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

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 all cited references 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, herpesvirus, 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 diligent research to solve the above problems, the inventors succeeded in treating tumors by directly administering OBP-301 to tumor tissue under endoscopy, and thus completed the present invention.

[0006] In other words, the present invention is as follows: (1) A method for administering a virus to tumor tissue using an endoscope, characterized by inserting an endoscopic puncture needle filled with a virus-containing solution into the tumor tissue and injecting the virus. (2) A method of treating a tumor using an endoscope, characterized by inserting an endoscopic puncture needle filled with a virus-containing solution into 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 five sites in the tumor tissue. (5) The method according to (1) or (2), wherein the virus is administered at least 0.1 mL per site in the tumor tissue. (6) The method according to (1) or (2), wherein the virus is administered over a period of 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 base of the tumor rim and / or to the periphery of the tumor tissue. (8) The method according to (1) or (2), wherein the virus is administered to the same lesion one or more times. (9) The method according to (1) or (2), wherein the virus is an oncolytic virus. (10) The method according to (1) or (2), wherein the virus is selected from the group consisting of adenovirus, herpesvirus and varicella stomatitis virus. (11) The method according to (1) or (2), wherein the virus is an 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 described in (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, herpesvirus and varicella stomatitis virus. (18) The device described in (14) in which the virus is an adenovirus. (19) The device described in (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. [Effects of the Invention]

[0007] This invention makes it possible to treat tumors by directly administering oncolytic viruses to tumor tissue under endoscopy. [Brief explanation of the drawing]

[0008] [Figure 1] This diagram shows a method for filling an endoscope puncture needle with a drug solution. [Figure 2] This figure shows the administration sites of OBP-301 to cancer tissue. [Figure 3] This figure shows the administration sites of OBP-301 to cancer tissue. [Figure 4] This figure shows a method for administering OBP-301 to cancer tissue. [Figure 5] It is a diagram showing the method of administering OBP-301 to cancer tissue. [Figure 6] It is a diagram showing the course of a case when a patient with esophageal cancer was treated with OBP-301. [Figure 7] It is a diagram showing the course of a case when a patient with esophageal cancer was treated with OBP-301. [Figure 8] It is a diagram showing the course of a case when a patient with esophageal cancer was treated with OBP-301. [Figure 9] It is a diagram showing the course of a case when a patient with esophageal cancer was treated with OBP-301.

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 the 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 (for example, 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 incorporated 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 easy handling and the like. 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). Further, OBP-702 in which a polynucleotide containing an Egr-1 promoter and p53 gene in this order is incorporated 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, and the like. 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 via endoscopy every two weeks. For example, OBP-301 can be directly administered endoscopically into cancer tissue a total of three times during a six-week radiotherapy period, on days 1, 18, and 32. For the sake of explanation, OBP-301 will be used as an example of the oncolytic virus used; however, those skilled in the art will be able to easily apply this invention to other viruses.

[0013] 1. Preparation of OBP-301 for injection During transport and storage of the OBP-301, maintain a temperature of -60°C or lower. When ready to administer OBP-301, remove the box from the refrigerator and take the vial out of the box. Next, thaw the frozen OBP-301 solution (also called "IP solution") at room temperature. Thawing the IP solution takes approximately 10 minutes. After thawing, the IP solution is stable for 4 hours. If necessary, the IP solution can be stored on ice before injection. The IP solution is 1 × 10⁶ per vial. 12 The container is filled to hold 2 mL of a solution with a concentration of VP / mL. Therefore, the required amount of IP solution is prepared depending on the size of the lesion and the volume of the void that needs to be filled with the IP solution.

[0014] 2. Device for administering IP solution into tumor tissue Figure 1 shows vials and syringes in preparation for administering IP solution into tumor tissue. In Figure 1A, prepare 1 to 3 vials 101 (2 vials are shown in the figure), as well as a 1 mL syringe 102 and a 2.5 mL syringe 103. Syringe 102 is for injecting the IP solution into the tumor tissue, and syringe 103 is for filling the tube (not shown) connected to the endoscopic puncture needle with the IP solution. In this invention, in addition to a vial 101 containing 1 to 3 OBP-301 units, one set of endoscopic puncture needles is prepared, for example, a Carr-Locke injection needle (sheath diameter 2.5 mm, length 230 cm, needle projection 5 mm, 25 gauge) or an esophageal TOP endoscopic puncture needle (length 1600 mm, needle projection 4 mm, 23 gauge). Then, the IP solution is taken out of the vial 101 using a syringe 103. The endoscope used can be appropriately selected depending on the type of cancer. For example, a gastrointestinal endoscope, airway endoscope, or ultrasound endoscope can be used.

[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 this invention, for the sake of explanation, the endoscopic puncture needle itself, as well as the endoscopic puncture needle 403 connected to the endoscopic tube 104 (see Figure 4), are collectively referred to simply as the "endoscopic puncture needle." A 2.5 mL syringe 103 containing the IP solution is attached to the end of the endoscopic puncture needle to be used, and the IP solution is slowly squeezed out to fill the entire endoscopic tube 104 (Figure 1B). At this time, care should be taken to prevent the IP solution from spilling from the tip of the puncture needle. After filling, the endoscopic tube 104 filled with the IP solution is gently placed on the processing table without pressing the syringe. This completes the preparation of the IP solution for administration. When administering IP solution to tumor tissue, syringe 103 is removed from the endoscope tube 104, syringe 102 filled with IP solution is attached to the tube, and the IP solution in syringe 102 is pushed in from the end (Figure 1C). This allows the IP solution filled in the endoscope tube 104 to be administered at a maximum dose of 1 mL (e.g., 0.2 ml x 5 doses). Since the IP solution to be administered into the tumor tissue is filled in the tube, the solution used to push it in is not limited to IP solution; for example, physiological saline can also be used. However, it is preferable to use IP solution as the pushing solution to reduce the risk of dilution of the IP solution administered into the tumor tissue.

[0016] 3. Method of administering IP solution to tumor tissue and method of treating tumors Next, we will describe the method of administering the IP solution to tumor tissue. In this specification, we will use type 2 esophageal cancer as an example. First, observe the entire cancerous area and determine the administration site. Figure 2 shows the locations for administering the IP solution to the tumor tissue 201 in the esophagus 10. The IP solution can be administered to at least five (e.g., 5-10) administration sites within the administration area, depending on the size, to ensure the solution covers the entire area. In Figure 2, the administration sites are indicated by black circles.

[0017] When administering the IP solution to tumor tissue, iodine staining should not be performed to prevent inactivation of the IP solution. Furthermore, if necessary, the tumor lesion should be observed, and the administration site should be determined using image-enhanced imaging (Figure 3). Figure 3 shows image enhancement of the administration area 301 in the esophagus 10 containing tumor tissue 201 using image-enhanced imaging.

[0018] Figure 4 shows the injection of IP solution into tumor tissue 201 from an endoscopic puncture needle 403. In Figure 4, the endoscope 401 is guided to the tumor tissue 201 in the esophagus 10. After the lesion is confirmed, the endoscopic puncture needle 403, to which the endoscopic tube 402 is connected, is inserted through the forceps channel, and the IP solution is injected sequentially from the caudal edge of the tumor toward the orthogonal edge, so that the IP solution, which is the drug solution, spreads throughout the entire tumor. This procedure is performed to prevent the injection site from becoming obscured by bleeding during administration. It is preferable to administer the IP solution to areas where cancer cells are actively dividing, and it is preferable to inject it towards the base of the tumor ridge or the edge of the tumor. It is also preferable to avoid administration to areas where necrosis may occur.

[0019] The IP solution is administered in a predetermined dose to at least five lesion sites (administration sites) in a balanced manner. When injecting the IP solution into the lesions, a 1 mL syringe is used, and the person administering the injection slowly injects the IP solution over approximately 5 seconds per site while checking the markings. In this invention, the amount of 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 administration is preferably 5 seconds or more per site, more preferably 5 seconds per site. In repeated administrations on days 18 and 32, it may become impossible to identify the cancer due to its shrinkage. In this case, the administration is performed at the same site as the administration site on day 1.

[0020] Next, we will explain the administration method for cases of esophageal stricture or superficial type. Figure 5 shows that the esophagus 10 has become narrowed by tumor tissue 201. If a normal endoscope cannot easily pass through due to the narrowing of the esophagus (Figure 5A), a transnasal endoscope should be used as needed, and 0.2 mL should be administered to at least five locations. In the case of superficial cancer or when the elevation of the cancer is minimal, the endoscope 401, endoscope tube 402, and endoscope puncture needle 403 should be positioned as horizontally as possible for intratumoral administration (Figures 5B, C). Furthermore, it is preferable to avoid submucosal injection of physiological saline to raise the elevation of the cancer, as this may dilute the drug.

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

[0022] Examples The present invention will be described in more detail below with reference to examples. However, the scope of the present invention is not limited to these examples. [Examples]

[0023] 1. Method A trial of OBP-301 (telomelysin) administration was conducted in esophageal cancer patients for whom standard treatments (surgical resection, chemotherapy) were not applicable.

[0024] The patient characteristics are shown in Table 1. [Table 1]

[0025] The dosage of OBP-301 was 1 × 10⁶ for Cohort 1. 11 VP / mL, and Cohort 2 is 1 × 10 12 The dose was set to VP / mL, and in each cohort, on day 1, 0.2 ml of telomelysin was administered to five affected areas of the thoracic esophagus using an endoscope under local anesthesia, for a total of 1 ml. Additional intratumoral administration of telomelysin was performed on days 18 and 32. In this example, radiation therapy of 2.0 Gy / day was administered five times a week (10 Gy per week) for six weeks starting from day 4 (total radiation dose: 60 Gy). The treatment period was 6 weeks, and the following evaluation items were assessed. (1) Primary endpoints: • Incidence of dose-limiting toxicity (DLT) • Rate of adverse events (2) Secondary evaluation items: • Tumor reduction effect (local treatment effect) of the treated lesion from the start of treatment to 18 weeks. • Tumor reduction effect from the start of treatment to week 18 (systemic treatment effect, Recist evaluation)

[0026] result The clinical course of case ID number 002 (Cohort 1) is shown in Figure 6 (esophageal photograph) and Figure 7 (CT image). Complete remission (CR) was achieved on day 71 after the start of treatment, and CR continued on day 127 (Figure 6). Furthermore, lymph node metastasis disappeared one year after treatment, and CR continued (Figure 7). The progress of case ID number 003 (Cohort 1) is shown in Figure 8 (esophageal photograph) and Figure 9 (CT image). In this case as well, complete response (CR) was confirmed on day 71 after the start of treatment (Figure 8), and the CR continued even on day 127 after the start of treatment (Figure 8). In addition, lymph node metastasis also 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 tumor tissue, comprising an oncolytic adenovirus, wherein the composition is administered using a flexible endoscope, with at least 1 mL of the oncolytic adenovirus-containing solution to at least 5 sites, at a rate of 0.1 mL or more per site. The oncolytic adenovirus is administered to the base of the tumor ridge and / or the periphery of the tumor tissue. The aforementioned composition.

2. A pharmaceutical composition for tumor treatment containing an oncolytic adenovirus, wherein the composition is administered by inserting a puncture needle for a flexible endoscope filled with a virus-containing solution into tumor tissue, and administering at least 1 mL of the oncolytic adenovirus-containing solution to at least 5 sites, at a rate of 0.1 mL or more per site. The oncolytic adenovirus is administered to the base of the tumor ridge and / or the periphery of the tumor tissue. The aforementioned 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 administered to the same lesion one or more times.

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), an E1A gene, an IRES sequence, and an E1B gene in that order is incorporated into its genome, or a virus (OBP-702) in which a polynucleotide containing an Egr-1 promoter and a p53 gene in that order is incorporated into the E3 region of OBP-301.

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