RESUMO
Among the many immunotherapies being developed and tested both preclinically and clinically, oncolytic viruses (OVs) are gaining traction as a forerunner in the search for potent new therapeutic agents, with a genetically engineered herpes simplex virus type 1 (HSV-1) recently approved by the FDA for the treatment of melanoma. The great potential of OVs to fight cancer is driving different approaches to improve OV-based therapy, with genetic modification of OVs to enhance host antitumor immunity being one of the most promising approaches. In this chapter we describe possible modifications in the OV genome that could increase its antitumor activity and immunostimulatory capacity, together with different methods to achieve these goals. Finally, we present different analyses to verify the desired genetic modification and evaluate its impact on host antitumor immunity in preliminary stages.
Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Engenharia Genética , Humanos , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Vírus Oncolíticos/genéticaRESUMO
Oncolytic viruses (OVs) preferentially target and kill cancer cells without affecting healthy cells through a multi-modal mechanism of action. While historically the direct killing activity of OVs was considered the primary mode of action, initiation or augmentation of a host antitumor immune response is now considered an essential aspect of oncolytic virotherapy. To improve oncolytic virotherapy, many studies focus on increasing virus replication and spread. In this article, we open for discussion the traditional dogma that correlates replication with the efficacy of OVs, pointing out several examples that oppose this principle.
RESUMO
The use of oncolytic viruses (OVs) for cancer treatment is emerging as a successful strategy that combines the direct, targeted killing of the cancer with the induction of a long-lasting anti-tumor immune response. Using multiple aggressive murine models of triple-negative breast cancer, we have recently demonstrated that the early administration of oncolytic Maraba virus (MRB) prior to surgical resection of the primary tumor is sufficient to minimize the metastatic burden, protect against tumor rechallenge, cure a fraction of the mice and sensitize refractory tumors to immune checkpoint blockade without the need for further treatment. Here, we apply our surgical model to other OVs: Vesicular stomatitis virus (VSV), Adenovirus (Ad), Reovirus (Reo) and Herpes simplex virus (HSV) and show that all of the tested OVs could positively change the outcome of the treated animals. The growth of the primary and secondary tumors was differently affected by the various OVs and most of the viruses conferred survival benefits in this neoadjuvant setting despite the absence of direct treatment following rechallenge. This study establishes that OV-therapy confers long-term protection when administered in the pre-operative window of opportunity.
Assuntos
Neoplasias Mamárias Experimentais/prevenção & controle , Terapia Neoadjuvante/métodos , Terapia Viral Oncolítica/métodos , Adenoviridae , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Vírus Oncolíticos , Período Pré-Operatório , Reoviridae , Simplexvirus , Células Vero , VesiculovirusRESUMO
Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.
