Method and device for administering oncolytic viruses to tumor tissue

Abstract

[Problem] To provide a method for administering a virus to tumor tissue using an endoscope. [Solution] A method for administering a virus to tumor tissue using an endoscope is characterized in that the virus is injected by inserting, into the tumor tissue, an endoscopic puncture needle filled with a virus-containing solution.

Description

[Technical field]

[0001] The present invention relates to a method for administering an oncolytic virus to tumor tissue using an endoscope, and to a method and device for treating tumors, the disclosures of all cited references being incorporated herein by reference in their entirety. [Background technology]

[0002] Oncolytic viruses have been proposed as a tool for new strategies in cancer treatment, and preclinical studies and clinical trials have explored their efficacy in clinical settings. Several viruses have been reported as oncolytic agents, including adenovirus, herpes virus, vesicular stomatitis virus, reovirus, vaccinia virus, and measles virus. And the antitumor ability of oncolytic adenovirus has been demonstrated in preclinical and clinical studies. OBP-301 is an oncolytic adenovirus that has been modified to selectively replicate genes in cancer cells by introducing the human telomerase reverse transcriptase (hTERT) promoter into its genome, and is expected to be useful in treating various types of cancer. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Fujiwara, T. et al. Curr Cancer Drug Targets, 7:191-201, 2007. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, there was a need to develop a tumor treatment method that would enhance the effect of OBP-301.In addition, there was a need for a method to administer oncolytic viruses without surgery, which would be less invasive for gastrointestinal cancer, especially gastrointestinal cancer that is distant from the esophagus. [Means for solving the problem]

[0005] As a result of intensive research into solving the above problems, the present inventors have succeeded in treating tumors by directly administering OBP-301 to tumor tissue under endoscopic control, thereby completing 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 endoscopic 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 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 in an amount of at least 0.1 mL per site in the tumor tissue. (6) The method according to (1) or (2), wherein the virus is administered for 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 ridge and / or the margin 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 additionally. (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, herpes virus and vesicular 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 an 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 described in (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 an hTERT promoter. (20) The device according to (16), wherein the oncolytic virus is OBP-301 or OBP-702. Effect of the Invention

[0007] INDUSTRIAL APPLICABILITY The present invention makes it possible to treat tumors by directly administering an oncolytic virus to tumor tissue under endoscopic control. [Brief description of the drawings]

[0008] [Figure 1] 1A to 1C are diagrams showing a method for filling an endoscope puncture needle with a medicinal liquid. [Diagram 2] FIG. 1 shows the administration site of OBP-301 into cancer tissue. [Diagram 3] FIG. 1 shows the administration site of OBP-301 into cancer tissue. [Figure 4] FIG. 1 shows a method for administering OBP-301 to cancer tissues. [Diagram 5] FIG. 1 shows a method for administering OBP-301 to cancer tissues. [Figure 6] FIG. 1 shows the progress of cases of esophageal cancer patients treated with OBP-301. [Figure 7] FIG. 1 shows the progress of cases of esophageal cancer patients treated with OBP-301. [Figure 8] FIG. 1 shows the progress of cases of esophageal cancer patients treated with OBP-301. [Figure 9] FIG. 1 shows the progress of cases of esophageal cancer patients treated with OBP-301. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention relates to a method for endoscopically administering a virus to a tumor tissue. In the present invention, the virus includes a replication-competent virus and a non-replication-competent virus. The replication-competent 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. 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) refers to a virus having a polynucleotide containing a human telomerase promoter (hTERT promoter), an E1A gene, an IRES sequence, and an E1B gene incorporated in the genome. The type of virus used in the present invention is not particularly limited, but adenovirus is preferred from the viewpoint of safety. Among adenoviruses, type 5 adenovirus is particularly preferred because it is easy to handle. The recombinant oncolytic adenovirus can be obtained by the method described in WO2004 / 005511. Alternatively, the recombinant oncolytic adenovirus OBP-301 can be obtained from Oncolys BioPharma Inc. under the name "Telomelysin" (registered trademark). In addition, OBP-702, in which a polynucleotide containing an Egr-1 promoter and a p53 gene in the above order is incorporated in the E3 region of OBP-301, can also be preferably used. OBP-702 is available from Oncolys BioPharma Inc.

[0011] The term "cancer" refers to a malignant tumor as understood in the art. For example, cancer has the property of uncontrolled growth in tissues that have the potential to spread (i.e., metastasize) to distant sites in the body. Examples of malignant tumors (cancers) to be administered include gastric cancer and gastroesophageal junction cancer, as well as 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 tissues via an endoscope every two weeks. For example, OBP-301 can be directly administered endoscopically into cancer tissues three times in total on days 1, 18, and 32 during a six-week radiation therapy period. For the sake of convenience, the following description will be given using OBP-301 as an example of the oncolytic virus used, but those skilled in the art will be able to easily apply the present invention to other viruses.

[0013] 1. Preparation of OBP-301 for Injection During transportation and storage, OBP-301 should be maintained at a temperature of -60°C or below. When OBP-301 is ready to be administered, remove the box from the refrigerator and remove the vial from the box. The cryopreserved OBP-301 solution (also called "IP solution") is then thawed at room temperature. The time to thaw the IP solution is approximately 10 minutes. Once thawed, the IP solution is stable for 4 hours. If necessary, the IP solution can be stored on ice prior to injection. The IP solution is at a concentration of 1 x 10 per vial. 12 The IP solution is filled to a concentration of VP / mL so that 2 mL can be withdrawn. Therefore, prepare the required amount of IP solution depending on the size of the lesion and the volume of the void that must be filled with IP solution.

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

[0015] The IP solution is filled into the endoscope puncture needle, specifically the endoscope tube 104 connected to the endoscope puncture needle, immediately before administration. In the present invention, for convenience of explanation, the endoscope puncture needle itself as well as the endoscope puncture needle 403 (see FIG. 4) connected to the endoscope tube 104 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 endoscope puncture needle to be used, and the IP solution is slowly pushed out to fill the entire endoscope tube 104 with the IP solution (FIG. 1B). At this time, care should be taken not to let the IP solution spill from the tip of the puncture needle. After filling, the endoscope 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 the IP solution to the tumor tissue, in order to administer the IP solution in the endoscope tube 104 into the tumor tissue, the syringe 103 is removed, the syringe 102 filled with the IP solution is attached to the tube, and the IP solution in the syringe 102 is pushed from the end (FIG. 1C). This allows the IP solution filled in the endoscope tube 104 to be administered at a maximum dose of 1 mL (for example, 0.2 mL x 5 administrations). Since the IP solution to be administered into the tumor tissue is filled in the tube, the solution to push it is not limited to the IP solution, and for example, physiological saline can also be used, but it is preferable to use the IP solution as the solution to be pushed in from the viewpoint of reducing the risk of diluting the IP solution administered into the tumor tissue.

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

[0017] When administering the IP solution to the tumor tissue, iodine staining is not performed to prevent inactivation of the IP solution. If necessary, the tumor lesion may be observed and the administration site may be determined using image-enhanced imaging (FIG. 3). FIG. 3 shows that an image of the administration area 301 in the esophagus 10 having tumor tissue 201 is enhanced by image-enhanced imaging.

[0018] FIG. 4 is a diagram showing the state of injecting IP solution from an endoscope puncture needle 403 into tumor tissue 201. In FIG. 4, an endoscope 401 is made to reach tumor tissue 201 in the esophagus 10. After a lesion is confirmed, an endoscope puncture needle 403 connected to an endoscope tube 402 is inserted from a forceps channel, and IP solution is injected from the tumor margin on the tail side toward the tumor margin on the mouth side so that the IP solution, which is a medicinal solution, spreads throughout the entire tumor. This operation is performed to prevent the administration site from becoming invisible due to bleeding during administration. The IP solution is preferably administered to a site where cancer cells are actively dividing, and is preferably injected toward the tumor rim base or tumor margin. In addition, it is preferable to avoid administration to a site where necrosis may occur.

[0019] The IP liquid is administered to at least five lesion sites (administration sites) in a balanced manner at a predetermined dose per site. When injecting the IP liquid into the lesion site, a 1 mL syringe is used, and the person in charge of injection slowly injects the IP liquid for about 5 seconds per site while checking the scale. In the present invention, the amount of IP liquid is preferably 0.1 mL or more, more preferably 0.15 mL or more, and particularly preferably 0.2 mL or more. Although the administration time is not limited, administration is preferably 5 seconds or more per site, more preferably 5 seconds per site. Repeated administration on the 18th and 32nd days may make it impossible to identify the cancer due to its shrinkage. In this case, administration is performed at the same site as the administration site on the 1st 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 been narrowed by tumor tissue 201. When a normal endoscope is difficult to pass due to the narrowing of the esophagus (FIG. 5A), a transnasal endoscope is used as necessary, and 0.2 mL is administered to five or more locations as a rule. In the case of superficial cancer or when the cancer is not highly elevated, the endoscope 401, the endoscope tube 402, and the endoscope puncture needle 403 are placed as horizontally as possible for intratumoral administration (FIGS. 5B and 5C). In addition, it is preferable not to inject saline submucosally to elevate the cancer, as this may dilute the drug.

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

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

[0023] 1. Method We conducted an administration test of OBP-301 (telomelysin) in patients with esophageal cancer for whom standard treatment (surgical resection, chemotherapy) was difficult to apply.

[0024] Patient demographics are shown in Table 1. [Table 1]

[0025] The dose of OBP-301 in cohort 1 was 1 × 10 11 VP / mL, and 1 × 10 for cohort 2 12 VP / mL, and in each cohort, 0.2 ml of telomelysin was administered to the affected area of ​​the thoracic esophagus using an endoscope under local anesthesia on the first day, for a total of 1 ml at five locations, and additional intratumoral administration of telomelysin was performed on the 18th and 32nd days. In this example, radiation was administered at 2.0 Gy / day, five times a week (10 Gy per week) from the 4th day for six weeks (total radiation dose: 60 Gy). The treatment period was 6 weeks, and the following evaluation items were performed. (1) Primary endpoint: Incidence of dose-limiting toxicities (DLT) Adverse event incidence (2) Secondary endpoints: - Tumor shrinkage of the target lesion from the start of treatment to 18 weeks (local treatment effect) Tumor shrinkage effect from the start of treatment to 18 weeks (systemic treatment effect, Recist evaluation)

[0026] result The progress of the case with ID number 002 (cohort 1) is shown in Figure 6 (esophageal photograph) and Figure 7 (CT photograph). Complete remission (CR) was achieved 71 days after the start of treatment, and CR was still continuing 127 days after the start of treatment (Figure 6). In addition, one year after treatment, lymph node metastasis had disappeared, and CR was still continuing (Figure 7). The progress of case ID number 003 (cohort 1) is shown in Figure 8 (esophageal photograph) and Figure 9 (CT photograph). In this case, CR was confirmed 71 days after the start of treatment (Figure 8), and CR was still continuing 127 days after the start of treatment (Figure 8). In addition, lymph node metastasis had also shrunk 3 months after treatment (Figure 9). [Explanation of symbols]

[0027] 10:Esophagus 101: vial, 102: 1mL syringe, 103: 2.5mL 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, the composition being administered using a flexible endoscope to at least five sites, with at least 1 mL of oncolytic adenovirus-containing solution administered at a volume of at least 0.1 mL per site; The oncolytic adenovirus is administered to the base of the tumor ridge and / or the periphery of the tumor tissue for at least 5 seconds per site in the tumor tissue. The composition.

2. A pharmaceutical composition for tumor treatment comprising an oncolytic adenovirus, the composition being 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 five sites in an amount of at least 0.1 mL per site; The oncolytic adenovirus is administered to the base of the tumor ridge and / or the periphery of the tumor tissue for at least 5 seconds per site in the tumor tissue. The 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 described in claim 1 or 2, wherein the oncolytic adenovirus is administered to the same lesion one or more additional times.

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

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

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