusual concept, but modern advances in technology of genetic modification of oncolytic viruses have improved the ability of targeting tumor cells more specifically, it triggered the development of novel ammunition to fight cancer. An effective virotherapeutic approach with oncolytic viruses exhibits the feasibility and safety under clinical approach. New strategies are being explored to overcome basic obstacles and challenges in virotherapy. Administration of oncolytic viruses, logically, will successfully augment new treatments against many kinds of tumors. Some encouraging antitumor responses shown by combination therapy are provoking strong immunity against established cancer. Chief developments in oncolytic virotherapy have seen in past several years. Significant understandings have been provided by findings on the interface among immune comebacks and viruses, whereas potential results have shown in clinical trials.
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Initial observations from as early as the mid-1800s suggested that patients suffering from hematological malignancies would transiently go into remission upon naturally contracting viral infections laid the foundation for the oncolytic virotherapy research field. Since then, research focusing on anticancer oncolytic virotherapy has rapidly evolved. Today, oncolytic viral vectors have been engineered to stimulate and manipulate the host immune system, selectively targeting tumor tissues while sparing non-neoplastic cells. Glioblastoma multiforme, the most common adult primary brain tumor, has a disasterous history. It is one of the most deadly cancers known to humankind. Over the last century our understanding of this disease has grown exponentially. However, the median survival of patients suffering from this disease has only been extended by a few months. Even with the best, most aggressive modern therapeutic approaches available, malignant gliomas are still virtually 100% fatal. Motivated by the desperate need to find effective treatment strategies, more investments have been applied to oncolytic virotherapy preclinical and clinical studies. In this review we will discuss the antiglioma oncolytic virotherapy research field. We will survey its history and the principles laid down to serve as basis for preclinical works. We will also debate the variety of viral vectors used, their clinical applications, the lessons learned from clinical trials and possible future directions.
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Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.
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One of the most promising strategies to treat cancer is attacking it with viruses. Oncolytic viruses can kill tumor cells specifically or induce anticancer immune response. A multiscale model for virotherapy of cancer is investigated through simulations. It was found that, for intratumoral virus administration, a solid tumor can be completely eradicated or keep growing after a transient remission. Furthermore, the model reveals undamped oscillatory dynamics of tumor cells and virus populations, which demands new in vivo and in vitro quantitative experiments aiming to detect this oscillatory response. The conditions for which each one of the different tumor responses dominates, as well as the occurrence probabilities for the other nondominant therapeutic outcomes, were determined. From a clinical point of view, our findings indicate that a successful, single agent virotherapy requires a strong inhibition of the host immune response and the use of potent virus species with a high intratumoral mobility. Moreover, due to the discrete and stochastic nature of cells and their responses, an optimal range for viral cytotoxicity is predicted because the virotherapy fails if the oncolytic virus demands either a too short or a very large time to kill the tumor cell. This result suggests that the search for viruses able to destroy tumor cells very fast does not necessarily lead to a more effective control of tumor growth.
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Oncolytic viruses, which may be naturally occurring or genetically engineered, are a type of virus that infects and destroy cancer cells preferentially. Owing to their selectivity, they outperform conventional chemotherapy and radiotherapy, which both have a tendency to impact non-target cells and cause unwanted adverse side effects. Oncolytic virotherapy is a type of cancer treatment in which oncolytic viruses are deliberately introduced into patients affected with cancers in order for them to infect and destroy cancer cells locally or systemically, in a manner analogous to chemotherapy but with a greater degree of selectivity. Multiple studies indicate that oncolytic virotherapy is effective in vitro but in vivo findings remain ambiguous due to the approach's primary limitation: inefficient therapeutic agent delivery to its target, which is heavily influenced by the immune system. Here, we propose overcoming this limitation by exploiting a recent discovery in cancer research: a carrier cell. By exploiting their tumor-promoting activities, mesenchymal stem cells may be employed for cancer therapy by serving as a carrier for the oncolytic viruses toward their target. This approach directly addresses the limitation of conventional oncolytic virotherapy, where oncolytic viruses are often poorly delivered after systemic administration.
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