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Proton therapy is a new way of beating cancer, with fewer side effects than conventional radiation treatments, explains Stephen Myers, a pioneering nuclear medicine scientist.
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by Virginia Greco, CERN.
The accelerator technology underpinning Europe’s first particle-therapy facilities, driven by the TERA Foundation during the past 25 years, is poised to unleash new treatment modes in more compact ways.
Last September the TERA Foundation – dedicated to the study and development of accelerators for particle therapy – celebrated its 25th anniversary. Led by visionary Italian physicist Ugo Amaldi, TERA gathered and trained hundreds of brilliant scientists who carried out research on accelerator physics. This culminated in the first carbon-ion facility for hadron therapy in Italy, and the second in Europe: the National Centre for Cancer Hadron Therapy (CNAO), located in Pavia, which treated its first patient in 2011.
The forerunner to CNAO was the Heidelberg Ion-Beam Therapy Centre (HIT) in Germany, which treated its first patient in 2009 following experience accumulated over 12 years in a pilot project at GSI near Darmstadt. After CNAO came the Marburg Ion-Beam Therapy Centre (MIT) in Germany, which has been operational since 2015, and MedAustron in Wiener Neustadt, Austria, which delivered its first treatment in December 2016.
While conventional radiotherapy based on beams of X-rays or electrons is already widespread worldwide, the treatment of cancer with charged particles has seen significant growth in recent years. The use of proton beams in radiation oncology was first proposed in 1946 by Robert Wilson, a student of Ernest Lawrence and founding director of Fermilab. The key advantage of proton beams over X-rays is that the absorption profile of protons in matter exhibits a sharp peak towards the end of their path, concentrating the dose on the tumour target while sparing healthy tissues. Following the first treatment of patients with protons at Lawrence Berkeley Laboratory in the US in 1954, treatment centres in the US, the former USSR and Japan gradually appeared. At the same time, interest arose around the idea of using heavier ions, which offer a higher radio-biological effectiveness and, causing more severe damage to DNA, can control the 3% of all tumours that are radioresistant both to X-rays and protons. It is expected that by 2020 there will be almost 100 centres delivering particle therapy around the world, with more than 30 of them in Europe (see “The changing landscape of cancer therapy”).
Europe entered the hadron-therapy field in 1987, when the European Commission launched the European Light Ion Medical Accelerator (EULIMA) project to realise a particle-therapy centre. The facility was not built in the end, but interest in the topic continued to grow. In 1991, together with Italian medical physicist Giampiero Tosi, Amaldi wrote a report outlining the design of a hospital facility for therapy with light ions and protons to be built in Italy. One year later, the pair established the TERA Foundation to raise the necessary funding to employ students and researchers to work on the project. Within months, TERA could count on the work of about 100 physicists, engineers, medical doctors and radiobiologists, who joined forces to design a synchrotron for particle therapy and the beamlines and monitoring systems necessary for its operation.
Ten years of ups and downs followed, during which TERA scientists developed three designs for a proton-therapy facility initially to be built in Novara, then in the outskirts of Milan and finally in Pavia. Political, legislative and economic issues delayed the project until 2001 when, thanks to the support of Italian health minister and oncologist Umberto Veronesi, the CNAO Foundation was created. The construction of the actual facility began four years later.
“We passed through hard times and we had to struggle, but we never gave up,” says Amaldi. “Besides, we kept ourselves busy with improving the design of our accelerator.”
Meanwhile, in Austria, experimental physicist Meinhard Regler had launched a project called Austron – a sort of precursor to the European Spallation Source. In 1995, together with the head designer – accelerator physicist Phil Bryant – he proposed the addition of a ring to the facility that would be used for particle therapy (and led to the name of the project being changed to MedAustron). Amaldi, Regler and Bryant then decided to work on a common project, and the “Proton-Ion Medical Machine Study” (PIMMS) was created. Developed at CERN between 1996 and 2000 under the leadership of Bryant and with the collaboration of several CERN physicists and engineers, PIMMS aimed to be a toolkit for any European country interested in building a proton–ion facility for hadron therapy. Rather than being a blueprint for a final facility on a specific site, it was an open study from which different parts could be included in any hadron-therapy centre according to its specific needs.
The design of CNAO itself is based on the PIMMS project, with some modifications introduced by TERA to reduce the footprint of the structure. The MedAustron centre, designed in the early 2000s, also drew upon the PIMMS report. Built between 2011 and 2013, with the first beam extracted by the synchrotron in autumn 2014, MedAustron received official certification as a centre for cancer therapy in December 2016 and, a few days after, treated its first patient. “In the past few years we have worked hard to provide the MedAustron trainees with a unique opportunity to acquire CERN’s know-how in the diverse fields of accelerator design, construction and operation,” says Michael Benedikt of CERN, who led the MedAustron accelerator project. Synergies with other CERN projects were also created, he explains. “The vacuum control system built for MedAustron was successfully used in the Linac4 test set-up, while in the synchrotron a novel radiofrequency system that was jointly developed for the CERN PS Booster and MedAustron is used. The synchrotron’s power converter control uses the same top-notch technology as CERN’s accelerators, while its control system and several of its core components are derived from technologies developed for the CMS experiment.”
All the existing facilities using hadrons for cancer therapy are based on circular cyclotrons and synchrotrons. For some years, however, the TERA Foundation has been working on the design of a linear accelerator for hadron therapy. As early as 1993, Amaldi set up a study group, in collaboration with the Italian institutions ENEA and INFN, dedicated to the design of a linac for protons that would run at the same frequency (3 GHz) as the electron linacs used for conventional radiotherapy. The linac could use a cyclotron as an injector, making it a hybrid solution called a cyclinac, which reduces the sizes of both accelerators while allowing the beam energy to be rapidly changed from pulse to pulse by acting on the radiofrequency system of the linac. In 1998 a 3 GHz 1.2 metre-long linac booster (LIBO) was built by a TERA–CERN–INFN collaboration led by retired CERN engineer Mario Weiss, and in 2001 it was connected to the cyclotron of the INFN South Laboratories in Catania where it accelerated protons from 62 MeV to 74 MeV. This was meant to be the first of 10 modules that would kick protons to 230 MeV.
In 2007 a CERN spin-off company called ADAM (Applications of Detectors and Accelerators to Medicine) was founded by businessman Alberto Colussi to build a commercial high-frequency linac based on the TERA design. Under the leadership of Stephen Myers, a former CERN director for accelerators and technology and initiator of the CERN medical applications office, ADAM is now completing the first prototype. It is called Linac for Image Guided Hadron Therapy (LIGHT), and the full accelerator comprises: a proton source; a novel 750 MHz RF quadrupole (RFQ) – designed by CERN – which takes the particles up to 5 MeV; four side-coupled drift-tube linacs (SCDTL) – designed by ENEA – to accelerate the beam from 5–37.5 MeV; and a different type of accelerating module, called coupled-cavity linac (CCL) – the LIBO designed by TERA – which gives the final kick to the beam from 37.5 to 230 MeV. The complex will be 24 m long, similar to the circumference of a proton synchrotron.
Compared to cyclotrons and synchrotrons, linear accelerators are lighter and potentially less costly because they are modular. Most importantly, they produce a beam much more suited to treat patients, in particular when the tumour is moving, as in the lungs. The machine developed by ADAM is modular in structure to make it easier to maintain and more flexible when it comes to upgrading or customising the system. In addition, thanks to an active longitudinal modulation system, the beam energy can be varied during therapy and thus the treatment depth changed. LIGHT also has a dynamic transversal modulation system, allowing the beam to be rapidly and precisely modulated to “paint the tumour” many times in a short time – in other words, delivering a homogeneous dose to the whole cancerous tissue while minimising the irradiation of healthy organs. The energy variation of cyclotrons and synchrotrons is 20–100 times slower.
“The beauty of the linac is that you can electronically modulate its output energy,” Myers explains. “Since our accelerator is modular, the energy can be changed either by switching off some of the units or by reducing the power in all of them, or by re-phasing the units. Another big advantage of the linac is that it has a small emittance, i.e. beam size, which translates into smaller, lighter and cheaper magnets and allows to have a simpler and lighter gantry as well.” In the last decade, LIBO has inspired other TERA projects. Its scientists have designed a linac booster for carbon ions (while LIBO was only for protons) and a compact single-room facility called TULIP, in which a 7 m-long proton linac is mounted on a rotating gantry.
The new frontier of hadron therapy, however, could be helium ion treatment. Some tests with these ions were done in the past, but the technique still has to be proven. TERA scientists are currently working on a new accelerator for helium ions, says Amaldi. “Helium can bring great benefit to medical treatments: it is lighter than carbon, thus requiring a smaller accelerator, and it has much less lateral scattering than protons, resulting in sharper lateral fall-offs next to organs at risk.” In order to accelerate helium ions with a linac, we need either a longer linac compared to the one used for protons or higher gradients, as demonstrated by high-energy physics research at CERN and elsewhere in Europe. The need for future, compact and cost-effective ion-therapy accelerators is being addressed by a new collaborative design study coordinated by Maurizio Vretenar and Alessandra Lombardi of CERN, dubbed “PIMMS2”. A proposal, which includes a carbon linac, is being prepared for submission to the CERN Medical Application group, potentially opening the next phase of TERA’s impressive journey.
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Advanced Oncotherapy #AVO – Exclusive distribution agreement for China and other geographies & new equity investments for a total consideration of £37m
Advanced Oncotherapy (AIM: AVO), the developer of next-generation proton therapy systems for cancer treatment, announces that it has signed an exclusive distribution agreement with Yantai CIPU Medical Technology Co. Ltd. to market and sell Advanced Oncotherapy’s LIGHT system across China, Macau, Taiwan, Hong-Kong and South Korea. Under the agreement, Yantai CIPU will make a payment of £16.5 million to Advanced Oncotherapy.
At the same time, the Company has secured £20.9 million of equity investments to fund the continuing technical development of its first LIGHT system and its installation at the Harley Street Proton Therapy Centre.
- Advanced Oncotherapy to raise a total £37.4 million of financing, of which £30.0 million from Yantai CIPU and £7.4 million from other investors;
- Yantai CIPU to pay Advanced Oncotherapy £16.5 million to market and sell Advanced Oncotherapy’s LIGHT systems across China, Macau, Taiwan, Hong-Kong and South Korea;
- Yantai CIPU to subscribe for 45 million shares at 30p, raising £13.5 million equity finance;
- Other investors to subscribe for 24.6 millionshares at 30p, raising £7.4 million. These other investors include members of the Board, as well as the members of the consortium formed by AB Segulah who are converting the loan made to the Company in July 2017 and interests of a total of £4.1 million;
- The subscription price of 30p per share represents a premium of 2% to the volume-weighted average share price of one month prior to 1 December 2017.
Distribution Agreement with Yantai CIPU
Yantai CIPU and the Company have entered into a distribution agreement whereby Yantai CIPU has been appointed as the exclusive distributor in the People’s Republic of China, Hong Kong, Macau, Taiwan and South Korea of the LIGHT system, the Company’s proprietary proton accelerator. As part of the distribution agreement, Yantai CIPU has agreed to pay Advanced Oncotherapy £16.5 million. The receipt of funds is subject to approval from the Government of the People’s Republic of China for the transfer of monies to the United Kingdom.
Having already identified eleven potential installation sites for the LIGHT system, Yantai CIPU and the Company have committed to a target of three installations over the first four years and the financing of ten further systems following the regulatory approval of the LIGHT system in China. Going forward, the Board remains confident that there will be a high demand for the product, particularly as precision medicine has been listed as one of the strategic industries to receive support in the People’s Republic of China’s 13th Five-Year Plan for economic and social development (2016-20).
As part of the distribution agreement, Advanced Oncotherapy will issue to Yantai CIPU 500,000 warrants to subscribe for Ordinary Shares pursuant to the terms of a warrant deed to be executed by the Company at the time of admission of the new Ordinary Shares as detailed below in respect of each binding purchase agreement for the sale of a LIGHT system up to a maximum of 11 purchase agreements. The Warrants are exercisable for five years after issuance at an exercise price equal to 130% of the one-month average share price prevailing on the date of the delivery of a LIGHT System.
About Yantai CIPU
Based in Yantai, China, Yantai CIPU invests in the health industry, including the field of high-end medical equipment companies, both in China and internationally. Yantai CIPU is ultimately owned by the Han family.
Equity Investment from Yantai CIPU
In addition, Advanced Oncotherapy has signed a subscription agreement with Yantai CIPU, whereby Yantai CIPU will subscribe for 45,000,000 ordinary shares of £0.25 each in the capital of Advanced Oncotherapy (“Ordinary Shares”) at a price of 30p per Ordinary Share (the “Subscription Shares”), providing gross funds of £13,500,000. Shareholders should be aware that these funds are not currently in the UK and the receipt of these funds and of the funds under the Distribution Agreement is subject to approval from the Government of the People’s Republic of China for the transfer of monies to the United Kingdom.
In addition, the Equity Investment by Yantai CIPU is subject to the approval of the Advanced Oncotherapy shareholders as set out below and to completion of customary due diligence in relation to a new substantial shareholder in an AIM quoted company.
It is expected that Mrs. Zhang RenHua and Mr. Chunlin Han, will join the Board of Advanced Oncotherapy following completion of the subscription by Yantai CIPU and completion of the requisite due diligence procedures for the appointment of directors to the board of an AIM quoted company. A further announcement regarding their appointment will be made in due course. The Board expects that the Company’s strategy for the LIGHT system’s commercial roll-out in Asia will benefit greatly from the Han family’s extensive knowledge and experience in this area. Together, the Company and Yantai CIPU intend to explore opportunities to manufacture parts of the LIGHT system in the region.
Conditional upon completion of the subscription by Yantai CIPU, certain existing or new shareholders in the Company have also agreed to subscribe for, and/or convert outstanding loans into, new Ordinary Shares.
This includes the consortium formed by AB Segulah, a significant shareholder of the Company, AFMS Radgivning Och Invest AB, Peter Gyllenhammar AB, Mijesi AB and Emendum AB, who are converting the loan made to the Company in July 2017 and interests of a total of £4.1 million into 13,555,617 Ordinary Shares (the “Conversion”).
Executive Directors Dr. Michael Sinclair, Pr. Stephen Myers, Nicolas Serandour, and Non-Executive Directors Henri Vanni, and Dr Nick Plowman have agreed to subscribe in total for 4,279,050 Ordinary Shares at a price of £0.30 per Ordinary Share, providing additional funds of £1,283,715.
The subscription by Yantai CIPU, the directors and other investors and the Conversion will be subject to shareholder approval for the authority to issue the relevant Ordinary Shares as set out in a Circular to be sent to shareholders shortly. Following completion of these transactions, the total number of shares in Advanced Oncotherapy will amount to 150,501,672. Yantai CIPU will hold 29.9% of the enlarged issued share capital of the Company.
The participations by Yantai CIPU, AB Segulah, other investors and certain directors in the transactions set out above and their resulting holdings in the enlarged share capital of the Company will be as follows:
|Investment||Number of newly subscribed shares||Percentage of enlarged share capital held after completion of the transactions|
|Yantai CIPU||£ 13,500,000||45,000,000||29.9%|
|Consortium led by AB Segulah (Loan Conversion)||£ 4,066,685||13,555,617||12.6%|
|Dr Michael Sinclair, Executive Chairman||£ 500,000||1,666,667||4.4%|
|Nicolas Serandour, CEO||£ 500,000||1,666,667||1.2%|
|Prof Stephen Myers, Executive Chairman of ADAM||£ 100,000||333,333||0.5%|
|Henri Vanni, NED||£ 137,500||458,333||1.1%|
|Dr. Nick Plowman, NED||£ 46,215||154,050||2.4%|
|Other investors||£ 2,019,543||6,731,812||4.9%|
Lancea LLP advised the Company on the Subscription and Distribution agreements made by Yantai CIPU.
Status of loan facility by Metric Capital Partners
Advanced Oncotherapy and Metric Capital Partners have confirmed their intention to continue to work towards the provision of a £24 million loan facility. Terms and conditions are being updated to reflect the developments since the initial announcement of the agreement with Metric Capital Partners in May 2016.
Commenting, Nicolas Serandour, CEO of Advanced Oncotherapy, said: “I am delighted that we have been able to conclude deals to provide shareholders not only with the security of longer-term financing, but which also introduce a new experienced strategic investor with strong distribution capacity and already established commercial interest in Asia, particularly in one of our key target markets, China.
“It is a little over a year now since I took on the role of Chief Executive Officer and I am pleased to note that as the calendar year draws to a close we have successfully integrated and tested the proton source, RFQ and SCDTL significantly de-risking the development process. We are also pleased with the progress of the Harley Street site with the next stage of sub-structural work well underway.
“This deal is consistent with our strategy to focus our resources on the technological development of the first LIGHT system and to establish partnerships with those businesses that have a strong track record of market access and a unique expertise in their own geographies. With our long-term financing arrangements now well engaged we can continue to focus on making our unique proton therapy technology available to patients around the world.”
For further information, please contact:
|Advanced Oncotherapy Plc||www.avoplc.com|
|Dr. Michael Sinclair, Executive Chairman||Tel: +44 20 3617 8728|
|Nicolas Serandour, CEO|
|Stockdale Securities (Nomad & Joint Broker)|
|Antonio Bossi / Ed Thomas||Tel: +44 20 7601 6100|
|Stifel Nicolaus Europe (Joint Broker)|
|Jonathan Senior / Ben Maddison||Tel: +44 20 7710 7600|
|Walbrook PR (Financial PR & IR)||Tel: +44 20 7933 8780 or email@example.com|
|Paul McManus / Anna Dunphy||Mob: +44 7980 541 893 / Mob: +44 7876 741 001|
|Lancea LLP (Advisors)|
|Pascal Isbell / Samuel Ogunsalu||Tel +44 20 3301 8015 / +44 20 3301 8005|
About Advanced Oncotherapy Plc www.avoplc.com
Advanced Oncotherapy is a provider of particle therapy with protons that harnesses the best in modern technology. Advanced Oncotherapy’s team “ADAM”, based in Geneva, focuses on the development of a proprietary proton accelerator called Linac Image Guided Hadron Technology (LIGHT). LIGHT’s compact configuration delivers proton beams in a way that facilitates greater precision and electronic control which is not achievable with older technologies.
Advanced Oncotherapy will offer healthcare providers affordable systems that will enable them to treat cancer with an innovative technology as well as lower treatment related side effects.
Advanced Oncotherapy continually monitors the market for any emerging improvements in delivering proton therapy and actively seeks working relationships with providers of these innovative technologies. Through these relationships, the Company will remain the prime provider of an innovative and cost-effective system for particle therapy with protons.