Mechanistic Insights for FLASH radiation for clinical use
What is the 'FLASH effect' and how can we use it to cure cancer?
This programme will investigate the biological mechanisms that underpin the observed and highly beneficial sparing effect of FLASH in normal tissues (1,2,3) and to investigate whether the therapeutic ratio can be further enhanced by altering the FLASH beam characteristics and combining it with pharmaceuticals. The knowledge to be gained from this proposed research will bring us closer to a clinical implementation of FLASH radiotherapy (RT). Mechanistically, the role of oxygen and radical-radical interaction, the induction of DNA damage response, and the inflammatory and immune response will be pursued to understand how FLASH radiation increases the therapeutic index of RT between normal tissue and tumour. On the technical side, this project will define optimal FLASH beam characteristics that can be applied in the clinic. This is a highly unique programme in the UK that can potentially benefit all future patients receiving RT as part of their cancer treatment.
Recent preclinical studies have shown that FLASH irradiation, which is radiation delivered in a fraction of a second, reduces incidence and severity of radiation side effects compared to conventional dose rate irradiation used in clinical practice. However, the treatment effect on tumours is not reduced. This has been called the “FLASH” effect. The benefit of FLASH-RT has been further shown in veterinarian clinical studies and in the first treatment of a human. FLASH-RT uses irradiators with a high radiation output that allows for the treatment to be delivered in fractions of a second, compared to several minutes for conventional treatments.
The short treatment times used in FLASH-RT, often less than 0.1 s, have the added value of minimising treatment delivery uncertainties caused by patient motion during delivery, for example, a reduced risk of missing a lung tumour due to the breathing motion. Carefully implemented, this would allow for smaller volumes of normal tissue being unnecessarily irradiated. Given both the radiobiological advantageous FLASH effect and its potential to “freeze” physiological motion, FLASH-RT has the potential to be an important (r)evolutionary step in cancer treatment. However, we do not yet understand the biology underpinning the FLASH effect.
Since the formation of our lab at Oxford in October of 2019, we have worked towards setting up the tools, infrastructure, collaborations and resources necessary to identify the biological mechanisms behind the highly beneficial FLASH effect, in order to explain the effect, and to find the optimal way of implementing the technique in clinical practice. Though severely hampered by restrictions following Covid-19, we have been able to setup a FLASH core for preclinical experiments (physics, in-vitro and in-vivo) at the institute, initiated several research collaborations (local, national and international), set up and equipped one in-vivo and one in-vitro lab area, and recruited a strong team of biologists and physicists.
We are now well-equipped to perform the studies described in the “Experimental plan” below. With these studies, we will learn why we have a FLASH effect at ultra-high dose rates, the magnitude of the effect and how it depends on beam characteristics and tissue environment, especially why we see a differential effect between tumour and normal tissues, if the effect can be further expanded and how FLASH-RT should be implemented clinically. Our previous studies and our preliminary data indicate that the FLASH effect is modulated by the oxygen content, indicating a contribution of transient hypoxia through oxygen depletion as well as reduced damage from ROS (reactive oxygen species), because of a much increased probability of radical-radical interactions at ultra-high dose rates. However, the relative importance of each for the FLASH effect is not yet known. We have additional in-vitro data indicating that part of the effect does not depend on oxygen and that it varies with cell type, indicating that the DNA damage response is also of importance for the FLASH effect. Finally, our in-vivo data (and others) show that the FLASH effect is most pronounced for the inflammatory response following irradiation. Possibly due to the reduced damage by ROS. In addition, the quick delivery for FLASH suggests that the impact on the immune system should be very different. Hence, our mechanistic studies will also focus on the impact of the inflammatory and immune responses following FLASH vs. conventional dose rate irradiation. In parallel, to better understand the effect, we will investigate how the beam characteristics affect the FLASH effect, in order to find the optimal beam for clinical translation of the technique. Here we will take advantage of our uniquely flexible beam from our linac and our national and international collaborations (see below). Our final part of the programme will focus on how to implement FLASH-RT in the clinic in a safe and efficient way, taking advantage of our expertise in treatment planning as well as our network of international and industry collaborators.