Method for administering oncolytic virus to tumor tissue, and device for administration

Abstract

To provide a method of administering a virus to tumor tissues using an endoscope.SOLUTION: A method of administering a virus to tumor tissues using an endoscope is provided, which comprises inserting an endoscopic puncture needle filled with a virus-containing solution into tumor tissues and injecting the virus into the tumor tissues.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for administering a tumor-lysing virus to tumor tissue using an endoscope, a method for treating tumors, and a device for administration or treatment. The entire disclosure of the cited documents is incorporated herein by reference in its entirety.

Background Art

[0002] Tumor-lysing viruses have been proposed as tools for a new strategy for cancer treatment, and their efficacy in clinical settings has been investigated in preclinical studies and clinical trials. As tumor-lysing agents, several viruses such as adenovirus, herpes virus, vesicular stomatitis virus, reovirus, vaccinia virus, and measles virus have been reported. And the antitumor ability of tumor-lysing adenovirus has been demonstrated in preclinical and clinical trials. OBP-301 is a tumor-lysing adenovirus modified by introducing a human telomerase reverse transcriptase (hTERT) promoter into the genome so that the gene can be selectively replicated in cancer cells, and treatment for various cancers is expected.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] Therefore, there has been a demand for the development of a method for treating tumors to further enhance the effect of OBP-301. In addition, there has been a demand for a method for administering a tumor-lysing virus with less burden on patients without performing surgical operations for digestive tract cancers, particularly digestive tract cancers more distant from the esophagus.

Means for Solving the Problems

[0005] As a result of intensive studies to solve the above problems, the present inventors have succeeded in treating tumors by directly administering OBP-301 to tumor tissues under endoscopy, and have completed the present invention.

[0006] That is, the present invention is as follows. (1) A method for administering a virus to a tumor tissue using an endoscope, comprising inserting an endoscope puncture needle filled with a virus-containing solution into the tumor tissue and injecting the virus. (2) A method for treating a tumor using an endoscope, comprising inserting an endoscope puncture needle filled with a virus-containing solution into the tumor tissue and injecting the virus. (3) The method according to (1) or (2), wherein the tumor is at least one selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, duodenal cancer, pancreatic cancer, colon cancer, head and neck cancer, anal cancer, rectal cancer, small intestine cancer, lung cancer, and liver cancer. (4) The method according to (1) or (2), wherein the virus is administered to at least 5 sites in the tumor tissue. (5) The method according to (1) or (2), wherein at least 0.1 mL of the virus is administered per site in the tumor tissue. (6) The method according to (1) or (2), wherein the virus is administered over at least 5 seconds per site in the tumor tissue. (7) The method according to (1) or (2), wherein the virus is administered to the tumor marginal base and / or the edge of the tumor tissue. (8) The method according to (1) or (2), wherein the virus is additionally administered one or more times to the same lesion. (9) The method according to (1) or (2), wherein the virus is a tumor-lysing virus. (10) The method according to (1) or (2), wherein the virus is selected from the group consisting of adenovirus, herpes virus, and vesicular stomatitis virus. (11) The method according to (1) or (2), wherein the virus is adenovirus. (12) The method according to (1) or (2), wherein the virus is an adenovirus containing the hTERT promoter. (13) The method according to (9), wherein the oncolytic virus is OBP-301 or OBP-702. (14) A device for administering a virus to tumor tissue or treating a tumor using an endoscope, comprising an endoscope and an endoscopic puncture needle filled with a virus-containing solution. (15) The device according to (14), wherein the tumor is at least one selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, duodenal cancer, pancreatic cancer, colon cancer, head and neck cancer, anal cancer, rectal cancer, small intestine cancer, lung cancer, and liver cancer. (16) The device according to (14), wherein the virus is an oncolytic virus. (17) The device according to (14), wherein the virus is selected from the group consisting of adenovirus, herpes virus, and vesicular stomatitis virus. (18) The device according to (14), wherein the virus is an adenovirus. (19) The device according to (14), wherein the virus is an adenovirus containing the hTERT promoter. (20) The device according to (16), wherein the oncolytic virus is OBP-301 or OBP-702. [Advantages of the Invention]

[0007] According to the present invention, it has become possible to directly administer an oncolytic virus to tumor tissue under an endoscope to treat the tumor. [Brief Description of the Drawings]

[0008]

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Mode for Carrying Out the Invention

[0009] The present invention relates to a method for endoscopically administering a virus to tumor tissue. In the present invention, the virus includes a proliferative virus and a non-proliferative virus. The proliferative virus includes an oncolytic virus. In one embodiment of the present invention, the virus includes an adenovirus, a herpes virus, a vesicular stomatitis virus, a reovirus, a vaccinia virus, and a measles virus, etc. Among these, an adenovirus, a herpes virus, and a vesicular stomatitis virus are preferred, and an adenovirus is particularly preferred. In the present invention, an adenovirus containing an hTERT promoter in its genome is preferred.

[0010] In a preferred embodiment of the present invention, the oncolytic virus includes a recombinant oncolytic virus. The recombinant oncolytic virus of the present invention (e.g., OBP-301) means a virus in which a polynucleotide containing a human telomerase promoter (hTERT promoter), E1A gene, IRES sequence, and E1B gene in this order is integrated into its genome. The type of virus used in the present invention is not particularly limited, but an adenovirus is preferred from the viewpoint of safety. Among adenoviruses, adenovirus type 5 is particularly preferred in terms of ease of handling, etc. The recombinant oncolytic adenovirus can be obtained by the method described in WO2004 / 005511. Alternatively, OBP-301, which is a recombinant oncolytic adenovirus, can be obtained from Oncolys BioPharma Inc. as "Telomelysin" (registered trademark). Also, OBP-702, in which a polynucleotide containing an Egr-1 promoter and p53 gene in this order is integrated into the E3 region of OBP-301, can also be preferably used. OBP-702 can be obtained from Oncolys BioPharma Inc.

[0011] The term "cancer" is a malignant tumor understood in the art. For example, cancer has the property of growing uncontrollably in tissues that have the potential to spread (i.e., metastasize) to distant parts of the body. Examples of malignant tumors (cancers) to be administered include not only gastric cancer and gastroesophageal junction cancer, but also esophageal cancer, duodenal cancer, pancreatic cancer, colon cancer, head and neck cancer, anal cancer, rectal cancer, small intestine cancer, lung cancer, liver cancer, etc. Head and neck cancer includes laryngeal cancer and pharyngeal cancer. Among these, gastric cancer, gastroesophageal junction cancer, duodenal cancer, small intestine cancer, colon cancer, anal cancer, and rectal cancer are preferred.

[0012] The oncolytic virus of the present invention (e.g., OBP-301) can be directly administered to cancer tissue through an endoscope every two weeks. For example, OBP-301 can be endoscopically directly administered into cancer tissue a total of three times on the 1st, 18th, and 32nd days within a six-week radiotherapy period. Hereinafter, for the convenience of explanation, OBP-301 will be taken as an example of the oncolytic virus used, but those skilled in the art can easily apply it to other viruses.

[0013] 1. Preparation of injectable OBP-301 During the transportation and storage of OBP-301, a temperature of -60°C or lower is maintained. When the preparation for administering OBP-301 is ready, take out the box from the refrigerator and take out the vial from the box. Next, thaw the cryopreserved OBP-301 solution (also referred to as "IP solution") at room temperature. The time required to thaw the IP solution is about 10 minutes. The thawed IP solution is stable for 4 hours. If necessary, the IP solution can be stored in ice before injection. The IP solution is filled so that 2 mL can be collected at a concentration of 1×10 12 VP / mL. Therefore, prepare the required amount of IP solution depending on the size and void volume of the lesion that must be filled with the IP solution.

[0014] 2. Device for administering IP solution into tumor tissue Figure 1 is a diagram showing a vial and a syringe in the preparation stage for administering IP solution into tumor tissue. In Figure 1A, prepare 1 to 3 vials 101 (2 vials are shown in the figure), a 1 mL syringe 102, and a 2.5 mL syringe 103. The syringe 102 is a syringe for injecting the IP solution into the tumor tissue, and the syringe 103 is a syringe for filling the IP solution into a tube (not shown) connected to an endoscopic puncture needle. In the present invention, in addition to vial 101 containing 1 to 3 OBP-301, a set of endoscopic puncture needles, for example, Carr-Locke injection needle (sheath diameter 2.5 mm, length 230 cm, needle protrusion 5 mm, 25 gauge), or TOP endoscopic puncture needle for esophagus (length 1600 mm, needle protrusion 4 mm, 23 gauge) is prepared. Then, the IP solution is taken out from vial 101 using syringe 103. The endoscope to be used can be appropriately selected according to the type of cancer. For example, a gastrointestinal endoscope, a respiratory endoscope, an ultrasonic endoscope, etc. can be adopted.

[0015] The IP solution is filled into the endoscopic puncture needle, specifically, the endoscopic tube 104 connected to the endoscopic puncture needle, immediately before administration. In the present invention, for the sake of convenience of explanation, in addition to the endoscopic puncture needle itself, the endoscopic puncture needle 403 (see FIG. 4) connected to the endoscopic tube 104 is also collectively referred to simply as the "endoscopic puncture needle". At the end of the endoscopic puncture needle to be used, a 2.5 mL syringe 103 containing the IP solution is attached, and the IP solution is slowly pushed out to fill the entire endoscopic tube 104 with the IP solution (FIG. 1B). At this time, prevent the IP solution from spilling from the tip of the puncture needle. After filling, gently place the endoscopic tube 104 filled with the IP solution on the treatment table without pressing the syringe. Thereby, the preparation of the IP solution for administration is completed. When administering the IP solution to the tumor tissue, in order to administer the IP solution in the endoscopic tube 104 into the tumor tissue, remove syringe 103, attach syringe 102 filled with the IP solution to the tube, and push the IP solution in syringe 102 from the end (FIG. 1C). Thereby, the IP solution filled in the endoscopic tube 104 can be administered in a maximum dose of 1 mL (for example, 0.2 ml × 5 administrations). Since the IP solution administered into the tumor tissue is filled in the tube, the solution to be pushed in is not limited to the IP solution, and for example, physiological saline can also be used, but from the point of reducing the risk of dilution of the IP solution administered into the tumor tissue, it is preferable to use the IP solution as the solution to be pushed in.

[0016] 3. Method for administering IP solution to tumor tissue and method for treating tumor Next, the method of administering the IP solution to the tumor tissue will be described. In this specification, type 2 esophageal cancer will be taken as an example for description. First, the entire cancer region is observed to determine the administration site. Figure 2 is a diagram showing the positions for administering the IP solution to the tumor tissue 201 of the esophagus 10. The IP solution can be administered to at least 5 sites (for example, 5 to 10 sites) in the administration region according to the size so that the solution can cover the entire region. In Figure 2, the administration sites are indicated by black circles.

[0017] When administering the IP solution to the tumor tissue, in order to prevent inactivation of the IP solution, iodine staining is not performed. Also, if necessary, the lesion part of the tumor is observed, and it is advisable to determine the administration site using image-enhanced imaging (Figure 3). Figure 3 shows that in the esophagus 10 having the tumor tissue 201, the image of the administration region 301 is enhanced by image-enhanced imaging.

[0018] Figure 4 is a diagram showing the state of injecting the IP solution from the endoscopic puncture needle 403 into the tumor tissue 201. In Figure 4, the endoscope 401 is advanced to the tumor tissue 201 of the esophagus 10. After the lesion is confirmed, the endoscopic puncture needle 403 connected to the endoscopic tube 402 is inserted through the forceps channel, and the IP solution, which is the chemical solution, is injected so that the IP solution spreads throughout the entire tumor from the caudal tumor margin toward the oral tumor margin in sequence. This operation is performed to prevent the administration site from becoming invisible due to bleeding during administration. The IP solution is preferably administered to the sites where cancer cells are actively dividing, and it is preferably injected aiming at the base of the tumor circumferential embankment or the edge of the tumor. Also, it is preferably avoided to administer to the sites where necrosis may occur.

[0019] The IP solution is administered evenly at a predetermined dose per site to at least 5 lesion sites (administration sites). When injecting the IP solution into the lesion, a 1 mL syringe is used, and the injector slowly injects the IP solution over approximately 5 seconds per site while checking the graduations. In the present invention, the amount of the IP solution is preferably 0.1 mL or more, more preferably 0.15 mL or more, and particularly preferably 0.2 mL or more. The administration time is not limited, but the administration is preferably 5 seconds or more per site, more preferably 5 seconds per site. In repeated administrations on the 18th and 32nd days, it may become impossible to identify the cancer due to cancer shrinkage. In this case, the administration is performed at the same site as the administration site on the first day.

[0020] Next, the administration method in the case of esophageal stricture or superficial type will be described. FIG. 5 is a diagram showing that the esophagus 10 has caused esophageal stricture due to the tumor tissue 201. When it is difficult for a normal endoscope to pass through due to esophageal stricture (FIG. 5A), a transnasal endoscope is used as necessary, and in principle, 0.2 mL is administered to 5 or more sites. In the case of superficial type or when there are few cancerous elevations, intratumoral administration is performed with the endoscope 401, the endoscope tube 402, and the endoscope puncture needle 403 as horizontal as possible (FIGS. 5B and C). In addition, submucosal injection of physiological saline for elevating the cancer is preferably not performed because it may dilute the drug.

[0021] Thus, by administering the virus according to the above method, cancer can be treated. Therefore, the present invention provides a method for treating cancer using an endoscope.

[0022] Examples Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited by these examples.

Examples

[0023] 1. Method An administration test of OBP-301 (telomerase) was conducted on esophageal cancer patients for whom standard treatments (surgical resection, chemotherapy) were difficult to apply.

[0024] The patient background is shown in Table 1. [Table 1]

[0025] The dosage of OBP-301 was 1×10 11 VP / mL for cohort 1 and 1×10 12 VP / mL for cohort 2. In each cohort, on the first day, 0.2 ml of telomerase was administered to five sites of the affected area of the thoracic esophagus under local anesthesia using an endoscope, for a total of 1 ml. Intratumoral additional administration of telomerase was performed on the 18th and 32nd days. In this example, radiation was administered at 2.0 Gy / day, 5 times a week (10 Gy / week) for 6 weeks (total radiation dose: 60 Gy) starting from the fourth day. The treatment period was 6 weeks, and the following evaluation items were evaluated. (1) Primary evaluation items: · Incidence rate of dose-limiting toxicity (DLT) · Incidence rate of adverse events (2) Secondary evaluation items: · Tumor shrinkage effect of the treatment target lesion from the start of treatment to the 18th week (local treatment effect) · Tumor shrinkage effect from the start of treatment to the 18th week (systemic treatment effect, Recist evaluation)

[0026] Results The course of case ID number 002 (cohort 1) is shown in Figure 6 (esophageal photograph) and Figure 7 (CT photograph). Complete remission (CR) was achieved on the 71st day after the start of treatment, and CR continued on the 127th day after the start of treatment (Figure 6). Also, lymph node metastasis disappeared 1 year after treatment, and CR continued (Figure 7). The course of case ID number 003 (cohort 1) is shown in Figure 8 (esophageal photograph) and Figure 9 (CT photograph). In this case as well, CR was confirmed on the 71st day after the start of treatment (Figure 8), and CR continued on the 127th day after the start of treatment (Figure 8). Also, lymph node metastasis decreased 3 months after treatment (Figure 9). [Explanation of symbols]

[0027] 10: Esophagus 101: Vial, 102: 1 mL syringe, 103: 2.5 mL syringe, 104: Tube 201: Tumor tissue 301: Administration area 401: Endoscope, 402: Endoscope tube, 403: Endoscope puncture needle

Claims

1. A composition for administration to a tumor tissue, comprising an oncolytic adenovirus, wherein the composition is administered, using a flexible endoscope, with at least 1 mL of a solution containing the oncolytic adenovirus at at least 5 sites, in an amount of 0.1 mL or more per site, wherein the oncolytic adenovirus is administered to the base of the tumor margin and / or the edge of the tumor tissue, said composition.

2. A pharmaceutical composition for treating a tumor, comprising an oncolytic adenovirus, wherein the composition is administered by inserting a puncture needle for a flexible endoscope filled with a virus-containing solution into the tumor tissue, with at least 1 mL of a solution containing the oncolytic adenovirus at at least 5 sites, in an amount of 0.1 mL or more per site, wherein the oncolytic adenovirus is administered to the base of the tumor margin and / or the edge of the tumor tissue, said composition.

3. The composition according to claim 1 or 2, wherein the tumor is at least one selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, duodenal cancer, pancreatic cancer, colon cancer, head and neck cancer, anal cancer, rectal cancer, small intestine cancer, lung cancer and liver cancer.

4. The composition according to claim 1 or 2, wherein the oncolytic adenovirus is additionally administered one or more times to the same lesion.

5. The composition according to claim 1 or 2, wherein the oncolytic adenovirus contains an hTERT promoter.

6. The composition according to claim 5, wherein the oncolytic adenovirus is a virus (OBP-301) in which a polynucleotide containing a human telomerase promoter (hTERT promoter), E1A gene, IRES sequence and E1B gene in this order is integrated into its genome, or a virus (OBP-702) in which a polynucleotide containing an Egr-1 promoter and p53 gene in this order is integrated into the E3 region of the OBP-301.

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