WO2020040296A1

WO2020040296A1 - Pegylated boron cluster compound, antitumor agent including pegylated boron cluster compound, and sensitizer including pegylated boron cluster

Info

Publication number: WO2020040296A1
Application number: PCT/JP2019/033062
Authority: WO
Inventors: 真白川; 久夫冨田; 亮太竹内; 均堀; 展幸亀川
Original assignee: 森田薬品工業株式会社; 学校法人福山大学
Priority date: 2018-08-23
Filing date: 2019-08-23
Publication date: 2020-02-27
Also published as: JPWO2020040296A1; JP7337342B2

Abstract

As an enhancer for boron neutron capture therapy, a compound is anticipated which has ideal effects and physical properties in terms of the therapeutic principles of boron neutron capture therapy. As a solution, the present invention provides: a PEGylated boron cluster compound characterized in that a boron cluster having a thiol group binds to a multi-arm polyethylene glycol with a maleimide functional group; an antitumor agent including a PEGylated boron cluster compound; and an enhancer including a PEGylated boron cluster compound used for boron neutron capture therapy.

Description

PEGylated boron cluster compound, antitumor agent containing PEGylated boron cluster compound, and sensitizer containing PEGylated boron cluster

The present invention relates to a sensitizer used for radiotherapy of cancer and an active ingredient thereof.

One of radiotherapy, nuclear reactors and the neutrons generated from the accelerator, boron neutron capture therapy for treating malignant tumors by α-rays generated by a nuclear reaction with the boron incorporated into malignant tumors ^{(10 B) (BNCT)} It has been known. According to the principle of this treatment, normal cells are hardly damaged, and only tumor cells can be selectively destroyed (Non-Patent Document 1).

As boron compounds used in clinical research on BNCT, boronophenylalanine (BPA) and borocaptate (BSH), a monomolecular compound of boron ion cluster, are known, but the therapeutic effect is sufficient from the viewpoint of tumor accumulation. However, it is necessary to further improve the boron concentration in the tumor and the boron concentration ratio (T / N ratio) in the tumor / normal tissue. For this reason, as a technique for further accumulating boron at a high concentration only in tumor tissue, a technique of encapsulating a hydrophilic boron compound such as BSH in a liposome whose surface is coated with polyethylene glycol (PEG) has been used (Non-Patent Document). 2). However, even with these methods, boron accumulation to an effective treatment area is difficult.

式 The following formula (II)

[In the formula, m and n are each independently an integer of 1 to 4, q is an integer of 1 to 280, and R ¹ and R ² are each independently a group having 8 to 22 carbon atoms. Is a hydrocarbon group. ]
Are known, and a liposome having a membrane coated with the boron cluster-modified PEG lipid derivative (PBL) is also known (Patent Document 1). However, development of a compound exhibiting a stronger effect is desired.

Japanese Patent No. 6206925

公知 Known boron compounds used in boron neutron capture therapy have been evaluated to a certain degree, but they have recurred frequently and were not ideal drugs. The conditions required for an ideal drug based on the principle of boron neutron capture therapy are that the boron concentration in the tumor is 20 ppm or more, the boron concentration ratio in tumor / blood (T / B ratio) and the boron concentration in tumor / normal tissue. The ratio (T / N ratio) must be 5 or more, and the compound must be water-soluble, and a compound that satisfies such conditions has been required.

The present invention
[1] a PEGylated boron cluster compound, wherein a boron cluster having a thiol group is bonded to a multi-arm polyethylene glycol having a maleimide functional group,
[2] the PEGylated boron cluster compound according to [1], wherein the boron cluster having a thiol group is a boron ion cluster monomolecular compound borocaptate (BSH);
[3] the PEGylated boron cluster compound according to [1] or [2], wherein the multi-arm polyethylene glycol is of a tetrafunctional group type;
[4] The structural formula is the following formula (1)

[Wherein, m, n, p, and q are the same or different and are each an integer of 1 to 100]. ]
A PEGylated boron cluster compound according to any one of [1] to [3], which is represented by:
[5] The structural formula is

A PEGylated boron cluster compound according to any one of [1] to [4], which is represented by:
[6] an antitumor agent comprising the PEGylated boron cluster compound according to any one of [1] to [5],
[7] an enhancer for use in radiotherapy for tumors, which comprises the PEGylated boron cluster compound according to any one of [1] to [5] as an active ingredient;
[8] The radiation treatment according to [7] is a neutron capture therapy, and the enhancer characterized in that the tumor according to [9] [7] or [8] is a malignant brain tumor, a malignant melanoma, The present invention relates to an enhancer characterized by being a head and neck tumor, a liver cancer, a lung cancer, a mesothelioma, or a bone soft tissue sarcoma.
The present invention also provides
[10] a boron neutron capture therapy for tumors, which comprises using the PEGylated boron cluster compound according to any one of [1] to [4];
[11] The boron neutron capture therapy for a tumor according to [10], wherein the tumor is a malignant brain tumor, a malignant melanoma, a head and neck tumor, a liver cancer, a lung cancer, a mesothelioma, or an osteosoft sarcoma. About.

FIG. 1 shows the results of the LC chromatogram of BAMP purity analysis. FIG. 2 shows the results of TOF-MS of BAMP. FIG. 3 shows the results showing the antitumor effects of BAMP and BSH. FIG. 4 shows the results showing the antitumor effect of BAMP, BSH, PBL-modified liposome, and BSH-encapsulated PBL-modified liposome. FIG. 5 is a diagram showing the antitumor effects of BAMP and BPA. FIG. 6 is a diagram showing the antitumor effect of the BAMP 24 mg ¹⁰ B / Kg administration group and the BAMP ¹⁰ mg ¹⁰ B / Kg administration group.

The PEGylated boron cluster compound of the present invention is characterized in that a boron cluster having a thiol group and a multi-arm polyethylene glycol having a maleimide functional group are bonded.

In the present invention, a boron cluster is a monomolecular compound of a boron ion cluster, and is a carborane, dodecaborate, an ion cluster represented by a molecular formula of B ₁₀ H ₁₀ , and a molecular formula of M (C ₂ B ₉ H ₁₀ ) 2 (M is a transition element) (they may have a substituent). However, it is particularly preferable to use borocaptate (BSH) as the compound bonded to the thiol group.

The multi-arm polyethylene glycol having a maleimide functional group refers to a polyethylene glycol (PEG) in which 3-8, preferably 4 PEG-branched multi-arm polyethylene glycol is combined with another compound. A compound in which a maleimide functional group for chemical modification is bonded to a multi-arm polyethylene glycol in order to perform the above. The number of maleimide functional groups bonded to the multi-multi-armed polyethylene glycol may be two or more, and preferably four. Such a multi-arm polyethylene glycol is commercially available as a polyethylene glycol modifier for DDS, Sambright (trade name, manufactured by Yuka Sangyo Co., Ltd.). Examples of a compound having two maleimide functional groups bonded to the multi-arm polyethylene glycol include: Sanbright 2TS-GL2-020BO3, Sunbright 2TS-GL2-020AZ3, Sunbright 2TS-B12-AZ, Sunbright 2TS-B12-DB, Sunbright 2TS-B12-BO, and three maleimide functional groups Compounds bonded to multi-arm polyethylene glycol include Sunbright 2TS-B12-BO and Sunbright 2TS-GL2-020MA4, where four maleimide functional groups are bonded to the multi-multi-arm polyethylene glycol. The compounds, Sunbright PTE-100MA, Sunbright PTE-200MA, Sunbright PTE-400MA, but are exemplified, especially preferably a compound four maleimide functional group is bonded to the multi-arm polyethylene glycol. Although a trade name is used as an example of a multi-arm polyethylene glycol having a maleimide functional group, the product is included in the multi-arm polyethylene glycol of the present invention if the structure is the same even if the trade name is different.

ＰＥＧ The PEGylated boron cluster compound of the present invention, in which the boron cluster having a thiol group and the multi-arm polyethylene glycol having a maleimide functional group are bonded, includes a compound of the following formula (I).

[Wherein, m, n, p, and q are the same or different and are each an integer of 1 to 100]. ]
In the above formula (I), m, n, p and q indicating the degree of polymerization of polyethylene glycol are the same or different and each represent an integer of 1 to 100, preferably 30 to 60, more preferably 40 to 50. . A particularly preferred structure of the present invention includes the following compound BAMP (boron-attached multi-arm peg).

In the method for producing a PEGylated boron cluster compound of the present invention, the boron cluster having a thiol group and the multi-arm polyethylene glycol provided with a maleimide functional group are different depending on the number of functional groups and the molecular weight of the multi-arm polyethylene glycol. At a weight ratio of 1 to 1:10, preferably 1: 2, in a buffer solution of pH 7.0 to pH 9.0, preferably pH 8.0, at room temperature of 10 to 30 ° C., preferably about 20 ° C. The reaction is carried out for 5 hours, preferably 2.5 to 3.5 hours, with stirring. As the buffer, any buffer such as a phosphate buffer and a Tris-HCl buffer may be used, but it is particularly preferable to use phosphate buffered saline (PBS).

脱 The obtained reaction solution is desalted by dialysis or the like to remove unnecessary low molecules, and stored as a solid by freeze-drying. Specifically, the reaction solution is put into a dialysis tube or the like, and dialyzed for 36 to 72 hours, preferably 48 hours, using distilled water or the like as an external solution while changing the external solution as needed. By freeze-drying for a time of from 36 to 36 hours, preferably for 24 hours, a solidified PEGylated boron cluster compound can be obtained.

The antitumor agent comprising a PEGylated boron cluster compound, wherein the boron cluster having a thiol group and the multi-arm polyethylene glycol having a maleimide functional group in the present invention are bound, A drug that contains a boron fluoride cluster compound and has the function of inhibiting the growth and division of tumor cells by alpha rays emitted by the nuclear reaction with neutrons when boron absorbed in or near the tumor indicates oral drugs or injections Although it can be used as an agent, it is preferably used as an injection. The tumor to which the antitumor agent is used may be any tumor, and examples include malignant brain tumor, malignant melanoma, head and neck tumor, liver cancer, lung cancer, mesothelioma, and osteosoft sarcoma.

An enhancer for radiotherapy of tumor, comprising a PEGylated boron cluster compound characterized in that a boron cluster having a thiol group and a multi-arm polyethylene glycol having a maleimide functional group according to the present invention are bonded. In boron neutron capture therapy (BNCT), which is one of radioactive treatments, α, which penetrates into tumor cells in advance and releases boron by neutron rays, in order to enhance the effect of neutrons on tumor growth inhibition or killing. An enhancer containing a PEGylated boron cluster compound which can be an enhancer of boron neutron capture therapy (BNCT) having a growth inhibitory or killing effect on tumor cells by X-rays may be used. It preferably refers to those in the form of injections.

The oral preparation, the topical absorption preparation or the injection in the antitumor agent and the enhancer used for radiotherapy is characterized in that a boron cluster having a thiol group and a multi-arm polyethylene glycol having a maleimide functional group are bonded to a PEG. Formulations can be readily formulated by combining the boron halide cluster compound with a pharmaceutically acceptable carrier well known in the art.

The injection can be prepared in the form of an injection by a conventional method as a solution or a solid form suitable for dissolving in a liquid before injection. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, injectable pharmaceutical compositions may, if desired, contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents and the like. Physiologically compatible buffers include, but are not limited to, Hanks's solution, Ringer's solution, or physiological saline buffer.

Gelling agents, creams, ointments, and tablets and capsules for oral administration of topical preparations for dermal administration and the like can be prepared by conventional methods, and are liquids such as solutions, suspensions, and emulsions; gels. , A paste, a cream, etc .; a solid, such as a powder, a granule, a tablet, a capsule encapsulated in a hard or soft capsule, and the like.

Excipients used in the formulation include excipients, binders, disintegrants, lubricants, coatings, bases, solvents, emulsifiers, dispersants, suspending agents, stabilizers, thickeners, pH Modifiers, antioxidants, preservatives, preservatives, flavoring agents, sweeteners, flavors, coloring agents and the like can be mentioned.

Excipients include silicic anhydride, calcium silicate, magnesium silicate, starch (corn starch, potato starch, wheat starch, etc.), sugars (glucose, lactose, sucrose, etc.), sugar alcohols (sorbitol, maltitol) , Mannitol, etc.).

Examples of the binder include gelatin, sodium caseinate, starch and modified starch (such as corn starch, hydroxypropyl starch, pregelatinized starch and partially pregelatinized starch), cellulose and its derivatives (crystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose, etc.), etc. Is mentioned.

Examples of the disintegrant include povidone, crospovidone, cellulose and derivatives thereof (crystalline cellulose, methylcellulose, etc.).

Lubricants include talc, synthetic aluminum silicate, magnesium silicate, calcium stearate, magnesium stearate and the like.

Examples of the coating agent include methacrylic acid copolymers (methacrylic acid / ethyl acrylate copolymer, etc.), methacrylate copolymers (ethyl acrylate / methyl methacrylate copolymer, ethyl acrylate / methyl methacrylate / methacrylate) Trimethylammonium ethyl copolymer) and the like.

Examples of the base include hydrocarbons (such as liquid paraffin) and polyethylene glycol (such as Macrogol 400 and Macrogol 1500).

(4) Examples of the solvent include purified water, monohydric alcohol (such as ethanol), and polyhydric alcohol (such as propylene glycol and glycerin).

Examples of the emulsifier include nonionic surfactants (such as sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester) and anionic surfactants (such as sodium alkyl sulfate and N-acyl glutamate). ), Purified soybean lecithin and the like.

Dispersants include gum arabic, propylene glycol alginate, nonionic surfactants (polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, etc.), anionic surfactants ( Sodium alkyl sulfate, etc.).

Examples of the suspending agent include sodium alginate, nonionic surfactants (polyoxyethylene lauryl ether, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, propylene glycol fatty acid ester, etc.).

Examples of the stabilizer include adipic acid, ethylenediaminetetraacetate (calcium disodium salt, disodium salt, etc.), α-cyclodextrin, β-cyclodextrin and the like.

Examples of the thickener include water-soluble polymers (such as sodium polyacrylate and carboxyvinyl polymer) and polysaccharides (such as sodium alginate, xanthan gum, and tragacanth).

Examples of the pH adjuster include hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid, sodium hydroxide, sodium hydrogen phosphate and the like.

The dose of the antitumor agent of the present invention and the enhancer used for radiotherapy are ideally preferably such that the boron concentration finally becomes 20 ppm or more in the tumor, and the dose is determined depending on the molecular weight of each active ingredient. Depending on the patient's body weight, the dose is 30 mg / Kg-300 mg / Kg, preferably 30 mg / Kg-200 mg / Kg, more preferably 30 mg / Kg-100 mg / Kg. The administration site must be applied to various sites such as intravenous, subcutaneous, and intramuscular, because the neutron irradiation site in BNCT differs depending on the tumor position. The dosing interval is also determined by the treatment strategy of BNCT, but may be terminated by a single dose.

The following is a prescription example.
Prescription example (injection)
BAMP lyophilized powder 1800mg
100 ml of distilled water for injection
Phosphate buffer 100%
Such compounds may be used as such, or in the form of a pharmaceutically acceptable salt, or a mixture thereof with a pharmaceutically acceptable carrier, in the form of a preparation known to those skilled in the art, or a BSH-encapsulated virus envelope vector or the like. In form, it can be advantageously used in boron neutron capture therapy (BNCT).

BNCT treatment using a PEGylated boron cluster compound formulation of the invention is performed by any suitable route of administration, in such a way that the PEGylated boron cluster compound accumulates in the target tumor. Preferably, the PEGylated boron cluster compound is concentrated in the tumor prior to irradiation, and advantageously the tumor: blood ratio before irradiation is about 2: 1 or at least 1.5: 1. The PEGylated boron cluster compound can be administered at one time or sequentially. After the desired accumulation of the compound in the tumor, the site is irradiated with an effective amount of low energy neutrons. The site can be irradiated through the skin, or the site can be completely or partially exposed prior to irradiation. Administration of the PEGylated boron cluster compound followed by irradiation can be repeated as needed. If desired, after removing the tumor as surgically as possible, the remaining tumor is destroyed using the PEGylated boron cluster compound of the present invention. In another embodiment, the patient is administered an appropriate amount of the PEGylated boron cluster compound and irradiated with an effective amount of ²⁵² californium, a naturally occurring neutron emitter. It is preferably inserted into the tumor and removed at an appropriate time.

Here, the type of tumor is not particularly limited, but brain tumors including glioblastoma and malignant glioma, malignant melanoma, breast cancer, and prostate cancer can be particularly suitable subjects. In addition, epithelial cell cancers such as lung cancer, uterine cancer, kidney cancer, and liver cancer, various sarcomas, and the like can be targeted.

[Example 1]
120 mg of Sunbright PTE-100MA (manufactured by Yuka Sangyo Co., Ltd.), which is a multi-arm polyethylene glycol having four maleimide functional groups, and 10B enriched sodium mercaptodecaborate, a monomolecular compound of a boron ion cluster (abbreviation) (BSH, manufactured by Katchem) in 10 ml of phosphate buffered saline (PBS) having a pH of 8.0 and mixed and stirred for 3 hours at room temperature. The reaction was performed while confirming the degree of progress by high performance liquid chromatography (HPLC).

The reaction mixture was placed in a dialysis tube (MWCO: 500 to 1000), placed in distilled water as an external dialysate, and dialyzed for 48 hours while exchanging the external dialysate every 12 hours. The reaction solution that had been desalted by dialysis was lyophilized for 24 hours to obtain a reaction product. The structure and yield of the obtained reaction product BAMP were analyzed by purity analysis LC chromatogram [column name: ACUITY UPLC BECH C18 (manufactured by Waters), eluent A: 0.1% TEA / H ₂ O, eluent B: 0.2% TFA / ACN, gradient conditions: B 25%, 6 minutes, 99% 0.5 mL / min, column temperature 50 ° C., analysis time 6.8 minutes] and TOF-MS [Shimadzu Biotech AXIMA (trade name: Shimadzu Corporation)]. The results are shown in FIGS. The purity of the obtained BAMP was 99.8%.
[Example 2]
BAMP obtained in Example 1, BSH (manufactured by Katchem), PBL-BSH obtained by encapsulating BSH in PBL-modified liposome by a conventional method (BSH encapsulated in liposome), and PBL-modified Liposomal (PBL-plane) four test compounds were administered to tumor-bearing mice, and the therapeutic enhancement effect and antitumor effect when performing boron neutron capture therapy (BNCT) were examined.
In the tumor-bearing mouse model, BALB / cA mice (female, 5 weeks old, weighing 16-20 g) were seeded with mouse colon cancer cells (CT26.3 × 10 ⁶ cells) on the right thigh, and the tumor diameter was 6-8 mm. It was manufactured so that it might become.
About 14 days after the treatment, the test compound was intravenously injected into the tail at a concentration of 10 mg ¹⁰ B / Kg in terms of boron (a concentration of 57 mg ¹⁰ B / Kg in the BSH-administered group to obtain the best antitumor effect). No pre-administration was performed for the group irradiated with only radiation (control) or the untreated group.
Twenty-four hours later, neutron irradiation was performed in the Kyoto University Research Reactor (KUR). The neutron dose was 5.2 × 10 ¹² neutron / cm ² and the irradiation time was 2 hours. The tumor inhibitory effect was measured by measuring the diameter of the tumor after irradiation over time by day 26 and comparing with the control group. As a control, a comparative study was performed using a group to which only neutron irradiation was performed and a group to which administration and irradiation were not performed (untreated group). In addition, the measurement of the tumor size was performed by the following formula.
[Major axis (mm)] X [minor (mm)] ^2/2 = tumor size ^(mm 3)
As a result, when comparing the tumor size between the BAMP-administered group and the BSH-administered group, the BAMP-administered group had a significantly stronger antitumor effect than the BSH-administered group, despite the higher boron dose. (FIG. 3).

The BAMP-administered group had a significantly stronger antitumor effect than the PBL-BSH group in which BSH was included in PBL-modified liposomes (FIG. 4).
[Example 3]
Two kinds of test compounds, BAMP and BPA (manufactured by Interpharma Co., Ltd.) obtained in Example 1, were administered to tumor-bearing mice, and the therapeutic enhancement effect and antitumor effect when boron neutron capture therapy (BNCT) was performed were evaluated. investigated. In the tumor-bearing mouse model, BALB / cA mice (female, 4 weeks old, weighing 16-20 g) were seeded with mouse colon cancer cells (CT26.5 × 10 ⁶ cells) on the right thigh, and the tumor diameter was 6-8 mm. It was manufactured so that it might become.
About 12 days after the treatment, BAMP was intravenously injected into the tail at two doses of 10 mg ¹⁰ B / Kg and 24 mg ¹⁰ B / Kg in terms of boron, and BPA was administered in a dose of 10 mg ¹⁰ B / Kg in terms of boron. .
Neutron irradiation was performed in the Kyoto University Research Reactor (KUR) 36 hours after the BAMP administration group and 2 hours after the BPA administration group. Irradiation was performed at a neutron dose of 1.8-4.0 × 10 ¹² neutron / cm ² for 1 hour. The anti-tumor effect was measured by measuring the tumor diameter after irradiation with time on day 24, and compared with the control group that was irradiated only. In addition, a comparative study using an untreated group that was not administered or irradiated was also performed. In addition, the measurement of the tumor size was performed by the following formula.
[Major axis (mm)] X [minor (mm)] ^2/2 = tumor size ^(mm 3)
As a result, when comparing the tumor size of BAMP administration group and BPA administration group, BAMP10mg ¹⁰ B / Kg dose group than BPA10mg ¹⁰ B / Kg dose group, the anti-tumor effect was significantly higher (Figure 5) .
Further, BAMP24mg ¹⁰ B / Kg dose group, BAMP10mg ¹⁰ B / anti-tumor effect was significantly higher than Kg dose group (FIG. 6), dose-dependency was observed in the effect of BAMP.

According to the present invention, there is provided an antitumor agent / radiotherapy sensitizer having a high water solubility, ideal for boron neutron capture therapy, a boron concentration of 20 ppm or more in a tumor, and a T / B ratio of 5 or more. You.

BAMP: BAMP administration group BSH: BSH administration group PBL-BSH: BSH administration group PBL-plane: PBL-modified liposome administration group PBL-plane: PBL-modified liposome administration group iradiation only2hour: neutron beam 2 hours irradiation group iradiation only1hour: neutron beam 1 hour Irradiation group no treatment: untreated group BAMP ¹⁰ mgB / Kg: BAMP ¹⁰ mg ¹⁰ B / Kg administration group BAMP 24 mg B / Kg: BAMP 24 mg ¹⁰ B / Kg administration group BPA ¹⁰ mgB / Kg: BPA ¹⁰ mg ¹⁰ B / Kg administration group iradiation only

Claims

(4) A PEGylated boron cluster compound, wherein a boron cluster having a thiol group is bound to a multi-arm polyethylene glycol having a maleimide functional group.
The PEGylated boron cluster compound according to claim 1, wherein the boron cluster having a thiol group is a boron ion cluster monomolecular compound borocaptate (BSH).
The PEGylated boron cluster compound according to claim 1 or 2, wherein the multi-arm polyethylene glycol is of a tetrafunctional group type.
The structural formula is the following formula (1)

[Wherein, m, n, p, and q are the same or different and are each an integer of 1 to 100]. ]
The PEGylated boron cluster compound according to any one of claims 1 to 3, which is represented by:
The structural formula is

The PEGylated boron cluster compound according to any one of claims 1 to 4, which is represented by:
(6) An antitumor agent comprising the PEGylated boron cluster compound according to any one of (1) to (5).
(6) An enhancer for radiotherapy of tumor, comprising the PEGylated boron cluster compound according to any one of (1) to (5) as an active ingredient.
(8) An enhancer, wherein the radiation therapy according to (7) is a neutron capture therapy.
(9) A potentiator, wherein the tumor according to (7) or (8) is a malignant brain tumor, a malignant melanoma, a head and neck tumor, a liver cancer, a lung cancer, a mesothelioma, or an osteosoft sarcoma.
A boron neutron capture therapy for tumors, comprising using the PEGylated boron cluster compound according to any one of claims 1 to 4.
11. The boron neutron capture therapy for a tumor according to claim 10, wherein the tumor is a malignant brain tumor, a malignant melanoma, a head and neck tumor, a liver cancer, a lung cancer, a mesothelioma, or a bone and soft tissue sarcoma.