12/16/2023 0 Comments Hammer and anvil vrAlthough the tumor exploits various evasion and survival mechanisms, it is ultimately powerless when it is attacked from two angles, namely the direct blow from the oncolytic effect and the subsequent immune attack from behind. The concept of using a powerful oncolytic virus, such as VSV, in combination with an immunotherapeutic strategy elicits an attack against cancer in much the same way as the hammer and anvil military tactic. Generally, in order for this strategy to be successful, the force attempting the maneuver must outnumber its opponent. This tactic involves two enemy infantry units fighting in a frontal assault, while a cavalry unit maneuvers around the enemy and attacks from behind, hammering it against the infantry line, which functions as the anvil. The hammer and anvil tactic is a military strategy that has been used since the beginning of organized warfare. Elevated doses have been shown to result in off-target toxicities, however, and to date, only a pseudotyped VSV vaccine vector and an attenuated oncolytic VSV expressing human interferon β have succeeded in clinical translation, due to safety concerns of administering wild-type virus. Despite the ability of VSV to infect a wide range of host cells, replication is limited to cells that are defective in their antiviral interferon signaling pathways, allowing for an inherent mechanism for tumor specificity. The entire VSV lifecycle occurs in the cytoplasm. The low endosomal pH then triggers a conformational change in the G protein, activating fusion to the endosomal membrane and causing the release of the viral genome into the cytosol and the initiation of the replication process. The VSV glycoprotein (G protein) mediates viral attachment and fusion to host cells via the ubiquitously expressed low density lipoprotein (LDL) receptor, followed by receptor-mediated endocytosis and internalization into endosomes. VSV is a negative-strand RNA virus from the Rhabdoviridae family with a relatively compact genome comprised of approximately 11,000 nucleotides encoding for five viral proteins. Vesicular stomatitis virus (VSV) represents a particularly attractive vector platform for viral-based immunotherapies due to its inherent tumor specificity, its rapid replication and cell-killing kinetics, its natural ability to stimulate immune responses, and the fact that there is an established genetic system available for generating recombinant vectors. They therefore have been exploited in rationally designed combination therapies involving oncolytic viruses as immunotherapeutics. They are probably best known for their inherent ability to cause tumor debulking via direct tumor cell lysis however, they additionally offer the potential to break immune tolerance and stimulate potent immune responses directed against uninfected tumor cells and distant metastases. Oncolytic viruses offer a novel treatment option, due to their eloquent multimodal mechanism of action. Although immunotherapies have the potential to offer safe, systemic, and long-lasting tumor responses, the tolerogenic microenvironment of most tumors is a challenge that must be addressed in order to fully exploit the therapeutic potential of this approach. In recent years, great progress has been made in the development of immune-based cancer therapies in which the body’s own immune system is harnessed to fight against the invading cancer. A summary of these approaches will be presented in this review. combination with adoptive immune cell therapy for potentially synergistic therapeutic responses. vaccination approaches to stimulate adaptive immune responses against a tumor antigen 4. virus-mediated expression of cytokines or immune-stimulatory molecules to enhance anti-tumor immune responses 3. modification of endogenous virus genes to stimulate interferon induction 2. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. Vesicular stomatitis virus (VSV), a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |