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Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator.

ABSTRACT: Although oncolytic viruses have shown great promise as cancer therapeutics, results from a recent phase III clinical trial indicate that their potency may need further improvement for a clear clinical benefit. Here, we report a novel strategy to increase the bystander effect of virotherapy by arming an oncolytic virus with a secreted form of a Her2 single chain antibody linked to a self-multimerizing Fas ligand extracellular domain (Her2-COL-sFasL). The rationale is that, due to its much smaller size, this apoptosis activator can overcome obstacles such as the dense collagen in the tumor tissues to spread more freely than the viral particles. When measured in vitro, Her2-COL-sFasL was found to efficiently induce caspase cleavage, resulting in an 80% reduction in cell viability. Once incorporated into the genome of an oncolytic type 2 herpes simplex virus, FusOn-H3, Her2-COL-sFasL potentiates the therapeutic efficacy of the virus in an aggressive syngeneic mammary tumor model. Our data suggest that arming an oncolytic virus with a secretable and self-multimerizing apoptosis inducer is a feasible strategy to improve the potency of virotherapy.

SUBMITTER: Loya SM

PROVIDER: S-EPMC4352111 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator.

Loya S M W SM Zhang X X

Gene therapy 20150108 3

Although oncolytic viruses have shown great promise as cancer therapeutics, results from a recent phase III clinical trial indicate that their potency may need further improvement for a clear clinical benefit. Here, we report a novel strategy to increase the bystander effect of virotherapy by arming an oncolytic virus with a secreted form of a Her2 single chain antibody linked to a self-multimerizing Fas ligand extracellular domain (Her2-COL-sFasL). The rationale is that, due to its much smaller ...[more]

PMID: 25567538

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Project description:BackgroundAntibody-drug conjugates (ADCs) are intended to bind to specific positive target antigens and eradicate only tumor cells from an intracellular released payload through the lysosomal protease. Payloads, such as MMAE, have the capacity to kill adjacent antigen-negative (Ag-) tumor cells, which is called the bystander-killing effect, as well as directly kill antigen-positive (Ag+) tumor cells. We propose that a dose-response curve should be independently considered to account for target antigen-positive/negative tumor cells.MethodsA model was developed to account for the payload in Ag+/Ag- cells and the associated parameters were applied. A tumor growth inhibition (TGI) effect was explored based on an ordinary differential equation (ODE) after substituting the payload concentration in Ag+/Ag- cells into an Emax model, which accounts for the dose-response curve. To observe the bystander-killing effects based on the amount of Ag+/Ag- cells, the Emax model is used independently. TGI models based on ODE are unsuitable for describing the initial delay through a tumor-drug interaction. This was solved using an age-structured model based on the stochastic process.Resultsβ∈(0,1] is a fraction parameter that determines the proportion of cells that consist of Ag+/Ag- cells. The payload concentration decreases when the ratio of efflux to influx increases. The bystander-killing effect differs with varying amounts of Ag+ cells. The larger β is, the less bystander-killing effect. The decrease of the bystander-killing effect becomes stronger as Ag+ cells become larger than the Ag- cells. Overall, the ratio of efflux to influx, the amount of released payload, and the proportion of Ag+ cells determine the efficacy of the ADC. The tumor inhibition delay through a payload-tumor interaction, which goes through several stages, may be solved using an age-structured model.ConclusionsThe bystander-killing effect, one of the most important topics of ADCs, has been explored in several studies without the use of modeling. We propose that the bystander-killing effect can be captured through a mathematical model when considering the Ag+ and Ag- cells. In addition, the TGI model based on the age-structure can capture the initial delay through a drug interaction as well as the bystander-killing effect.

Dataset Information

Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator.

Publications

Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator.

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