Devices, apparatus and methods for mini-beam radiation therapy

Abstract

1. A method for generating mini-beams, comprising the steps of: focusing the incident beam through a first quadrupole according to a first direction; focusing the incident beam through a second quadrupole according to a second direction orthogonal to the first direction; deflecting the incident beam through a third magnet according to a third direction; and deflecting the incident beam through a fourth magnet according to a fourth direction different from the third direction; and adjusting the magnetic field gradients generated by the first quadrupole and / or the second quadrupole, respectively, such that the focal length of the first quadrupole is greater than or equal to 60 cm and / or less than or equal to 250 cm and / or the focal length of the second quadrupole, respectively, is greater than or equal to 50 cm and / or less than or equal to 200 cm, so that the focused beam meets the criteria of a mini-beam along a volume extending between the foci of the first quadrupole and the foci of the second quadrupole.

Description

[Technical field]

[0001] Funding The project leading to the results disclosed in this invention has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 817908).

[0002] The present invention relates to a method, device and apparatus for providing charged particle mini-beam radiation therapy, in particular to a scanning nozzle and a method for generating proton mini-beams for proton mini-beam radiation therapy (pMBRT). [Background technology]

[0003] It is known in the art that the output proton beams of beamlines in medical facilities, for example of Pencil Beam Scanning (PBS) nozzles, have a narrow divergence, usually less than 5 mrad, with a beam size of at least 4 mm full width at half maximum (FWHM). However, it has been found that tissue sparing can be significantly improved with pMBRT techniques, which require a beam size of less than 2 mm FWHM, which is not obtainable with conventional PBS nozzles. That is why the pMBRT technique performed in clinical centers known for the state of the art consists of emitting a proton beam from a proton beam source towards a target and placing a collimator at a predefined distance from the target to generate an array of areas of high dose values, called peaks, adjacent to areas of low dose values, called valleys. Such mini-beams significantly improve the dose tolerance and sparing of normal tissues. These collimators, called multi-slit collimators, consist of an array of slices and slits, with one slice being placed between two slits. Such a pMBRT device is arranged to form a proton beam and consists of a proton beam source, a nozzle, and a collimator. Due to the bulk of current nozzles and the rather long beam propagation distances, the creation of mini-beams in clinical centers is only possible with the use of collimators.

[0004] One drawback of using a collimator is the reduction in proton beam flux through the collimator: to deliver the doses required for pMBRT delivery, high beam currents at the accelerator exit are required, which can cause other problems or require longer delivery times.

[0005] Another major drawback of using a collimator is that the proton beam is scattered by the collimator, which can cause significant harmful secondary effects or adverse side effects in the vicinity of the patient. Harmful secondary effects are generated in the immediate vicinity of the patient and at the therapist's height during manipulation of the collimator after treatment.

[0006] Finally, the valley dose of pMBRT using collimators tends to increase, resulting in a lower peak-to-valley dose ratio (PVDR) and a sparing effect on healthy tissue, which is yet another drawback of collimators.

[0007] As described by Grevillot et al., the minimum spot size at isocenter reached by the state of the art is 4 mm FWHM. This limitation remains a drawback, since the sparing effect offered by minibeams occurs with beams smaller than 2 mm FWHM. The advantages of pMBRT, as well as the relationship between beam size and sparing effect, are known in the art and are described, for example, in Meyer et al., British Radiological Society, 91, 20180466 (2018), which deals with the sparing effect of minibeams.

[0008] There is a great need to generate mini-beams from nozzles. Therefore, reducing the beam spot size at the isocenter to less than 2 mm remains a major challenge, and despite recent efforts, current nozzles are not able to provide mini-beams from nozzles so far.

[0009] The article by Grevillot et al., Physics in Medicine & Biology, 60, 7985-8005 (2015) is known in the art. It teaches that the quality of the proton beam can be increased by reducing the lateral penumbra of the patient by reducing the air gap between the nozzle exit and the isocenter, which may be the target to be treated. It is known in the art and described by Grevillot et al. that it is difficult to reduce the air gap. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO2004004771 [Patent Document 2] WO2004056875 [Patent Document 3] WO2006121168 [Patent Document 4] WO2008156712 [Patent Document 5] WO2009014708 [Patent Document 6] WO2009114335 [Patent Document 7] WO2013043569 [Patent Document 8] WO2014047350 [Patent Document 9] US6,984,720 [Patent Document 10] US8,017,114 [Patent Document 11] US7,109,003 [Patent Document 12] US8,143,379 [Patent Document 13] WO1997020574 [Patent Document 14] WO2007123737 [Patent Document 15] US8,491,895 [Patent Document 16] US20130177557 [Patent Document 17] US5,773,578 [Non-patent literature]

[0011] [Non-Patent Document 1] Meyer et al., British Society of Radiology, 91, 20180466 (2018) [Non-Patent Document 2] Grevillot et al., Physics in Medicine & Biology, 60, 7985-8005 (2015), Summary of the Invention

[0012] The object of the present invention is to provide a mini-beam scanning nozzle and a method for generating a charged particle mini-beam. Such a mini-beam scanning nozzle comprises: - address at least some of the shortcomings of the state of the art; and / or - suitable for attachment to a current-charged particle radiotherapy (RT) device and positioned so as not to generate harmful secondary effects generated in the immediate vicinity of the patient; and / or - suitable for mounting in a current charged particle RT machine and arranged to reduce flux losses of the proton beam upstream of the patient; and / or - suitable for installation in current charged particle RT instruments and arranged to increase PVDR; and / or - Smaller in size than current nozzles; and / or - Providing a charged particle mini-beam from an incident beam of charged particles; and / or - Eliminates the need to use a collimator.

[0013] According to the present invention there is provided a method of generating a minibeam, the method comprising the steps of: - focusing said incident beam through a first quadrupole according to a first direction; - focusing the incident beam through a second quadrupole according to a second direction orthogonal to the first direction; - deflecting the incident beam through a third magnet according to a third direction; - deflecting the incident beam through a fourth magnet according to a fourth direction different from the third direction; - adjusting the magnetic field gradients generated by the first quadrupole and / or the second quadrupole, respectively, such that the focal length of the first quadrupole is greater than or equal to 60 cm and / or less than or equal to 250 cm and / or the focal length of the second quadrupole, respectively, is greater than or equal to 50 cm and / or less than or equal to 240 cm, so that the focused beam meets the mini-beam criterion along a volume extending between the focal point of the first quadrupole and the focal point of the second quadrupole.

[0014] Preferably, the fourth direction is orthogonal to the third direction. In the method, the mini-beams include: -Energy above 10MeV and / or below 1000MeV; A divergence of less than 15 milliradians, and / or from the incident beam of charged particles exhibiting an absolute value of a correlation coefficient between the size of the incident beam and the divergence of the incident beam that is greater than or equal to 0.8 and / or less than or equal to 1.

[0015] Preferably, the minibeams produced by the method according to the invention are intended to be used for minibeam radiotherapy.

[0016] According to the invention, the term adjustment may be understood as setting.

[0017] According to the present invention, the magnetic field gradient may be determined, set or adjusted based on parameters of the incident beam, such as energy, and / or divergence, and / or size, and / or the absolute value of the correlation coefficient between the size of the incident beam and the divergence of the incident beam.

[0018] The mini beams are -Energy above 10MeV and / or below 1000MeV; Divergence of less than 1 milliradian, · It can be generated from an incident beam of charged particles exhibiting an absolute value of the correlation coefficient between the size of the incident beam and the divergence of the incident beam that is greater than or equal to 0.8 and / or less than or equal to 1.

[0019] The mini beams are -Energy above 10MeV and / or below 1000MeV; Divergence less than 15 milliradians; from an incident beam of charged particles exhibiting an absolute value of a correlation coefficient between the size of the incident beam and the divergence of the incident beam that is greater than or equal to 0.95 and / or less than or equal to 1. Preferably, the absolute value of the correlation coefficient of said incident beam is equal to 1.

[0020] Optionally, the energy of the particles of the incident beam of charged particles is less than 1000 MeV / nucleon.

[0021] Optionally, the energy of the particles of the incident beam of charged particles is comprised between 50 MeV and 250 MeV, preferably between 100 MeV and 230 MeV.

[0022] The greater the divergence of the incident beam, the higher the absolute value of the correlation coefficient between the incident beam size and the divergence of the incident beam. The lower the absolute value of the correlation coefficient between the incident beam size and the divergence of the incident beam, the lower the divergence of the incident beam.

[0023] The size of the incident beam may be defined as the diameter of the incident beam. If the incident beam is considered as a Gaussian beam, the size of the beam may be defined by a couple consisting of the vertical full width at half maximum (vFWHM) and the horizontal FWHM (hFWHM).

[0024] The focal length of the second or first quadrupole, respectively, may be defined as the distance between the second or first quadrupole, respectively, and the focal point of the second or first quadrupole, respectively.

[0025] The distance between the first quadrupole focus and the second quadrupole focus may be 50 cm or less so that the focused beam meets the minibeam criterion along a volume extending between the first quadrupole focus and the second quadrupole focus.

[0026] Preferably, the focal length of the first quadrupole and / or the focal length of the second quadrupole is 60cm or more, more preferably 70cm or more, even more preferably 80cm or more, and in a preferred manner 90cm or more.

[0027] Preferably, the focal length of the second quadrupole is 180cm or less, more preferably 160cm or less, even more preferably 150cm or less, in a preferred manner 140cm or less, in a more preferred manner 130cm or less, and in a particularly preferred manner 120cm or less.

[0028] Preferably, the focal length of the first quadrupole is 220cm or less, more preferably 200cm or less, even more preferably 180cm or less, in a preferred manner 160cm or less, in a more preferred manner 140cm or less, and in a particularly preferred manner 130cm or less.

[0029] Adjusting the magnetic field gradients generated by the second quadrupole and / or the first quadrupole may be defined as controlling the magnetic field gradients generated by the second quadrupole and / or the first quadrupole such that the vFWHM and hFWHM of the focused beam meet the minibeam criterion. Preferably, the vFWHM and hFWHM of the focused beam meet the minibeam criterion in a volume extending between the foci of the first quadrupole and the foci of the second quadrupole.

[0030] The incident beam can be deflected through third and fourth magnets to move the intersection point between the charged particle minibeam and the target.

[0031] The first and second quadrupoles and the third and fourth magnets may be part of a nozzle. The nozzle may be a scanning nozzle. The nozzle may be a scanning nozzle according to the present invention.

[0032] Preferably, downstream of the exit of the scanning nozzle, said focused beam is focused and deflected according to a beam path.

[0033] The target is preferably intended to be positioned relative to the nozzle and / or the nozzle is preferably intended to be positioned relative to the target, whereby the target is located within a volume extending between the focus of the first quadrupole and the focus of the second quadrupole, and the focused beam meets the minibeam criterion.

[0034] The method may include the step of disposing a beam, first and second quadrupoles, and third and fourth magnets in a volume, the beam contained in a vacuum environment, the vacuum environment extending over a distance greater than 50 cm and less than 200 cm.

[0035] Preferably, the magnet is not in a vacuum chamber, only the beam. A vacuum chamber or tube passes through the magnet. However, it is possible to design a system where all components are in a vacuum environment, but only the ionization chamber is in an air-filled environment.

[0036] The vacuum environment may be generated in a vacuum chamber, which may be a vacuum chamber of a scanning nozzle.

[0037] The distance from the edge of the vacuum environment to the focus of the second quadrupole may be more than a few cm and / or up to 50 cm.

[0038] Preferably, the distance from the edge of the vacuum environment to the focus of the second quadrupole may be 10 cm or more.

[0039] Preferably, the distance from the edge of the vacuum environment to the focus of the second quadrupole may be 40cm or less, more preferably 30cm or less.

[0040] The edge of the vacuum environment may be an edge of the vacuum environment and / or an edge of a vacuum chamber and / or an edge of a vacuum chamber.

[0041] The FWHM of the incident beam may be 50 mm or less.

[0042] The value of the magnetic field gradient generated by the first and second quadrupoles required for the focused beam at the focus of the second quadrupole to meet the minibeam criterion is 0 T.cm -1 or more and / or 1.6T.cm -1 It can be the following:

[0043] The distance separating the first quadrupole from the second quadrupole may be less than 15cm, preferably less than 6cm, more preferably 3cm or less.

[0044] The incident beam of charged particles may exit a beamline of a medical facility, in other words, the incident beam of charged particles may be an output beam of a beamline of a medical facility.

[0045] The charged particles may be ions. Preferably, the charged particles are protons or carbon ions.

[0046] The operating frequency of the third and fourth magnets may be greater than or equal to 1 Hz and / or less than or equal to 200 Hz.

[0047] According to the invention, a mini-beam is defined as the maximum size of the beam at which the desired tissue sparing effect occurs. This maximum beam size is defined as the full width at half maximum (FWHM) value of the beam equal to 2 mm at the entrance plane of the irradiated target. By analogy, this maximum beam size can also be defined as equal to 2.355 σ of the beam Gaussian distribution, where σ is the standard deviation. The entrance plane of the irradiated target can be located in a volume extending between the foci of the first quadrupole and the foci of the second quadrupole.

[0048] Preferably, according to the invention, said mini-beam is defined as a beam exhibiting a FWHM of less than or equal to 2 mm.

[0049] The mini-beams according to the invention may exhibit a horizontal full width at half maximum (hFWHM) of the mini-beam of 2 mm or less and a vertical FWHM (vFWHM) of 2 mm or less. In other words, the mini-beams according to the invention may exhibit a FWHM of 2 mm or less.

[0050] Preferably, according to the invention, the minibeam exhibits a FWHM in the volume extending between the focus of the first quadrupole and the focus of the second quadrupole of less than 1 mm, more preferably less than 0.9 mm, in a preferred manner less than 0.8 mm and in a more preferred manner less than 0.7 mm.

[0051] The method may comprise the step of measuring the intensity and / or spatial position of the focused beam downstream of the first and second quadrupoles and the third and fourth magnets along the beam path. Preferably, the method may comprise the step of measuring the intensity and / or spatial position of the focused beam at a position located between the fourth magnet and the focus of the first quadrupole.

[0052] According to the present invention, there is also provided a mini-beam scanning nozzle (MSN) for charged particle mini-beam radiotherapy, the MSN comprising, along a beam path of the charged particles in the mini-beam scanning nozzle: a first quadrupole arranged to focus the incident beam according to a first direction; a second quadrupole arranged to focus the incident beam according to a second direction orthogonal to the first direction; a third magnet arranged to deflect the incident beam according to a third direction; a fourth magnet arranged to deflect the incident beam according to a fourth direction different from the third direction; The first quadrupole and / or the second quadrupole, respectively, are arranged to generate a magnetic field gradient adjusted such that the focal length of the first quadrupole is greater than or equal to 60 cm and / or less than or equal to 250 cm and / or the focal length of the second quadrupole, respectively, is greater than or equal to 50 cm and / or less than or equal to 200 cm, so that the focused beam meets the minibeam criterion along a volume extending between the focus of the first quadrupole and the focus of the second quadrupole.

[0053] The MSN may comprise a vacuum chamber in which the beam passing through the first and second quadrupoles and the third and fourth magnets is contained, the vacuum chamber preferably being located within the bore of the magnet.

[0054] The distance between the exit face of the vacuum chamber and the focal point of the second quadrupole may be less than 50 cm.

[0055] The outlet face of the vacuum chamber may be an outlet face of a vacuum environment and / or an outlet face of a vacuum tank.

[0056] Preferably, the volume extending between the focus of the first quadrupole and the focus of the second quadrupole, in which the focused beam meets the minibeam criterion, is included between a few cm from the edge of the vacuum environment and the focus of the second quadrupole.

[0057] The MSN can be arranged to generate minibeams from an incident beam of charged particles exiting a beamline of a medical facility, the MSN being intended to be placed downstream of the beamline in the path of the incident beam of charged particles.

[0058] The third and / or fourth magnets may be scanning dipole magnets.

[0059] Optionally, the first quadrupole, and / or the second quadrupole, and / or the third magnet, and / or the fourth magnet are superconducting magnets.

[0060] Optionally, the first and / or second quadrupoles are 0 T.cm -1 or more and / or 1.6T.cm -1 4, arranged to generate the following magnetic field gradient:

[0061] Optionally, the first, second, third and / or fourth magnets are part of a multipole magnet, which may comprise eight or more poles.

[0062] Optionally, the first, second, third and / or fourth magnets are part of an octupole magnet.

[0063] A third and / or fourth magnet may be arranged to deflect the beam propagating within the vacuum chamber so as to move the point of intersection between the charged particle minibeam and the target.

[0064] The scanning nozzle may include one or more ionization chambers.

[0065] Optionally, the gaseous substance filling said ionization chamber is an inert gas or a noble gas.

[0066] Preferably, the gaseous substance filling the ionization chamber is air or helium or a mixture of gases.

[0067] The MSN according to the invention may be arranged to carry out the method according to the invention.

[0068] Use of an MSN according to the invention for carrying out a method according to the invention.

[0069] Use of the MSNs according to the present invention for flash charged particle minibeam radiotherapy.

[0070] Optionally, the MSNs can be used to irradiate a tumor. Optionally, the MSNs can be used to treat a tumor located in a patient. Optionally, the MSNs can be used to treat cancer.

[0071] According to the present invention, - along the beam path of the charged particles in the nozzle, a first quadrupole arranged to focus an incident beam according to a first direction; a second quadrupole positioned to focus the incident beam according to a second direction orthogonal to the first direction; a third magnet arranged to deflect the incident beam according to a third direction; a mini beam scanning nozzle (MSN) arranged to generate a mini beam of charged particles comprising a fourth magnet arranged to deflect the incident beam according to a fourth direction different from the third direction, There is also provided a system for charged particle mini-beam radiotherapy, in which the first quadrupole and / or the respective second quadrupole are arranged to generate a magnetic field gradient adjusted such that the focal length of the first quadrupole is greater than or equal to 60 cm and / or less than or equal to 250 cm and / or the focal length of the respective second quadrupole is greater than or equal to 50 cm and / or less than or equal to 240 cm, so that the focused beam meets the mini-beam criterion along a volume extending between the focus of the first quadrupole and the focus of the second quadrupole.

[0072] The system for charged particle mini-beam radiotherapy comprises a beam source, -Energy above 10MeV and / or below 1000MeV; Divergence less than 15 milliradians; and / or The device may comprise a beam source arranged to generate an incident beam of charged particles exhibiting an absolute value of a correlation coefficient between the size of the incident beam and the divergence of the incident beam that is greater than or equal to 0.8 and / or less than or equal to 1.

[0073] Use of said system for flash charged particle mini-beam radiotherapy.

[0074] Preferably, particularly for flash charged particle minibeam radiotherapy, the beam source is arranged to generate an incident beam exhibiting a dose rate of at least 40 Gray per second, preferably at least 100 Gray, and an exposure time of less than 500 milliseconds, preferably less than 100 milliseconds.

[0075] The beam source may include a beamline at a medical facility.

[0076] The MSN of the system for charged particle minibeam radiotherapy may be an MSN according to the invention.

[0077] Further inventive objects, features and advantages will become apparent from the following detailed description of several embodiments of the invention which proceeds with reference to the drawings. [Brief description of the drawings]

[0078] [Figure 1] FIG. 1 is a schematic perspective view of an arrangement of nozzle components according to the present invention. [Diagram 2] Figure 2a is a schematic side view of a setup currently used in medical facilities for radiation therapy, Figure 2b is a schematic side view of a further possible setup of a radiation therapy setup, Figure 2c is a schematic side view of a further possible setup of a radiation therapy setup, and Figure 2d is a schematic side view of a further possible setup of a radiation therapy setup. [Diagram 3] FIG. 3 is four bar graphs illustrating the minimum focused beam size achieved by the nozzle arrangements of FIGS. 2a, 2b, 2c, and 2d, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] The embodiments described below are not limiting and other embodiments comprising a selection of the features described below may be considered. The selection may comprise a feature separated from the set of features (even if this selection is separated from a sentence containing other features) if the selection provides a technical advantage or is sufficient to distinguish the invention from the state of the art. The selection preferably comprises no structural features or at least a feature described by its technical function together with part of the structural details if this part is sufficient to provide a technical advantage or is sufficient to distinguish the invention from the state of the art on its own.

[0080] An embodiment of a method for generating mini-beams according to the invention is described. The method is intended to be used for mini-beam radiotherapy. The method comprises: focusing the incident beam 6 through a first quadrupole 10 according to a first direction x; focusing the incident beam 6 through a second quadrupole 11 according to a second direction y perpendicular to the first direction x; deflecting the incoming beam 6 through a third magnet 12 according to a third direction y; deflecting the incoming beam 6 according to a fourth direction x perpendicular to the third direction y, through a fourth magnet; adjusting the magnetic field gradients generated by the first quadrupole 10 and / or the second quadrupole 11, respectively, such that the focal length of the first quadrupole 10 is ≧60 cm and / or ≦250 cm and / or the focal length of the second quadrupole 11, respectively, is ≧50 cm and / or ≦240 cm, so that the focused beam 16 fulfills the mini-beam criterion along a volume extending between the foci of the first quadrupole 10 and the foci of the second quadrupole 11. In practice, the magnetic field gradient generated by the first quadrupole 10 can be pre-determined or set, for example, such that the target 7 (for example, tumor 7), or the cross section 18 of the target 7, or the entrance face 18 of the target 7, is located at a given distance of the exit face 33 of the nozzle 2 according to the invention. The magnetic field gradient generated by the second quadrupole 11 is then adjusted according to the invention, such that the focused beam 16 meets the criterion of a mini-beam at the target 7, or at the cross section 18 of the target 7, or at the entrance face 18 of the target 7. Conversely, the magnetic field gradient generated by the second quadrupole 11 can be pre-determined or set, for example, such that the target 7, or the cross section 18 of the target 7, or the entrance face 18 of the target 7, is located at a given distance of the exit face 33 of the nozzle 2 according to the invention.

[0081] Surprisingly, it has been found that adjusting the focal length of the quadrupoles 10, 11 is one of the main parameters for reducing the size of the focused beam 16 to a size below 2 mm so that it can meet the minibeam criterion. Indeed, state of the art nozzles have demonstrated focal lengths of over 250 cm, see for example Grevillot et al., who disclosed sizes of over 700 cm.

[0082] Furthermore, by reducing the focal length of the quadrupoles 10, 11, the overall length of the nozzle can be reduced, which may facilitate the processing process. Reducing the focal length of the quadrupoles 10, 11 also improves the quality of the proton beam by reducing scattering and reducing the lateral penumbra.

[0083] A typical pMBRT system comprises a beam source, which comprises a proton accelerator, such as a cyclotron, and a beam transport system, which comprises magnets and is arranged to transport an incoming proton beam 6 from the proton accelerator to the nozzle 2. In other treatments, the protons may be replaced with other ions, such as carbon ions. After the transport system, the beam is finally shaped with a collimator to produce an array of high dose value regions and / or deflected to produce a scanning beam.

[0084] An embodiment according to the invention comprises a proton mini-beam radiotherapy (pMBRT) system (not shown), which comprises a nozzle 2 according to the invention, which is arranged to shape an incident proton beam 6 into a proton mini-beam 16 and to guide said proton mini-beam 16 towards a tumor (not shown) located in a patient 7.

[0085] In some pMBRT systems, the patient is positioned on a gantry that is part of the pMBRT system. The nozzle 2 is connected to a gantry (not shown), which is positioned to rotate the nozzle 2 around the patient 7, allowing treatment with multiple fields from different angles to better target the tumor and spare surrounding healthy tissue.

[0086] Typical σ values ​​for the current proton beam 6 used in the current facility are between 2 mm and 10 mm. Standard energy values ​​for the current proton beam 6 used in the current facility are between 60 MeV and 230 MeV. The standard divergence exhibited by the current proton beam 6 is approximately 3 mrad (milliradians).

[0087] Figure 1 shows an embodiment of an arrangement of a nozzle 2 according to the invention that has been found to be suitable for mini-beam generation, compared to many different potential nozzle arrangements that have been investigated (see below) that are not suitable. The nozzle 2 comprises a vacuum chamber 9 arranged to receive an incoming proton beam 6. The proton beam coming from the transport system propagates into the vacuum chamber 9. According to the beam path, in other words from left to right in Figure 1, the nozzle 2: a first quadrupole 10; a second quadrupole 11; a first scanning dipole 12; a second scanning dipole 13.

[0088] In a preferred arrangement, the nozzle 2 also comprises an ionization chamber 14 .

[0089] The vacuum chamber 9 extends from the inlet face 32 of the nozzle 2, where the proton beam 6 enters the vacuum chamber 9, to the outlet of the dipole 13, where the proton mini-beam 16 leaves the vacuum chamber 9, through the ionization chamber 14, towards the target 7, which may be a tumor for example. The quadrupoles 10, 11 and the dipoles 12, 13 leave the vacuum environment of the vacuum chamber 9. The proton beam propagates in said vacuum chamber through each quadrupole 10, 11 and then between the two poles of each scanning dipole 12, 13, being positioned equidistant from each pole of the scanning dipole 12, 13. The proton mini-beam 16 then passes through the ionization chamber 14 before leaving said vacuum chamber and propagating towards the target 7.

[0090] The first quadrupole 10 is arranged to focus the proton beam 6 propagating in the vacuum chamber 9 according to the y direction and the second quadrupole 11 is arranged to focus the proton beam 6 propagating in the vacuum chamber 9 according to the x direction. Each of the first quadrupole 10 and the second quadrupole 11 is arranged to provide a variable magnetic field gradient. According to the beam path, downstream of the second quadrupole 11 the proton beam is focused to fulfill the mini-beam criterion along a volume extending between the foci of the first quadrupole 10 and the foci of the second quadrupole 11.

[0091] The ionization chambers 14 are positioned to measure the intensity and size and position of the proton minibeam 16. The wall portions of each ionization chamber that are on the beam path may be made of mylar. The ionization chambers 14 are filled with air or helium.

[0092] The first scanning dipole 12 is arranged to deflect the proton beam 6 propagating in the vacuum chamber 9 according to the y-direction and the second scanning dipole 13 is arranged to deflect the proton beam 6 propagating in the vacuum chamber 9 according to the x-direction. Each of the first scanning dipole 12 and the second scanning dipole 13 is arranged to provide a substantially uniform magnetic field of variable intensity. A processing unit for use in connection with the nozzle 2 is arranged to control the magnetic field gradient value provided by each of the first scanning dipole 12 and the second scanning dipole 13 to deflect the proton beam 6 propagating in the vacuum chamber 9 to move an intersection point between the proton mini-beam 16 and a given cross-section 18 of the target 7. The intersection point between the proton mini-beam 16 and the cross-section 18 of the target 7 is moved to scan the target 7 according to a given pattern 17. According to an embodiment, the pattern 17 exhibits a crenellated shape. The pattern can also be any type of alternating sequence of areas of high dose values, called peaks, and areas of low dose values, called valleys. By way of non-limiting example, the areas can be circular or elliptical or square or rectangular, and can be concentric. The first scanning dipole 12 and the second scanning dipole 13 each exhibit an operating frequency of 1 Hz to 200 Hz. In most cases, an operating frequency range of 3 Hz to 100 Hz is appropriate. Downstream of the second scanning dipole 13, the proton beam 16 is focused and deflected according to a beam path.

[0093] The embodiments in Fig. 2a, Fig. 2c and Fig. 2d show a chamber 2 including a vacuum chamber 9 that transmits the beam. The vacuum chamber passes through components 10-13. Magnets are not located inside the vacuum chamber but around it. The other components are in an air-filled volume. In Fig. 2b the entire chamber 2 is in a vacuum environment and is therefore considered a vacuum chamber 9. In all figures including Fig. 2b the ionization chamber 14 is always located in an air-filled volume.

[0094] Fig. 2a shows a setup currently used in medical facilities for radiation therapy. The current setup comprises a snout 23 arranged to receive a collimator and obtain a proton beam 24 formed from the focused beam 16, which is not a minibeam, before impacting the target 7. The snout 23 is in ambient air and is attached to a snout holder 25. The ionization chamber 14 is located downstream of the vacuum chamber 9. The current setup comprises a vacuum window 28 arranged in the ambient air upstream of the vacuum chamber 9. The first and second quadrupoles 10 and 11 as well as the first and second scanning magnets 12 and 13 are located outside the vacuum chamber 9.

[0095] As mentioned above and shown in FIG. 2a, quite a number of different modifications of the current setup have been tested. These modifications have resulted in a variety of possible configurations of the setup. Of these many different potential configurations, four are shown in FIG. 2b, FIG. 2c, and FIG. 2d. In addition to the current setup shown in FIG. 2a, each of these four configurations was investigated as described below. The modifications made comprise, among others, the arrangement of elements relative to each other and / or the distance between the elements and the target, and / or the removal of the snout 23, snout holder 25, and ionization chamber 14, and / or the addition of additional elements in various places of the setup, in particular a pair of additional quadrupoles 30, 31.

[0096] Simulations of the proton beam propagating through the nozzle were performed. The simulations were Monte Carlo simulations performed in TOPAS versions 3.2 and 3.1. For each given setup configuration investigated, incident proton beam energies of 100 MeV, 150 MeV, and 200 MeV were considered, and the magnetic field gradients in each of the quadrupoles 10, 11 were set to 0 T.cm. -1 to 0.8T.cm -1 Up to 0.016T.cm -1steps, resulting in 51 different magnetic field strengths for each quadrupole 10, 11. Furthermore, two orientations of the focusing planes of the quadrupoles 10, 11 were considered. The minimum beam size for each setup arrangement was then determined by comparing the sizes simulated for each of these 51 × 51 × 2 configurations of the quadrupoles 10, 11. It should be noted that the magnetic field applied to the pole tips generates a magnetic field gradient inside the quadrupoles 10, 11.

[0097] Figure 3 shows the minimum size of the focused beam 16 calculated from the simulation, showing four bar graphs, from left to right, achieved by the setup arrangements of Figures 2a, 2b, 2c and 2d. The bar graphs of Figures 3a, 3b and 3d, associated with the arrangements of Figures 2a, 2b and 2d, show the horizontal FWHM (hFWHM) and vertical FWHM (vFWHM) of the proton beam 24 formed at the target 7 for incident proton beam 6 energies of 100 MeV and 200 MeV, while the chart of Figure 3c, associated with the arrangement of Figure 2c, shows the horizontal FWHM (hFWHM) and vertical FWHM (vFWHM) of the focused beam 16 at the target 7 for incident proton beam 6 energies of 100 MeV and 200 MeV. None of the presented arrangements are suitable for providing a mini-beam, i.e. a beam exhibiting an hFWHM and vFWHM of less than 2 mm. Of the many different potential configurations investigated, only the configuration of the setup according to the invention shown in Figure 1 makes it possible to achieve a mini beam. The minimized beam size of the nozzle 2 according to the invention shown in Figure 1, derived from the simulations described above, is shown in Chart 1.

[0098] Thus, compared to the conventional pencil beam scanning (PBS) of FIG. 2a, which generates a beam with a minimum FWHM of 5 mm at the target 7, the beam 16 generated by the nozzle 2 according to the present invention meets the criteria of a mini beam at the target 7 and can be used for pMBRT. [Table 1]

[0099] Throughout the remainder of the description, a nozzle 2 according to the invention will be considered as shown in Figure 3. The exact dimensions of the nozzle 2 and the functions of its components, the distances separating them from each other and from the target 7, have been simulated using an analytical magnetic field calculation code and checked with Monte Carlo methods using the TOPAS code versions 3.2 and 3.1. Said components include a first quadrupole 10 and a second quadrupole 11, a third scanning dipole 12 and a fourth scanning dipole 13, and an ionization chamber 14.

[0100] The size of each component of the nozzle 2, the distance separating them from each other and the distance separating them from the target 7 are introduced. The length of each component given below describes the size of the component along the beam path. The size of each component is defined by the distance separating the entrance and exit faces of the component.

[0101] It has been found that one of the main parameters related to the arrangement of the nozzle 2 to be controlled in order to achieve a mini-beam is the distance d2 separating the exit face of the second quadrupole 11 from the cross section 18 of the target 7. To obtain a minimum size of the focused beam 16, the distance d2 must be less than 200 cm. A distance d2 less than 200 cm is achievable only by the arrangement of the nozzle 2 according to the invention and because the nozzle 2 according to the invention does not use a snout 23 or a physical collimator. Indeed, as shown in FIG. 2a, the distance d2 in current setups used in medical facilities is generally greater than 230 cm.

[0102] It has been observed that another relevant parameter to be controlled in order to achieve a mini beam is the distance (d5) between the exit face 33 of the vacuum tank 2 and the cross section 18 of the target 7. From calculations, in order to obtain a minimum size of the focused beam 16, this distance d5 is less than 50 cm. Again, such a distance d5 is achievable because the nozzle 2 according to the invention does not use a snout 23 or a physical collimator.

[0103] The state of the art believes that mini-beams, especially those generated from medical facilities, are only achievable by using a collimator and / or collimator attached to the snout 23. It would therefore be counterintuitive to remove the snout 23 and / or collimator.

[0104] As shown with reference to FIG. 1 , the distance between the inlet face 32 of the nozzle 2 and the inlet face of the first quadrupole 10, the length of the first quadrupole 10 (Iq1) and the length of the second quadrupole 11 (Iq2), the distance d1 separating the first quadrupole 10 and the second quadrupole 11, the length of the first scanning dipole 12 (Id1), the length of the second scanning dipole 13 (Id2), the distance (d6) between the exit face of the second quadrupole 11 and the inlet face of the first scanning dipole 12, The distance (d4) between the exit face of the first scanning dipole 12 and the entrance face of the second scanning dipole 13, the distance (d7) between the exit face of the second scanning dipole 13 and the entrance face of the ionization chamber 14, the length (li1) of the ionization chamber 14, the distance between the exit face of the ionization chamber 14 and the exit face 33 of the nozzle 2, and the distance d5 between the exit face 33 of the nozzle 2 and the cross-section 18 of the tumor are adapted so that d2 and d5 match the above values.

[0105] The following example is the arrangement of a particular embodiment of the nozzle 2 and its components relative to the target 7. This is not a limitation, but a preferred embodiment among many given for the purpose of further explanation. The quadrupoles 10, 11 are generally cylindrical in shape. From the calculations, the diameter of this assembly is 20 cm in this embodiment, the diameter being perpendicular to the beam path. The height and width of the dipoles 12, 13 and the ionization chamber 9 are 20 cm. The diameter of the vacuum chamber 9 is about 5 cm. Vacuum is kept in the nozzle 2. In this preferred embodiment, the distance Iq1, which is equal to Iq2, is less than 20 cm, preferably comprised between 3 cm and 20 cm, more preferably comprised between 5 cm and 15 cm, and in this embodiment is equal to 10 cm. The distance d1 is less than 15 cm, preferably less than 6 cm, and in this embodiment is equal to 3 cm. The distance li1 is less than 30 cm, preferably comprised between 2 cm and 15 cm, and in this embodiment is equal to 10 cm. The distance d2 is less than 200 cm, and in this embodiment is preferably between 90 cm and 110 cm. The distance (d3) between the beam entrance face 32 of the nozzle 2 and the cross-section 18 of the tumor is less than 260 cm, and in this embodiment is generally comprised between 130 cm and 160 cm, and preferably between 130 cm and 150 cm. The distance Id1 is equal to Id2 and is less than 40 cm, and in this embodiment is equal to 25 cm. The distance d4 is less than 10 cm, and in this embodiment is equal to 0 cm. The distance d6 is less than 15 cm, and in this embodiment is equal to 5 cm. The distance d7 is less than 30 cm, and in this embodiment is equal to 15 cm.

[0106] The nozzle 2 according to the invention avoids the use of a collimator. The use of a collimator in current pMBRT devices results in a large part of the total flux of the proton beam 6 being lost. The dose rate is therefore significantly reduced. The nozzle 2 according to the invention allows the total flux of the proton beam 6 to be delivered to the tumor. The dose rate is therefore significantly increased compared to current pMBRT. Furthermore, by avoiding the use of a collimator, the generation of harmful secondary effects near the patient can be significantly reduced.

[0107] In order for the focal length of the second quadrupole 11 to be less than 200 cm, and therefore for the FWHM of the focused beam 16 to meet the minibeam criterion, the magnetic field gradients to be generated were investigated. To this end, it was found that minimizing Ω, where Ω=(hFWHM), is a suitable approach. 2 +(vFWHM) 2 It is.

[0108] The calculations are for the 51x51x2 quadrupole 10 and 11 configurations, 0 T.cm -1 to 0.8T.cm -1 Up to 0.016T.cm -1 The experiment was performed using a magnetic field gradient defined by the magnetic fields applied to the pole tips of the first quadrupole 10 and the second quadrupole 11, which were incremented in steps of

[0109] In order for the focused beam 16 to meet the criterion of a mini-beam along the volume extending between the foci of the first quadrupole 10 and the foci of the second quadrupole 11, the magnetic field gradients generated by the first quadrupole 10 and / or the second quadrupole 11 are adjusted by a processing unit such that the focal length of the first quadrupole 10 is greater than or equal to 60 cm and / or less than or equal to 250 cm and / or the focal length of the second quadrupole 11 is greater than or equal to 50 cm and / or less than or equal to 240 cm. According to an embodiment, the magnetic field gradient generated by the quadrupoles 10, 11 is the focus of the first quadrupole 10 tends to be greater than 108 cm and the focus of the second quadrupole 11 tends to be less than 128 cm, or - the focus of the first quadrupole 10 is adjusted to be no greater than 128 cm and the focus of the second quadrupole 11 to be no greater than 108 cm. Thus, the target 7, or the cross section 18 of the target 7, or the entrance face 18 of the target 7, will be located at an optimum distance from the exit face 33 of the nozzle 2, which is between 10 cm and 30 cm.

[0110] The inventors have shown that the focusing ability of the nozzle strongly depends on the parameters of the incident beam 6. In particular, the inventors have observed that it is necessary to control at least one of the following: the divergence of the incident beam 6 and the correlation coefficient between the size of the incident beam 6 and the divergence of the incident beam 6. Counter-intuitively, the size of the incident beam 6 has only a small effect.

[0111] From the calculation, in order for the FWHM of the focused beam 16 to satisfy the criteria of a mini beam, the divergence of the incident beam 6 is less than 15 milliradians, and / or The absolute value of the correlation coefficient between the size of the incident beam 6 and the divergence of the incident beam 6 is found to be greater than or equal to 0.8 and / or less than or equal to 1. The combination of an incident beam 6 divergence of less than 15 milliradians and an absolute value of the correlation coefficient between the incident beam 6 size and the incident beam divergence of 0.95 or more and / or less than or equal to 1 ensures that the focused beam 16 meets the mini-beam criterion. Conversely, the combination of an incident beam 6 divergence of less than 1 milliradian and an absolute value of the correlation coefficient between the incident beam 6 size and the incident beam divergence of 0.9 or more and / or less than or equal to 1 ensures that the focused beam 16 meets the mini-beam criterion. Indeed, the combination of a divergence of the incident beam 6 less than 1 milliradian and an absolute value of the correlation coefficient between the size of the incident beam 6 and the divergence of the incident beam being greater than or equal to 0.95 and / or less than or equal to 1 ensures that the beam 16 focused by the nozzle 2 according to the present invention meets the criterion of a mini beam.

[0112] From one specific medical facility (or specific medical setup) to another, the divergence of the incident beam 6, the absolute value of the correlation coefficient between the size of the incident beam 6 and the divergence of the incident beam 6, the energy of the incident beam 6 and the location of the medical facility will be different. Therefore, the magnetic field gradients generated by the first quadrupole 10 and / or the second quadrupole 11 are adjusted through a processing unit such that the focal length of the second quadrupole 11 is more than 50 cm and / or less than 240 cm, so that the focused beam 16 meets the criterion of a mini-beam at the focus of the second quadrupole 11. The focus of the first quadrupole 10 and the focus of the second quadrupole 11 are arranged such that the target 7, or a cross section 18 of the target 7, or an entrance face 18 of the target 7, is located in a volume extending between the focus of the first quadrupole 10 and the focus of the second quadrupole 11.

[0113] Thus, in contrast to current setups which comprise collimators specifically designed for a given medical facility and / or patient, the nozzle 2 according to the present invention is suitable for use in all medical facilities by simply adjusting the magnetic field gradients of the first quadrupole 10 and / or the second quadrupole 11.

[0114] The invention is not limited to the above embodiments, and many adjustments can be made within the scope of the invention.

[0115] Thus, in combinable alternatives of the above embodiments: the energy of the incident beam 6 is greater than or equal to 10 MeV and / or less than or equal to 1000 MeV, preferably less than 500 MeV / nucleon, more preferably comprised between 100 MeV and 230 MeV; and / or the focal length of the first quadrupole 10 is greater than or equal to 60 cm and / or less than or equal to 250 cm; and / or the focal length of the first quadrupole 10 and / or the focal length of the second quadrupole 11 is greater than or equal to 60 cm, more preferably greater than or equal to 70 cm, even more preferably greater than or equal to 80 cm, and in a preferred manner greater than or equal to 90 cm; and / or the focal length of the second quadrupole 11 is less than or equal to 180 cm, more preferably less than or equal to 160 cm, even more preferably less than or equal to 150 cm, in a preferred manner less than or equal to 140 cm, more preferably less than or equal to 130 cm, and in a particularly preferred manner less than or equal to 120 cm; and / or the focal length of the first quadrupole 10 is less than or equal to 220 cm, more preferably less than or equal to 200 cm, even more preferably less than or equal to 180 cm, in a preferred manner less than or equal to 160 cm, more preferably less than or equal to 140 cm, and in a particularly preferred manner less than or equal to 130 cm; and / or the distance d5 is greater than or equal to 10 cm and / or less than or equal to 40 cm, more preferably less than or equal to 30 cm; and / or the FWHM of the incident beam 6 is less than 50 mm, and / or the operating frequency of the third magnet 12 and the fourth magnet 13 is greater than or equal to 1 Hz and / or less than or equal to 200 Hz; and / or said focused beam 16 exhibits a FWHM at the target 7 of less than or equal to 0.6 mm, more preferably less than or equal to 0.5 mm.

[0116] In some embodiments, the MSNs according to the invention are useful for treating skin cancer, breast cancer, brain cancer, cervical cancer, testicular cancer, rectal cancer, anal cancer, cardiac sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma, gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucanoma, erythroma, thyroid cancer ... gonoma, gastrinoma, carcinomatous tumor, non-β islet cell tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibrous pancreatic tumor, adenomatous tumor, lipoma) lipomas); liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteosarcoma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningiomas (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependyma) tumors, germinomas, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, neoplastic cervical dysplasia), ovary (ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granuloma medullary cell tumor, Sertoli-Leydig cell tumor, dysplastic tumour, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma embryonal rhabdomyosarcoma, fallopian tubes (carcinoma);Skin: may be used to treat cancers including, but not limited to, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, lenticular dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland: may be used to treat solid tumors such as neuroblastoma;

[0117] As used herein, the term "cancer" refers to any cancer that may affect any of the following tissues or organs: breast; liver; kidneys; heart, mediastinum, pleura; floor of the mouth; lips; salivary glands; tongue; gums; oral cavity; palate; tonsils; larynx; trachea; bronchi; lungs; pharynx, hypopharynx, oropharynx, nasopharynx; esophagus; digestive tract, such as stomach, intrahepatic bile duct, biliary tract, pancreas, small intestine, colon; rectum; urinary tract, such as bladder, gallbladder, ureters; rectosigmoid junction; anus, anal canal; skin; bones; joints, articular cartilage of the hands and feet; eyes and adnexa; brain; peripheral nerves, autonomic nervous system; spinal cord, cranial nerves, meninges; various parts of the central nervous system; connective tissue, subcutaneous tissue, and other soft tissues; retroperitoneum, peritoneum; adrenal glands; thyroid gland; endocrine glands and associated structures; female reproductive organs, such as ovaries, uterus, cervix; male reproductive organs, such as penis, testes, prostate, etc.

[0118] The cancer may be selected from the group consisting of glioblastoma, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, bladder cancer, rectal cancer, cervical cancer, and head and neck cancer.

[0119] The cancer may be selected from the group consisting of benign, metastatic and malignant neoplasms, including acralentinous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, astrocytic tumor, Bartholin's gland carcinoma, basal cell carcinoma, bronchial adenocarcinoma, capillary, carcinoid, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondrosarcoma, choroidal plexus papilloma / carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumor, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulin ... Also included are: epithelial tumor, interepithelial tumor, interepithelial squamous cell carcinoma, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanoma, malignant melanoma, malignant mesothelial tumor, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinoma, somatostatin-secreting tumor, squamous cell carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well-differentiated carcinoma, and Wilms' tumor.

[0120] In some embodiments, the minibeams generated by the methods according to the present invention are used for minibeam radiotherapy in combination with any anti-cancer drug.

[0121] In some embodiments, MSNs according to the present invention may be used in the treatment of cancer in combination with any anti-cancer agent.

[0122] In some embodiments, the MSNs according to the present invention can be used in combination with additional cancer treatments. In particular, the MSNs according to the present invention can be used in combination with targeted therapy, immunotherapy such as immune checkpoint therapy and immune checkpoint inhibitors, costimulatory antibodies, or chemotherapy.

[0123] Immune checkpoint therapies, such as checkpoint inhibitors, include, but are not limited to, programmed cell death-1 (PD-1) inhibitors, programmed cell death ligand-1 (PD-L1) inhibitors, programmed cell death ligand-2 (PD-L2) inhibitors, lymphocyte-activation gene 3 (LAG3) inhibitors, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitors, T cell immunoreceptor containing Ig and ITIM domains (TIGIT) inhibitors, B and T lymphocyte attenuator (BTLA) inhibitors, V domain Ig suppressor of T cell activation (VISTA) inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA4) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, killer immunoglobulin-like receptor (KIR) inhibitors, KIR2L3 inhibitors, KIR3DL2 inhibitors, and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitors. In particular, checkpoint inhibitors include antibodies anti-PD1, anti-PD-L1, anti-CTLA-4, anti-TIM-3, anti-LAG3.Co-stimulatory antibodies transmit positive signals through immune regulatory receptors, such as, but not limited to, ICOS, CD137, CD27, OX-40, GITR.

[0124] Examples of anti-PD1 antibodies include nivolumab, cemiplimab (REGN2810 or REGN-2810), tislelizumab (BGB-A317), tislelizumab, spartalizumab (PDR001 or PDR-001), ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034, pidilizumab, nivolumab (ONO-4538, BMS-936558, MDX1106, GTPL7335 or Opdivo), pembrolizumab (MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda) and the antibodies described in International Patent Applications WO2004004771, WO2004056875, WO2006121168, WO2008156712, WO2009014708, WO2009114335, WO2013043569, and WO2014047350.

[0125] Examples of anti-PD-L1 antibodies include, but are not limited to, LY3300054, atezolizumab, durvalumab, and avelumab.

[0126] Examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab (see, e.g., U.S. Patents US6,984,720 and US8,017,114), tremelimumab (see, e.g., U.S. Patents US7,109,003 and US8,143,379), single chain anti-CTLA4 antibodies (see, e.g., International Patent Applications WO1997020574 and WO2007123737), and antibodies described in U.S. Patent US8,491,895.

[0127] Examples of anti-VISTA antibodies are described in US patent application US20130177557.

[0128] Examples of inhibitors of the LAG3 receptor are described in US Pat. No. 5,773,578.

[0129] An example of a KIR inhibitor is IPH4102, which targets KIR3DL2.

[0130] In some embodiments, MSNs according to the present invention may be used in combination with targeted therapy. Targeted therapy agents are drugs designed to interfere with specific molecules necessary for tumor growth and progression. For example, targeted therapeutic agents, such as therapeutic monoclonal antibodies, target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors. Small molecules can penetrate the cell membrane and interact with targets inside the cell. Small molecules are usually designed to interfere with the enzymatic activity of target proteins, such as proteasome inhibitors, tyrosine kinase or cyclin-dependent kinase inhibitors, histone deacetylase inhibitors, etc. Targeted therapy may also use cytokines.Examples of such targeted therapies include, but are not limited to, adotrastuzumab emtansine (HER2), afatinib (EGFR (HER1 / ERBB1), HER2), aldesleukin (Proleukin), alectinib (ALK), alemtuzumab (CD52), axitinib (kit, PDGFR beta, VEGFR1 / 2 / 3), belimumab (BAFF), belinostat (HDAC), bevacizumab (VEGF ligand), blinatumomab (CD19 / CD3), bortezomib (proteasome), brentuximab vedotin (CD30), bosutinib (ABL), brigatinib (ALK), kadria. Bozantinib (FLT3, KIT, MET, RET, VEGFR2), canakinumab (IL-1 beta), carfilzomib (proteasome), ceritinib (ALK), cetuximab (EGFR), cofimetinib (MEK), crizotinib (ALK, MET, ROS1), dabrafenib (BRAF), daratumumab (CD38), dasatinib (ABL), denosumab (RANKL), dinutuximab (B4GALNT1(GD2)), elotuzumab (SLAMF7), enasidenib (IDH2), erlotinib (EGFR), everolimus (mTOR), gefitinib (EGFR), ibritumomab These include tiuxetan (CD20), sonidegib (Smoothened), sipulcel-T, siltuximab (IL-6), sorafenib (VEGFR, PDGFR, KIT, RAF), tocilizumab (IL-6R), temsirolimus (mTOR), tofacitinib (JAK3), trametinib (MEK), tositumomab (CD20), trastuzumab (HER2), vandetanib (EGFR), vemurafenib (BRAF), venetoclax (BCL2), vismodegib (PTCH, Smoothened), vorinostat (HDAC), divaflibercept (PIGF, VEGFA / B), and olaparib (PARP inhibitor).

[0131] In some embodiments, the MSNs according to the present invention may be used in combination with chemotherapy. As used herein, the term "chemotherapy" has its general meaning in the art and refers to a treatment consisting of administering a chemotherapeutic agent to a patient. The chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylameramines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenthiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (synthetic adult analogs, including KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictiin a; spongiostatin; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma and calicheamicin omegal; dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin;Neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epi Mitomycins such as rubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C; mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethotrexate; fluda Purine analogues such as ancitabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; azathioprine; Minolevulinic acid; Eniluracil; Amsacrine; Bestravcil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diaziquone; Erformitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitraerin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide;Methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine; PSK polysaccharide complex; Razoxane; Rhizoxin; Schizofuran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, such as paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitors RFS 2000; difluoromethylomitin (DMFO); retinoids such as retinoic acid; capecitabine; anthracyclines, nitrosoureas, antimetabolites, epipodophyllotoxins, enzymes such as L-asparaginase; anthracenediones; hormones and antagonists including corticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate. These include, but are not limited to, progestins; estrogens such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogens such as tamoxifen; androgens including testosterone propionate and fluoxymesterone / equivalents; antiandrogens such as flutamide, gonadotropin releasing hormone analogs, and leuprolide; nonsteroidal antiandrogens such as flutamide; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0132] Furthermore, features, alternatives, and embodiments of the invention may be related to one another, provided they are not mutually exclusive.

Claims

1. 1. A method for generating mini-beams, the mini-beams comprising: - Energy of 10 MeV or more and 1000 MeV or less; - Divergence of less than 15 milliradians, or generated from said incident beam of charged particles exhibiting an absolute value of the correlation coefficient between the diameter of said incident beam and the divergence of said incident beam that is greater than or equal to 0.8 and less than or equal to 1; The method comprises: - focusing said incident beam through a first quadrupole according to a first direction; - focusing said incident beam through a second quadrupole according to a second direction orthogonal to said first direction; - deflecting said incident beam through a third magnet according to a third direction; - deflecting said incident beam through a fourth magnet according to a fourth direction different from said third direction; receiving said incident beam in a vacuum chamber; - creating a vacuum environment in said vacuum chamber; adjusting the magnetic field gradients generated by the first quadrupole such that the focal length of the first quadrupole is ≧60 cm and ≦250 cm, and the magnetic field gradients generated by the second quadrupole such that the focal length of the second quadrupole is ≧50 cm and ≦200 cm, so that the focused beam meets the mini-beam criterion along a volume extending between the foci of the first quadrupole and the foci of the second quadrupole; - a nozzle comprises said vacuum chamber, the separation of the exit face of said second quadrupole from the cross section of the target is less than 200 cm; a method in which the distance between the exit face of the nozzle and the cross section of the target is less than 50 cm.

2. 10. The method of claim 1, comprising the step of disposing the beam, the first and second quadrupoles, and the third and fourth magnets in a vacuum environment, the vacuum environment extending over a distance greater than 50 cm and less than 200 cm.

3. The method of claim 2 , wherein the distance from an edge of the vacuum environment to the focal point of the second quadrupole is more than a few cm and / or is 50 cm or less.

4. The method of claim 1 , wherein the FWHM of the incident beam is less than 50 mm.

5. The value of the magnetic field gradient generated by the first and second quadrupoles required for the focused beam at the focus of the second quadrupole to meet the minibeam criterion is 0 T.cm －１ and / or 1.6 T.cm －１ 5. The method according to any one of claims 1 to 4, wherein:

6. 6. The method of claim 1, wherein a distance separating the first quadrupole from the second quadrupole is less than 15 cm.

7. The method of claim 1 , wherein the incident beam of charged particles originates from a beamline of a medical facility.

8. The method of claim 1 , wherein the charged particles are ions.

9. 9. The method according to claim 1, wherein the operating frequency of the third and fourth magnets is greater than or equal to 1 Hz and / or less than or equal to 200 Hz.

10. 10. The method according to claim 1, wherein the mini-beam according to the invention exhibits a horizontal full width at half maximum (hFWHM) of the mini-beam less than or equal to 2 mm and a vertical FWHM (vFWHM) less than or equal to hFWHM.

11. A mini-beam scanning nozzle (MSN) for charged particle mini-beam radiotherapy, comprising: along a beam path of the charged particles in the mini-beam scanning nozzle: a first quadrupole arranged to focus an incident beam according to a first direction; a second quadrupole arranged to focus the incident beam according to a second direction orthogonal to the first direction; a third magnet arranged to deflect the incident beam according to a third direction; a fourth magnet arranged to deflect the incident beam according to a fourth direction different from the third direction; a vacuum chamber arranged to receive the incident beam; a nozzle including said vacuum chamber; Equipped with a vacuum environment is generated within the vacuum chamber; The first quadrupole and the second quadrupole are - in order for the focused beam to meet the minibeam criterion along a volume extending between the foci of the first quadrupole and the foci of the second quadrupole, the focal length of the first quadrupole is greater than or equal to 60 cm and less than or equal to 250 cm, and the focal length of the second quadrupole is greater than or equal to 50 cm and less than or equal to 200 cm; a distance separating the exit face of the second quadrupole from the cross section of the target of less than 200 cm; The distance between the nozzle exit face and the cross section of the target is less than 50 cm; a mini beam scanning nozzle (MSN) arranged to generate a magnetic field gradient tuned to

12. 12. The mini beam scanning nozzle (MSN) of claim 11, comprising a vacuum chamber in which the first and second quadrupoles and the third and fourth magnets are disposed.

13. 13. A mini beam scanning nozzle (MSN) according to claim 12, wherein the distance between the exit face of the vacuum chamber and the focal point of the second quadrupole is less than 50 cm.

14. A mini-beam scanning nozzle (MSN) according to any one of claims 11 to 13, arranged to generate said mini-beams from an incident beam of charged particles exiting a beamline of a medical facility and intended to be arranged downstream of said beamline in the path of said incident beam of charged particles.

15. A mini beam scanning nozzle (MSN) according to any one of claims 11 to 14, arranged to carry out a method according to any one of claims 1 to 10.

16. 1. A system for charged particle mini-beam radiation therapy, comprising: a beam source, - Energy of 10 MeV or more and 1000 MeV or less; - Divergence of less than 15 milliradians, or a beam source arranged to generate an incident beam of charged particles exhibiting an absolute value of a correlation coefficient between the diameter of the incident beam and the divergence of said incident beam that is greater than or equal to 0.8 and less than or equal to 1; along the beam path of said charged particles in a mini beam scanning nozzle, a first quadrupole arranged to focus the incident beam according to a first direction; a second quadrupole arranged to focus the incident beam according to a second direction orthogonal to the first direction; a third magnet arranged to deflect the incident beam according to a third direction; a fourth magnet arranged to deflect the incident beam according to a fourth direction different from the third direction; a vacuum chamber arranged to receive the incident beam; - a nozzle including said vacuum chamber; a mini beam scanning nozzle (MSN) arranged to generate a mini beam of charged particles, a vacuum environment is generated within the vacuum chamber; The first quadrupole and the second quadrupole are - in order for the focused beam to meet the minibeam criterion along a volume extending between the foci of the first quadrupole and the foci of the second quadrupole, the focal length of the first quadrupole is greater than or equal to 60 cm and less than or equal to 250 cm, and the focal length of the second quadrupole is greater than or equal to 50 cm and less than or equal to 200 cm; a distance separating the exit face of the second quadrupole from the cross section of the target of less than 200 cm; The distance between the nozzle exit face and the cross section of the target is less than 50 cm; The system is arranged to generate a magnetic field gradient adjusted so as to

17. The system of claim 16 , wherein the beam source comprises a baseline of a medical facility.

18. The system according to claim 16 or 17, wherein the MSN is an MSN according to any one of claims 11 to 15.

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