O

t Foster replicating anijl less cytotoxic virus

Time scale (arbitrary units)

Start of virus therapy

Fig. 12.7 Simulation of therapy using an oncolytic virus in order to stimulate a tumor-specific CTL response. If the virus replicates at a fast rate and is weakly cytotoxic, the level of immuno-stimulatory signals is high. Hence the tumor-specific response is strong and drives the tumor extinct. Parameters were chosen as follows: k=10; r=0.5; s=0.5; d=0.1; b=0.1; cj- = 0.2. The fast replicating and weakly cytotoxic virus is characterized by (3=0.5 and a = 0.2. The slower replicating and more cytotoxic virus is characterized by (3=0.1 and a = 0.6.

A note of caution: the model assumes that the production of immuno-stimulatory signals induced by the virus is proportional to the amount of viral replication. If cellular debris following virus-mediated destruction of cells also contributes to these signals, then the effect of viral cytotoxicity could be more complex. However, the exact nature and concept of the so-called danger signals is still controversial. The model takes into account the simple observation that presence of signals typical of viral replication can enhance immunity to tumors.

12.4 Interactions between virus- and tumor-specific CTL

In this section, the two types of CTL responses studied above are brought together. That is, both the virus- and the tumor specific CTL responses are taken into consideration. The model is explained schematically in Figure 12.1 and given by the following set of differential equations [Wodarz (2001)]:

Zv ZT

In this model the virus- and the tumor specific CTL responses are in competition with each other, because both can reduce tumor load and hence the strength of the stimulus required to induce CTL proliferation. In the following these competition dynamics are examined.

If the virus has reached 100% prevalence in the tumor cell population in the absence of CTL, then virus- and tumor specific CTL cannot coexist. If cv > (cTb)1/2, then the virus-specific CTL response is established. On the other hand, if cv < (crb)1/2, then the tumor-specific CTL response becomes established.

If both infected and uninfected tumor cells are present in the absence of CTL, the situation is more complicated. Now, three outcomes are possible. Either the virus-specific response becomes established, or the tumor-specific response becomes established, or both responses can coexist. The virus-specific response persists if cv > kcx (r — s + a — d) / (¡3k + r — s). The tumor-specific response persists if ct > c2r/{k[cv{r — d) — b/3}}. Coexistence of

both CTL responses is only observed if both of these conditions are fulfilled. This outcome is described by the following equilibrium expressions:

0 0

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