Research project Modelling radiobiological effects from high-dose radiotherapy: vascular damage and immune activation

In addition to the direct cell-killing effect of ionizing radiation, the high doses employed in stereotactic body radiotherapy (SBRT) have been observed to cause significant damage to the tumour vasculature. This has been proposed to contribute to a secondary form of cell killing. However, the tumour vasculature has also been observed to restore itself following high doses, which could make the outcome of a potential vascular effect highly dependent on when subsequent fractions are delivered during the treatment. Sudden collapses of vessels also occur spontaneously in tumours as a result of e.g. fluctuations in the interstitial fluid pressure, causing cells to become acutely hypoxic and hence resistant to radiation which could equally be expected to result from a radiation-induced vascular collapse. In contrast to chronically hypoxic cells, these cells are metabolically active and likely therefore represent the most resistant clonogens, posing a significant threat to the success of the treatment. Thus, if the time between two fractions is neither enough for damaged vessels to regenerate nor for the acutely hypoxic tumour cells to become chronically hypoxic and starved, a decrease in the biological effectiveness of the treatment is expected. Similar to the vascular effect, the timing of SBRT fractions in relation to each other could be of great importance for the resulting impact on the treatment outcome from a radiation-induced immune response. While this relationship has so far not been properly investigated, it is reasonable to assume that depending on when a subsequent fraction is delivered, the resulting biological effect could in the best case be enhanced by the synergistic effect of the radiation cell killing and the immune response, or, in the worst case be reduced if the radiation kills immune cells preventing them from attacking tumour cells. The proper timing of treatment fractions becomes even more delicate as the radiotherapy is combined with immune stimulants. Together with the aforementioned vascular effect, an immune activation contributing to cell kill could make the final outcome of an SBRT or a radioimmunotherapy treatment highly complex to predict, and not at all satisfactorily described by the 5 R’s. By using radiobiological modelling, an endless number of combinations and scenarios could be considered and evaluated, increasing the likelihood of identifying successful treatment strategies. This project aims to expand the currently very limited knowledge of the tumour response to the combination of radiotherapy and immunotherapy. Radiobiological modelling of the tumour volume and its key physiological parameters such as the vasculature and oxygenation is based on experimental data provided by Prof Susanta Hui, head of the radiobiology laboratory at the Beckman Research Center of City of Hope, Duarte, CA, US, and is expected to contribute to the understanding of the radiobiological mechanisms of radioimmunotherapy as well as advance the development towards incorporating these effects on an individual patient basis.

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