Fig 1.
Interaction of immune cells and oncolytic virus with tumor cells.
Susceptible (Uninfected) normal and tumor cells become infected by an oncolytic virus (vesicular stomatitis virus (VSV)). After successful viral propagation within the infected cells, infected cells undergo lysis (cell rupture) producing a progeny of new infectious viruses which spread and infect other susceptible cells. Debris from infected cells activates the virus-specific immune cells which then induces killing of infected cells and clearance of free virus. The tumor-specfic immune cells recognise (due to expression of tumor-associated antigens (TAAs)) and kill both uninfected and infected tumor cells.
Table 1.
Model variables.
Table 2.
Parameter values used in the model simulations.
Fig 2.
Model fit to uninfected tumor growth data.
Model fitting to experimental tumor growth data using Eq 2, the uninfected (susceptible) tumor cell population, TS, and other model variables set to zero. The susceptible tumor cell population is fitted to the data with two-sided 95% confidence intervals (dashed lines) computed from exponential distribution statistics. A black dashed line is just a straight line between data points. Parameter values are rT = 0.00258, KT = 3.12 × 108, βT = γT = 0.
Fig 3.
Snapshots of the sensitivity analysis of the model.
Sensitivity indices of the model parameters with oncolytic virus taken as a baseline PRCC analysis variable. Analysis was computed based on the baseline parameter values presented in Table 2, with a viral dose of V = 109 plaque-forming units (pfu). The sensitivity analysis shows statistically significant PRCC values (p-value < 0.01) at: (a) 24 hours and (b) 96 hours, respectively.
Fig 4.
Multi-viral dosing scheme under scenario 1.
Plots of the susceptible normal and tumor cell populations when a virus is administered at three successive times, with a viral dose of V = 109 pfu when . Fig 4(a) shows how the oncolytic virus reduces the susceptible normal cell population during multiple-viral dose scheme. Fig 4(b) shows how successive viral doses can lead to tumor eradication or at least keep the tumor in transient dormancy, which is followed by tumor relapse.
Fig 5.
Single-viral dosing scheme under scenario 2.
Plots of individual susceptible normal and tumor cell populations when the single dose of V = 109 pfu is administered at three different time points when . Fig 5(a) shows a reduction and rapid self-renewing of the susceptible normal cell population during an oncolytic virotherapy. Fig 5(b) shows the reduction of uninfected tumor cell population under the single-viral dose scheme.
Fig 6.
Scenario 1: Comparison of cell depletion under multi-viral dosing scheme.
Fig 6(a) indicates reduction of normal cell population when . Fig 6(b) shows reduction of tumor cells when
. The corresponding cell depletion profile is provided in Table 4.
Fig 7.
Scenario 2: Comparison of cell depletion under single-viral dosing scheme.
Relative comparison of cell depletion when the oncolytic virus is administered at three distinct time points. Fig 7(a) indicates reduction of normal cell population when . Fig 7(b) shows reduction of tumor cells when
.
Table 3.
Minimum cell reduction achievable when R0N = (1 − R0T)/2.
Fig 8.
Simulation of cell depletion when under scenario 1.
Fig 8(a) indicates a decline in normal cell population. Fig 8(b) shows the tumor shrinks down to zero over time.
Table 4.
Minimum cell reduction achievable when R0N = 3(1 − R0T)/4.