Questing for an optimal, universal viral agent for oncolytic virotherapy

Abstract

One of the most promising strategies to treat cancer is attacking it with viruses designed to exploit specific altered pathways. Here, the effects of oncolytic virotherapy on tumors having compact, papillary and disconnected morphologies are investigated through computer simulations of a multiscale model coupling macroscopic reaction diffusion equations for the nutrients with microscopic stochastic rules for the actions of individual cells and viruses. The interaction among viruses and tumor cells involves cell infection, intracellular virus replication and release of new viruses in the tissue after cell lysis. The evolution in time of both viral load and cancer cell population, as well as the probabilities for tumor eradication were evaluated for a range of multiplicities of infection, viral entries and burst sizes. It was found that in immunosuppressed hosts, the antitumor efficacy of a virus is primarily determined by its entry efficiency, its replicative capacity within the tumor, and its ability to spread over the tissue. However, the optimal traits for oncolytic viruses depends critically on the tumor growth dynamics and do not necessarily include rapid replication, cytolysis and spreading currently assumed as necessary conditions to a successful therapeutic outcome. Our findings have potential implications on the design of new vectors for the viral therapy of cancer.

Mathematical Model for Radial Expansion and Conflation of Intratumoral Infectious Centers Predicts Curative Oncolytic Virotherapy Parameters

“…Our model agrees with previous models that show the efficacy of virotherapy to be determined by entry efficiency and resulting location of infection, replicative capacity, and ability to spread, all of which determine the extent of damage incurred during the oncolytic phase [9], [12], [13], [14], [15], [17], [18], [19], [20]. Previous models predict that the location of infectious centers occurring from intratumoral injections and subsequent virus spread or extravasation within the tumor effect tumor destruction [12], [15], [19], [20].…”

“…Previous mathematical models, although informative, are theoretically derived and then fit to experimentally observed parameters [3], [4], [5], [6], [7], [8], [9], [10], [13], [15], [16], [17], [18], [20]. Conversely, this model was developed from in vivo experimental observations.…”

“…This approach allowed for the differentiation of therapeutic phases due to data that revealed the rapid speed of viral spread relative to the rate of tumor growth or adaptive immune response results in the formation of finite foci of infection at the end of the oncolytic phase of therapy. This justifies the exclusion of complex population dynamics considered by theoretical approaches, as they occur in the later immunotherapeutic phase [3], [5], [10], [11], [12], [13], [15], [16], [17], [18], [19], [20]. The current model is thereby simplified to predict therapeutic parameters to achieve cure prior to the involvement of complex population dynamics.…”

“…Mathematical models which capture the resulting complexity of virus-tumor interactions have been developed to improve intuitive understanding of oncolytic therapy, predict tumor response and long-term recurrence, and guide the development of more effective oncolytic virotherapy approaches [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Many existing models are theoretical rather than inductive, and treat infected tumors as dynamic systems with considerations for the kinetic interplay between concurrent processes of exponential virus spread, tumor growth, and the antiviral immune response [3], [4], [5], [6], [7], [8], [9], [10], [13], [15], [16], [17], [18], [20]. While some models do account for spatial constraints on virus spread, they remain complex, time dependent stochastic models [7], [12], [15], [17].…”

Multiscale model for the effects of adaptive immunity suppression on the viral therapy of cancer

“…We simulated the model considering a viral agent able to eradicate compact solid tumors in the absence of an adaptive immune response, as reported in reference [16]. When applied to immune-competent hosts characterized by typical immunological parameters (see the Supplementary Information), a virotherapy based on such oncolytic virus invariably fails.…”