U

50 100 150 200 250 300 350

Time (arbitrary units)

Fig. 11.8 Effect of dendritic cell vaccination on tumor dynamics assuming that the growth rate has not yet progressed beyond a threshold, so that we are in the bistable parameter region of the model. A single vaccination event can induce immunity which can control the tumor at low levels. Parameters were chosen as follows: r=0.3; k=10; d=0.1; 7 =1; A=1; ¿1 =0.01; a=0.5; &2=l-5; rj =0.5; e=l; q=0.5; fj, =0.1.

order to achieve success. If the tumor size is very large, then an elevated level of dendritic cells cannot shift the ratio of cross-presentation to direct presentation sufficiently to induce sustained immunity. A combination of vaccination and chemotherapy can, however, result in success. This is because chemotherapy reduces the size of the tumor and also induces death of tumor cells. Both factors contribute to a higher ratio of cross-presentation to direct presentation and to induction of immunity. Once a sustained CTL response has been induced, tumor cells are kept at low levels. However, the cancer is unlikely to be eradicated. Consequently, it can evolve over time. Thus, induction of CTL mediated control in the model is likely to result in a temporary phase of tumor dormancy. This phase is again broken after the overall growth rate of the tumor has evolved beyond the threshold at which the CTL control outcome becomes unstable.

These considerations result in the following suggestions. Dendritic cell vaccination should be administered repeatedly until the last tumor cell has been eradicated. If the tumor has already progressed relatively far, this is the only way to prevent immediate relapse of the cancer. If the tumor is less progressed, temporary tumor dormancy can be achieved by a single vaccination event. Tumor persistence and evolution will, however, break this dormancy phase, resulting in renewed cancer growth after a certain period of time. Thus, in this case, repeated vaccination is also advisable in order to keep the level of cross-presentation above a threshold and to avoid tumor persistence. In all cases, the model suggests that a combination of immunotherapy with conventional therapy is beneficial because conventional therapy can reduce the growth rate of the tumor. If conventional therapy increases the chances of developing immunological control of the tumor, conventional therapy would have to be applied only temporarily which would have significant clinical benefits.

Chapter 12

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