• Spatio-Temporal Dynamics of Hypoxia during Radiotherapy.

      Kempf, Harald; Bleicher, Marcus; Meyer-Hermann, Michael; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2015)
      Tumour hypoxia plays a pivotal role in cancer therapy for most therapeutic approaches from radiotherapy to immunotherapy. The detailed and accurate knowledge of the oxygen distribution in a tumour is necessary in order to determine the right treatment strategy. Still, due to the limited spatial and temporal resolution of imaging methods as well as lacking fundamental understanding of internal oxygenation dynamics in tumours, the precise oxygen distribution map is rarely available for treatment planing. We employ an agent-based in silico tumour spheroid model in order to study the complex, localized and fast oxygen dynamics in tumour micro-regions which are induced by radiotherapy. A lattice-free, 3D, agent-based approach for cell representation is coupled with a high-resolution diffusion solver that includes a tissue density-dependent diffusion coefficient. This allows us to assess the space- and time-resolved reoxygenation response of a small subvolume of tumour tissue in response to radiotherapy. In response to irradiation the tumour nodule exhibits characteristic reoxygenation and re-depletion dynamics which we resolve with high spatio-temporal resolution. The reoxygenation follows specific timings, which should be respected in treatment in order to maximise the use of the oxygen enhancement effects. Oxygen dynamics within the tumour create windows of opportunity for the use of adjuvant chemotherapeutica and hypoxia-activated drugs. Overall, we show that by using modelling it is possible to follow the oxygenation dynamics beyond common resolution limits and predict beneficial strategies for therapy and in vitro verification. Models of cell cycle and oxygen dynamics in tumours should in the future be combined with imaging techniques, to allow for a systematic experimental study of possible improved schedules and to ultimately extend the reach of oxygenation monitoring available in clinical treatment.
    • Therapeutic Potential of Bacteria against Solid Tumors.

      Hatzikirou, Haralampos; López Alfonso, Juan Carlos; Leschner, Sara; Weiss, Siegfried; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-04-01)
      Intentional bacterial infections can produce efficacious antitumor responses in mice, rats, dogs, and humans. However, low overall success rates and intense side effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the proinflammatory cytokine TNFα in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor-effector cell recruitment model under the influence of functional tumor-associated vasculature. In this model, bacterial infections and TNFα enhanced immune activity and altered vascularization in the tumor bed. Information to predict bacterial therapy outcomes was provided by pretreatment tumor size and the underlying immune recruitment dynamics. Notably, increasing bacterial loads did not necessarily produce better long-term tumor control, suggesting that tumor sizes affected optimal bacterial loads. Short-term treatment responses were favored by high concentrations of effector cells postinjection, such as induced by higher bacterial loads, but in the longer term did not correlate with an effective restoration of immune surveillance. Overall, our findings suggested that a combination of intermediate bacterial loads with low levels TNFα administration could enable more favorable outcomes elicited by bacterial infections in tumor-bearing subjects. Cancer Res; 77(7); 1553-63. ©2017 AACR.