Dynamics of multiple myeloma tumor therapy with a recombinant measles virus - PubMed (original) (raw)
Dynamics of multiple myeloma tumor therapy with a recombinant measles virus
D Dingli et al. Cancer Gene Ther. 2009 Dec.
Abstract
Replication-competent viruses are being tested as tumor therapy agents. The fundamental premise of this therapy is the selective infection of the tumor cell population with the amplification of the virus. Spread of the virus in the tumor ultimately should lead to eradication of the cancer. Tumor virotherapy is unlike any other form of cancer therapy as the outcome depends on the dynamics that emerge from the interaction between the virus and tumor cell populations both of which change in time. We explore these interactions using a model that captures the salient biological features of this system in combination with in vivo data. Our results show that various therapeutic outcomes are possible ranging from tumor eradication to oscillatory behavior. Data from in vivo studies support these conclusions and validate our modeling approach. Such realistic models can be used to understand experimental observations, explore alternative therapeutic scenarios and develop techniques to optimize therapy.
Conflict of interest statement
Conflict of interest
The authors declare no conflict of interest.
Figures
Figure 1
In vivo growth of myeloma tumor xenografts. In this figure, the growth of four representative untreated tumors is depicted. Tumor growth data were fitted to the Gompertz (top panel: a, b) and general logistic model (bottom panel: c,d). Both models fit the experimental data well and the fitting enables parameter estimation. The best fit was determined using the modified Akaike selection criterion.
Figure 2
Myeloma tumor therapy with MV-NIS. Two representative examples of therapy with MV-NIS are shown. In (a), is an example of a tumor that initially responds and then regrows while in (b), the tumor is eradication after a single injection of MV-NIS. The total tumor volume was measured and the model fitted to the data. MV-NIS always slows down tumor growth. Within each of these figures, the triangles represents the fit for the untreated tumor. The remainder of the lines correspond to the solutions of the system of equations (3)–(7) fitted to the virally treated mice (circles) with the measured tumor load y(t) + x(t) + s(t), and estimated values for uninfected cells (y(t)), infected cells (x(t)) and syncytium volume (s(t)), as in the legend.
Figure 3
In vivo population oscillations. The model predicts the occurrence of oscillations in the tumor and virus population. The figure presents two treated tumors that exhibit oscillations in size as a function of time. In (a), the oscillations are not damped and will persist, whereas in (b), the oscillations are damped and the populations will reach a steady state. Note that in (a), the peak of infected cells always follows that of the uninfected population.
Figure 4
Curative therapy with MV-NIS. Tumor virotherapy can lead to eradication of the xenograft. Tumor control can be relatively fast (a) or slow (b), but in all cases of tumor eradication observed, the tumor population exhibited a monotonic decrease in size without oscillations.
Figure 5
Tumor eradication is a time-dependent variable. Prolonged observation of the animals is essential to have reliable outcomes. In (a), therapy was considered a failure but longer observation would have shown tumor control (b). In contrast (c), a tumor that was considered eliminated would have recurred (d).
Figure 6
Population oscillations and tumor eradication. Extended simulations show that as a result of virotherapy, the tumor may experience various types of oscillations. In (a), the tumor initially grows but then is rapidly controlled and monotonically decreases to very low levels. In (b), the tumor is reduced to low levels only to grow rapidly to a large size. The virus catches up with it and eliminates it. (c) Sometimes the virus cannot lower the tumor burden low enough and the population exhibits oscillations with increasing amplitude. (d) The impact of initial dose of virus on tumor eradication dynamics.
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