D

Slower replicating and more cytotoxic virus

Faster replicating and 5 cytotoxic virus less c

Log tumor-specific CTL responsiveness, cT

Fig. 12.6 Dependence of overall tumor load on the strength of the tumor-specific CTL response. The higher the strength of the tumor-specific CTL, the lower tumor load. If the strength of the tumor-specific CTL crosses a threshold, tumor load becomes independent of CTL parameters. The faster the rate of virus replication and the smaller the degree of viral cytotoxicity, the further the overall tumor load can be reduced. Parameters were chosen as follows: k=10; r=0.5; s=0.5; d=0.1; b=0.1. The fast replicating and weakly cytotoxic virus is characterized by ¡3=1 and a = 0.2. The slower replicating and more cytotoxic virus is characterized by ¡3=0.5 and a = 0.5.

We investigate how the responsiveness of the tumor-specific CTL, cr, influences the size of the tumor, x + y. The presence of the tumor-specific CTL can have the following effects. If the virus achieves 100% prevalence in the tumor cell population, then x + y = (b/cx)1^2. Thus, an increase in the responsiveness of the tumor-specific CTL results in a decrease in tumor load (Figure 12.6). If cT > b(/3k + r - s)2/[k(r - s + a- d)}2, the virus is not 100% prevalent in the tumor cell population. This switch is thus promoted by a high responsiveness of the tumor-specific CTL relative to the replication rate of the virus (Figure 12.6). In this case, the size of the tumor is given by x + y = k(r — s + a — d)/(/3k + r — s). This is the minimum tumor size that can be achieved. Thus, if the CTL responsiveness against the tumor lies above a threshold, tumor load reaches its minimum (Figure 12.6). Note that it also becomes independent of the strength of the CTL. Hence, a CTL responsiveness that lies above this threshold is not detrimental to the patient. In this situation, tumor size is determined by the replication rate and the cytotoxicity of the virus (Figure 12.6). The higher the replication rate of the virus and the lower the degree of viral cytotoxicity, the smaller the tumor. The reason is that fast viral replication and low cytotoxicity result in higher virus load which in turn results in stronger signals to induce the tumor-specific CTL. Figure 12.7 shows a simulation of treatment underscoring this result.

Slower replicating and more cytotoxic virus

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