High dose rate irradiator platform to investigate the mechanisms of FLASH radiotherapy

Radiation therapy is a highly effective anti-cancer treatment, but its use is associated with risks of significant damage to normal tissues which can lead to long-term side effects. In recent years, there has been great interest in integrating new cancer treatments that activate the immune system, so-called immunotherapy, alongside radiation therapy to "vaccinate" patients against their own cancers. Thus far, results from clinical trials of such combinations have been rather contradictory, with some showing benefit and others failing to do so. Indeed, there are concerns that the radiation delivered to the tumour and nearby lymph nodes may, in fact, damage the very immune response one is trying to trigger.
New technologies offer the prospect of maintaining the favourable direct anti-tumour effects of radiation and, simultaneously, reducing damage to normal tissues, including immune cells and those that support the tumour (the so-called stroma). We propose to use a technology platform, the small animal radiation research platform or SARRP, to test two specific approaches to sparing the immune system from radiation-induced damage. The techniques are called ultrahigh dose-rate (or FLASH) and spatial dose modulation (or SDM). With FLASH, the dose is given in tiny fractions of a second (milliseconds or less) rather than over minutes, as with conventional dose-rates. In SDM radiotherapy, in contrast to established practice, we avoid trying to irradiate every part of the tumour evenly. Instead, we deliberately give the radiotherapy unevenly in peaks and troughs across the tumour, relying on the damage caused in the irradiated part to be sufficient to trigger processes that clear the unirradiated portion. Both approaches can reduce normal tissue damage, but the mechanisms by which they achieve such effects, while maintaining tumour control, are largely unknown. The new technology funded by this application will allow us, for the first time, to evaluate differential effects of giving radiation at FLASH dose-rates (affecting temporal factors), by SDM radiotherapy (affecting spatial factors) or as dual-modality of partial tumour irradiation (SDM mode) at FLASH dose-rates (affecting spatio-temporal factors).

In order to use the new SARRP-FLASH that is capable of delivering spatially modulated radiotherapy in animal models, we will need to solve a number of physics/engineering-related problems, including being able to measure the doses we deliver accurately in time and space and being able to integrate both the FLASH and SDM effects at the same time during an episode of irradiation. After that, we will analyse the effects of each of the components, FLASH and SDM, as single modalities or combined as a novel FLASH-SDM technique. In all cases, the gold-standard against which we compare our results will be whole tumour (so-called broad-beam) radiotherapy at conventional dose-rates.
We will use well-established lab techniques to measure the effects of the different radiation techniques on components of the tumour, separately analysing tumour, immune and stromal (fibroblast) cells. The new SARRP-FLASH platform will allow us to look at effects of radiation alone and radiation combined with drug therapies (including immunotherapies). We have access to animal models that will allow us to understand the effects of FLASH and SDM on the migration of immune cells in and out of the tumour, including to nearby lymph nodes (the marshalling yards of immune responses), and on the activation status of immune cells inside and outside the tumour. Finally, in preparation for translation to patients, we will evaluate how to use magnetic resonance imaging and ultrasound scans to measure the effects of FLASH, SDM and FLASH-SDM. These studies will allow us to propose so-called biomarkers that will predict who will benefit from these new treatment approaches and how to optimise their effects to enhance direct and immune-related killing of cancer cells.

Radiation therapy (RT) aims to achieve tumour control with minimal radiation-induced toxicity for each patient. We propose to use the SARRP-FLASH system to test two specific approaches to sparing the immune system from radiation-induced damage: ultrahigh dose-rate (or FLASH) and spatial dose modulation (or SDM). Both approaches can reduce normal tissue damage, but the mechanisms by which they achieve such effects, while maintaining tumour control, are largely unknown.

We will establish reliable protocols for calculation and verification of the delivered dose covering SDMs of GRID and microbeam therapy at dose-rates between 0.05 and 200 Gy/s, in parallel with the implementation of GRID and microbeam technology. Our pre-clinical research will focus on elucidating the mechanisms of anti-tumour immune responses under FLASH, SDM and combined FLASH-SDM conditions, either with radiotherapy alone or in combinations with drug therapies. We will also evaluate imaging biomarkers of therapy response.

We hypothesise that FLASH and SDM (at either non-FLASH or FLASH dose-rates) have differential anti-tumour activities, relative to conventional dose-rate broad-beam RT, by virtue of their distinct effects on immune and stromal cells within the tumour immune microenvironment. We further posit that detailed analysis of temporal, spatial and combined temporo-spatial modulation achievable with FLASH and SDM (as single modalities or as dual FLASH-SDM) will afford unique insights into optimal development of immunotherapy-RT combinations for clinical translation.

Establishing the UK's first 'Photon FLASH' preclinical research platform at ICR will enable researchers' access to a globally unique research infrastructure and stimulate national and international collaborations to explore the mechanisms of two highly promising emerging new RT paradigms. Ultimately, this will drive clinical translation of FLASH and SDM.