The Laser-hybrid Accelerator for Radiobiological Applications (LhARA) initiative has been conceived to deliver a new facility that will harness a laser driven ion beam using strong focusing and rapid acceleration to advance our understanding of cancer and its response to radiation. The pioneering techniques the LhARA collaboration will develop have the potential to enhance or even transform radiotherapy. ​

Radiotherapy

To understand LhARA's purpose, it is important to understand the principles of radiation therapy (radiotherapy).  

Radiotherapy exposes cells to ionising radiation, causing DNA damage and disruption to DNA repair mechanisms. This inhibits cell proliferation and induces cell death with the greatest impact on rapidly proliferating cells. The high rate of cancerous cell division makes them particularly susceptible to radiotherapy, though the treatment also affects healthy cells that divide frequently. To avoid an excessive dose to normal tissue, careful planning and sophisticated techniques are employed.

Sarah Quinlan, Director of Radiotherapy UK comments

'Radiotherapy is a lifesaving, incredibly cost-effective cancer treatment that is needed by 1 in 2 cancer patients and it is instrumental in 40% of all cancer cures. Radiotherapy can be delivered externally by a radiation therapy machine that directs beams of radiation at cancer from outside the body or it can be delivered internally, using radioactive materials placed inside the body close to the cancer cells.' 

​External radiotherapy can use different particles as the source of ionising radiation. These particles can be accelerated and precisely focused to their required energy and beam characteristics using particle accelerators. Once accelerated, the particles are directed towards a patient. Each type of particle interacts with matter differently, according to their atomic properties like mass or charge. An ideal particle will exhibit favourable properties in two key parameters: dose-depth profile, how energy is transferred to tissues as the particle traverses the body, and Relative Biological Effectiveness (RBE), effectiveness of an ion species relative to a reference beam (typically photons) of equivalent energy to achieve a biological endpoint, like cell death for instance.

Depth dose profiles of Photons, Carbon Ions, Protons and Helium Ions in water: Diagram to showcase the characteristic Bragg peak shown by ions (between 140 - 150mm). 

Dose distribution in water is reflective of its distribution in homogenous tissue. 

​Precision in radiotherapy: Understanding dose-depth profile and Relative Biological Effectiveness

The dose-depth profile of charged particles or ions has been measured for decades; having been researched across multiple different ions species, since the 1940s. Whilst their properties differ on an individual basis, charged particles generally share a similar depth—dose profile.  

Travelling through a medium, they will transfer energy to electrons inside the atoms that make up that medium. Energy is deposited along their path, gradually slowing them down. As ions slow down, interaction becomes more frequent and the energy they deposit increases, eventually culminating in a sharp increase in energy just before the ions stop. This sharp increase is known as the Bragg peak. The position of the Bragg peak is dependent on numerous factors, such as initial energy and heterogeneity of the tissue. By accounting for all these contributing factors, clinicians can perform calculations that accurately estimate the depth where the Bragg peak will occur.

​Water Phantom developed by Imperial College London: Uses a combination of scintillation (light) and acoustic signals to determine the position of the Bragg peak for a proton beam of a given energy

Ion beams of varying intensity are directed at the tumour to position Bragg peaks throughout its volume, effectively targeting the tumour whilst minimising the exposure dose to normal tissue. Iain McNeish, Professor of Oncology and co-champion of the LhARA initiative at Imperial states

'This is particularly important for tumours like glioma, primary cancer within the brain; the ability to deliver high doses of radiotherapy to tumours whilst minimising damage surrounding normal tissues, such as the brain, is vital.​'

​​​​Instantaneous dose rate distribution for a glioma patient from two beam angles: Dose intensity increases progressively from dark blue (lowest) to light blue, peaking in red (highest),​

Whilst the dose-depth profiles of ion species may appear similar, the extent of damage to the cancer cells can vary significantly. The relationship between dose and biological impact is very complicated and is not completely understood; various sources of uncertainty can limit the accuracy of RBE estimation. For example, the RBE can change according to tissue heterogeneity and tumour type.

The RBE of heavy ions like helium or carbon has been measured to be as high as 3, meaning it is three times as effective as photon beams of equivalent energy. Treatment using these heavier ions may provide an advantage to patients, however, the uncertainty on RBE for ions of different energies within different conditions limits the accuracy of treatment.  

Dr Richard Hutgenberg, Medical Physicist at the University of Swansea comments on this uncertainty stating

'Ion therapy is at its beginnings; we are still not certain of the best ions for each treatment. It may be that if we consider the entire population and different types of cancers that different ions are more suited to different cancers. Additionally, long term side effects may be more or less significant'. 

Discrepancy between RBE model predictions and experimental measurements have been observed. Experimentation can refine and improve the accuracy of these models. By studying the biological response to radiation – a field known as radiobiology – clinicians can reduce RBE uncertainty for different ions and energies and identify key factors that influence it. ​

Exceptional Flexibility at high throughput

The LhARA collaboration intends to characterise the dose-depth profile and reduce RBE uncertainty for a variety of ions and energies. Their unique laser-driven approach combined with their innovative methods of beam focusing and acceleration will enable the delivery of a range of ion beams, from protons to carbon ions. This versatility can support a rich experimental programme, enabling groundbreaking research into the biological impact of ion beam therapy. Techniques developed as part of this research have the potential to enhance, or even transform, radiotherapy.

LhARA 3D rendering of the planned facility: The facility will harness a high-powered, pulsed laser to generate an intense ion flux. These are captured and focused into bunches using electron – plasma lenses, undergoing rapid acceleration through a fixed field alternating gradient (FFA) accelerator. The beam properties will be measured from generation, during focusing, through to acceleration by sensitive detection instrumentation.

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​Compact and cost-effective design

LhARA's design excludes the presence of a rotating gantry, a prominent feature in conventional ion therapy facilities. This complex of focusing magnets directs the particle beam to various positions, at variable energies, from different angles. Leo Cancer Care is a manufacturing company that aims to remove the need for a gantry, they have pioneered the use of a fixed beam and rotating patient. They are an established partner of the LhARA collaboration and are due to manufacture specialised equipment for patient positioning and imaging. 

On the shortcomings of particle therapy; CEO and Cofounder of Leo Cancer Care, Stephen Towe stated (Quote abbreviated for the sake of brevity)

'These rotating structures traditionally have been anywhere from 100 tons for proton therapy all the way up to 600 tons. And to give you an idea, that is in the order of 90 elephants worth of weight that rotates around a patient...

Rotating 600 tons of equipment around a 100-kilogram patient is like renting cranes to pick up your house and rotate the house around you as you stand with the bulb...

Leo Cancer Care's approach therefore sees the cost, size and complexity come down enormously, to a level where particle therapy not only makes clinical sense but also makes financial sense.'

LhARA leverages novel and alternative technology, advancing the techniques used in conventional ion therapy facilities, for beam production, beam focusing and beam acceleration. A defining feature and namesake of LhARA is its laser.

Many radiobiological experiments make use of laser driven ion beams. These are unsuitable for clinical use, however, due to the limitations in energy range and energy output. To address these challenges, LhARA aims to develop a high repetition laser and a durable target which can withstand the lasers intense bombardment.

LhARA from the perspective of a standing person in the centre of the facility: Two prominent spires are visible—these mark the beamline's direction toward the end stations, which are specialized chambers designed to receive and analyze the particle beam. Directly ahead, the observer can see the FFA magnets, which guide and focus the beam. Note that radiation shielding is not depicted in this visualization.

Beam production

A powerful, pulsed laser will bombard an ultra-thin target 10x a second, producing short and bright particle pulses, with each pulse separated by fractions of a second.

Laser acceleration provides a more flexible time configuration of beam pulses, meaning researchers can explore radiobiological processes in more detail and evaluate the application of new experimental techniques, potentially paving the way for their clinical application.

Laser set up at SCAPA: An intracrite network of focusing and reflective lenses which guides laser pulses to their desired position and required characteristics. 

LhARA's proposed target system: 

One of the proposed options for LhARA’s laser target involves a tape drive system that feeds tape drives around rotating spools. This continuous delivery mechanism ensures uniformity in the target material, thereby maintaining consistent beam quality.​

Beam focusing

Despite the state-of-the-art ion generation apparatus, the ions it produces vary greatly in their energy and position. To transform this chaotic cloud into a focused and consistent beam, immediate and precise focus is needed. Unlike conventional accelerators which rely on high field magnets to focus and capture the beam, LhARA proposes the use of innovative technology called a Gabor lens.

Gabor lenses are unique among focusing methods, they focus by using a state of matter called plasma. At high temperatures, energetic electrons form plasma. Plasma can be influenced by both electric and magnetic fields; careful tuning of these fields can confine electron plasma to the center of the Gabor lens. Electron plasma exerts a powerful force onto positive ions passing through, overcoming their natural tendency for mutual repulsion.

Close-up of a Gabor lens demonstrator. The green dots—pollen particles illuminated by green light—are suspended by electric fields, simulating how an ion beam is focused as it passes through a Gabor lens

Focusing achieved by Gabor lenses is far more effective than high field magnets, achieving the equivalent focusing effect using a magnetic field strength 40x lower (meaning a magnet of 10T has the same focusing strength as a Gabor lens of 250mT)! 

Not only does this make Gabor lenses more cost effective but also enables the focusing of ion beams of greater energy, and to greater precision. Researchers from the University of Swansea and Manchester are actively engaged in Gabor lens R&D. They have developed a prototype (pictured below), which they are currently using to conduct tests and identify ideal parameters for the apparatus.​

Gabor lens prototype from the University of Swansea

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Beam acceleration

Fixed Field Alternating Gradient (FFAs) are well suited for radiobiological applications, offering many advantages over conventional accelerators such as synchrotrons and cyclotrons. Cyclotrons require the use of an energy degrader; this instrument modifies the energy extracted after acceleration, producing variable energies that will position Bragg peaks throughout the tumour. Despite the energy modulation, degraders require downstream instruments to prevent growth of the beam and reduce excessive energy spread.

In synchrotrons, energy delivery is managed by ramping magnets which increase their field strength to bend beams of varying energy at a given frequency. This approach eliminates the need for a degrader though energy range is limited by the ramping frequency and these pulsing magnets consume substantial quantities of power.

LhARA co-spokesperson, Professor Ken Long of Imperial College London / STFC states

'The FFA's unique mechanism excludes the need for a degrader and is not subject to the high-power consumption requirements or frequency limitations of the synchrotron. The FFA allows for the extraction of variable energies providing a greater range of depth and dose without the use of a degrader and the subsequent downstream correction. The FFA ring can accelerate a wide range of different ions, given the same ratio of momentum and charge, with much less fine tuning than conventional acceleration methods.'

Essentially, the use of an FFA ring allows for a more compact, versatile and cost-effective facility. 

3D rendering of an FFA ring: Average radius of the beam is 3.5m, person is included for scale. Blue arcs represent the injection line where the beam arrives at the accelerator ring. ​

LhARA will be built in two stages. First, it will create and focus ion beams to study their effects on laboratory cultivated cells, conducting in vitro study. Transfer lines will then be attached to the FFA accelerator, enabling the delivery of high energy beams to in vitro and eventually live organisms / in vivo.

Sample preparation equipment at Scottish Centre for the Application of Plasma based Accelerators (SCAPA): 

This equipment will be used to prepare in vitro biological samples to study the imapct of laser driven proton beams.

After publication of their pre-Conceptual Design Report (CDR) in 2020, outlining their facility design and future R&D roadmap, LhARA collaboration was granted £2 million from UK Research and Innovation in 2022 to produce a Conceptual Design Report for a facility design that will serve the Ion Therapy Research Facility.

Currently, the collaboration is preparing for a proof of principle experiment, due to occur over the summer of 2025. This experiment will demonstrate the feasibility of the laser-hybrid approach and investigate the biological impact of a laser driven proton beam. They then plan on developing radiobiological, and eventually clinical, techniques in subsequent experiments. 

Close up of Proof of Principle LAser-driven Radiobiology (PoPLaR) experimental set up: 

The set up is incomplete with the collaboration due to install quadrapole magnets. 

A laser-driven proton beam will enter from the left and impact either - a biological sample or a detector viewed by a diagnostic camera - dependent on the experiment. 

Summary

The LhARA initiative seeks to advance cancer care by developing a new laser-based cancer treatment facility. Through a unique scientific approach; combining physics, engineering, biology and oncology, the LhARA collaboration will develop innovative treatments that could improve outcomes for cancer patients. 

LhARA collaboration at their 7^th Collaboration meet. Hosted at University College London.

Learn more about the LhARA collaboration by visiting their website, and explore their latest scientific publications to stay up to date with their research - here.  ​

Proofread and editted by Prof Ken Long​