Application of oncolytic virus in combination with chemotherapy and anti-PD-1 antibody to inhibition of liver metastasis of gastric cancer

Abstract

The invention discloses an application of combination of oncolytic virus, chemotherapeutic drug and anti-PD-1 monoclonal antibody in treatment of gastric cancer liver metastasis. Specifically, the invention provides an application of an active component combination, the active component combination comprises a recombinant human type 5 adenovirus, a chemotherapeutic drug and an optional anti-PD-1 monoclonal antibody, and the active component combination is used for preparing a pharmaceutical composition for synergistically treating gastric cancer liver metastasis. Clinical experiments prove that the active component composition disclosed by the invention can effectively and synergistically inhibit liver metastasis of gastric cancer.

Description

Technical Field

[0001] The present invention relates to the technical field of anti-tumor drugs, and specifically to the use of oncolytic viruses, chemotherapy drugs and anti-PD-1 monoclonal antibodies in the synergistic inhibition of gastric cancer liver metastasis and related drugs. Background Art

[0002] Over the past decade, due to advances in diagnosis and treatment technology, the annual mortality rate of gastric cancer in my country has dropped from 3.8% to 2.3%. For patients with advanced gastric cancer, the tumor cannot be removed due to infiltration into adjacent organs, peritoneal metastasis, liver metastasis, positive free cancer cells in the abdominal cavity, or other distant metastasis. After the failure of first-line treatment for gastric cancer, especially for those with primary drug resistance, follow-up treatment options are very limited.

[0003] At present, clinical research on new drugs for the second and third-line treatment of gastric cancer focuses on new anti-HER2 drugs, anti-angiogenesis or multi-target tyrosine kinase inhibitors (TKI) alone or in combination with chemotherapy, monoclonal antibodies or dual antibodies targeting targets other than HER2 such as Claudin18.2, different immune checkpoint antagonists, and combination regimens of the above drugs, etc. In particular, there are no clear treatment guidelines for the treatment of gastric cancer liver metastasis. Summary of the invention

[0004] The purpose of the present invention is to provide an active ingredient combination comprising an oncolytic virus, a chemotherapeutic drug and an anti-PD-1 monoclonal antibody for use in the treatment of gastric cancer liver metastasis, as well as a drug comprising the active ingredient combination.

[0005] The first aspect of the present invention provides a use of an active ingredient combination, the active ingredient combination comprising:

[0006] The first active ingredient is oncolytic virus, the second active ingredient is chemotherapeutic drug, and the optional third active ingredient is anti-PD-1 monoclonal antibody, and the combination is used to prepare a pharmaceutical composition or a drug kit for the synergistic treatment of gastric cancer liver metastasis.

[0007] In another preferred embodiment, the oncolytic virus refers to a recombinant human adenovirus type 5 or a derivative having the same function, preferably, a recombinant human adenovirus type 5.

[0008] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0009] In another preferred embodiment, in the genome of the oncolytic virus, the E1B-55kDa and E3 region gene fragments of human adenovirus type 5 are deleted.

[0010] In another preferred embodiment, the chemotherapy drug is selected from the following group: oxaliplatin, S-1, irinotecan, calcium folinate, 5-fluorouracil or a combination thereof.

[0011] In another preferred embodiment, the second active ingredient is a chemotherapy drug combination comprising irinotecan, calcium folinate and 5-fluorouracil.

[0012] In another preferred embodiment, the second active ingredient is a chemotherapy drug combination comprising oxaliplatin and S-1.

[0013] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: sintilimab, carrelizumab, tilelizumab, toripalimab, nivolumab, pembrolizumab or a combination thereof.

[0014] In another preferred embodiment, the third active ingredient is sintilimab.

[0015] In another preferred embodiment, the oncolytic virus is administered at a rate of 0.5×10 12 VP to 2.5×10 12 VP is administered at a dose of 1 to 20 mg / kg, preferably 2 to 15 mg / kg, and more preferably 3 to 10 mg / kg.

[0016] The second aspect of the present invention provides a combination of active ingredients, which comprises an oncolytic virus, a chemotherapeutic drug and an optional anti-PD-1 monoclonal antibody.

[0017] In another preferred embodiment, the active ingredient combination consists of oncolytic virus, chemotherapy drug and anti-PD-1 monoclonal antibody.

[0018] In another preferred embodiment, the active ingredient combination consists of oncolytic viruses and chemotherapeutic drugs.

[0019] In another preferred embodiment, the oncolytic virus refers to a recombinant human adenovirus type 5 or a derivative having the same function, preferably, a recombinant human adenovirus type 5.

[0020] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0021] In another preferred embodiment, in the genome of the oncolytic virus, the E1B-55kDa and E3 region gene fragments of human adenovirus type 5 are deleted.

[0022] In another preferred embodiment, the chemotherapy drug is selected from the following group: oxaliplatin, S-1, irinotecan, calcium folinate, 5-fluorouracil or a combination thereof.

[0023] In another preferred embodiment, the chemotherapy drug is a combination of irinotecan, calcium folinate and 5-fluorouracil.

[0024] In another preferred embodiment, the chemotherapy drug is a combination of oxaliplatin and S-1.

[0025] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: sintilimab, carrelizumab, tilelizumab, toripalimab, nivolumab, pembrolizumab or a combination thereof.

[0026] In another preferred embodiment, the active ingredient combination consists of recombinant human adenovirus type 5, sintilimab, and chemotherapy drugs, and the chemotherapy drugs are a combination of oxaliplatin and S-1.

[0027] In another preferred embodiment, the active ingredient combination consists of recombinant human adenovirus type 5 and chemotherapy drugs, and the chemotherapy drugs are a combination of irinotecan, calcium folinate, and 5-fluorouracil.

[0028] In another preferred embodiment, the active ingredient combination is used to prepare a pharmaceutical composition or a drug kit for synergistically treating gastric cancer liver metastasis.

[0029] In a third aspect of the present invention, a pharmaceutical composition for treating gastric cancer liver metastasis is provided, wherein the pharmaceutical composition comprises (a) an oncolytic virus, (b) a chemotherapeutic drug, (c) an anti-PD-1 monoclonal antibody and (d) a pharmaceutically acceptable carrier.

[0030] In another preferred embodiment, the oncolytic virus refers to a recombinant human adenovirus type 5 or a derivative having the same function, preferably, a recombinant human adenovirus type 5.

[0031] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0032] In another preferred embodiment, in the genome of the oncolytic virus, the E1B-55kDa and E3 region gene fragments of human adenovirus type 5 are deleted.

[0033] In another preferred embodiment, the chemotherapy drug is selected from the following group: oxaliplatin, S-1, irinotecan, calcium folinate, 5-fluorouracil or a combination thereof.

[0034] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: sintilimab, carrelizumab, tilelizumab, toripalimab, nivolumab, pembrolizumab or a combination thereof.

[0035] A fourth aspect of the present invention provides a medicine kit, comprising:

[0036] (a) a first preparation, wherein the first preparation contains an oncolytic virus and a pharmaceutically acceptable carrier;

[0037] (b) a second preparation, the second preparation comprising a chemotherapeutic drug and a pharmaceutically acceptable carrier;

[0038] (c) a third preparation, comprising an anti-PD-1 monoclonal antibody and a pharmaceutically acceptable carrier; and

[0039] (d) instructions, which describe a method for treating gastric cancer liver metastasis by combining oncolytic virus, chemotherapy drug and anti-PD-1 monoclonal antibody.

[0040] In another preferred embodiment, the first preparation, the second preparation and the third preparation are independent of each other.

[0041] In another preferred embodiment, the first preparation, the second preparation and the third preparation are freeze-dried preparations or liquid preparations.

[0042] In another preferred embodiment, the first preparation, the second preparation, and the third preparation are injections.

[0043] In another preferred embodiment, the first preparation is administered before the second preparation and the third preparation.

[0044] In another preferred embodiment, the second preparation and the third preparation are administered simultaneously.

[0045] In another preferred embodiment, the second preparation is administered before the third preparation.

[0046] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0047] In another preferred embodiment, in the genome of the oncolytic virus, the E1B-55kDa and E3 region gene fragments of human adenovirus type 5 are deleted.

[0048] In another preferred embodiment, the chemotherapy drug is selected from the following group: oxaliplatin, S-1, irinotecan, calcium folinate, 5-fluorouracil or a combination thereof.

[0049] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: sintilimab, carrelizumab, tilelizumab, toripalimab, nivolumab, pembrolizumab or a combination thereof.

[0050] The fifth aspect of the present invention provides a method for treating liver metastasis of gastric cancer, which comprises administering a therapeutically effective amount of the active ingredient combination as described in the second aspect of the present invention and / or the pharmaceutical composition as described in the third aspect of the present invention to a subject in need, thereby treating liver metastasis of gastric cancer.

[0051] In another preferred embodiment, the subject in need is a human or a non-human mammal.

[0052] In another preferred embodiment, the non-human mammals include monkeys, gorillas, cows, pigs, dogs, sheep, rabbits or mice.

[0053] In another preferred embodiment, the subject in need thereof suffers from gastric cancer.

[0054] In another preferred embodiment, the subject in need thereof suffers from gastric cancer with liver metastasis.

[0055] In another preferred embodiment, in the active ingredient combination or pharmaceutical composition, the oncolytic virus is administered by intratumoral injection; the chemotherapy drug can be administered by intravenous injection, intraperitoneal injection, intravenous infusion or oral administration; and the anti-PD-1 monoclonal antibody can be administered by intravenous injection.

[0056] In another preferred embodiment, the method further comprises administering supportive therapeutic drugs for treating tumors to a subject in need thereof.

[0057] In another preferred embodiment, the supportive treatment drugs include: antibiotics, analgesics, nutritional drugs or a combination thereof.

[0058] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 Shown is the comparison of tumor volume of gastric cancer liver metastasis in clinical case 1 before and after treatment.

[0060] Figure 2 Shown is the comparison of tumor volume of gastric cancer liver metastasis in clinical case 2 before and after treatment. DETAILED DESCRIPTION

[0061] After extensive and in-depth research, the inventor unexpectedly discovered for the first time that when a specific recombinant human adenovirus type 5 (Ankorui) is used in combination with a chemotherapeutic drug, or a chemotherapeutic drug and an anti-PD-1 monoclonal antibody, it has a synergistic therapeutic effect in inhibiting gastric cancer liver metastasis. Clinical experiments have shown that the combined use of recombinant human adenovirus type 5 with chemotherapeutic drugs and anti-PD-1 monoclonal antibodies can effectively inhibit the growth of gastric cancer liver metastasis tumors. On this basis, the present invention was completed.

[0062] the term

[0063] As used herein, the term "first active ingredient" refers to recombinant human adenovirus type 5, or oncolytic virus. It should be understood that the term includes derivatives having the same function as recombinant human adenovirus type 5. In a preferred embodiment of the present invention, the "first active ingredient" is a recombinant human adenovirus type 5 injection with the trade name of Ankorui.

[0064] As used herein, the term "second active ingredient" refers to a chemotherapeutic drug. The chemotherapeutic drug is selected from the group consisting of oxaliplatin, S-1, irinotecan, folinic acid, 5-fluorouracil, or a combination thereof. In a preferred embodiment of the present invention, the "second active ingredient" refers to a chemotherapeutic drug combination comprising irinotecan, folinic acid, and fluorouracil (i.e., FOLFIRI). In another preferred embodiment of the present invention, the "second active ingredient" refers to a chemotherapeutic drug combination comprising oxaliplatin (Aihen or Eloxatin) and S-1 (i.e., SOX).

[0065] As used herein, the term "third active ingredient" refers to an anti-PD-1 monoclonal antibody. The anti-PD-1 monoclonal antibody is selected from the group consisting of sintilimab, carrelizumab, tislelizumab, toripalimab, nivolumab, pembrolizumab, or a combination thereof. In a preferred embodiment of the present invention, the "third active ingredient" is sintilimab.

[0066] As used herein, the terms "active ingredient combination of the present invention", "substance combination of the present invention" and "pharmaceutical ingredient combination of the present invention" are used interchangeably to refer to the combination of the above-mentioned first active ingredient, second active ingredient and third active ingredient.

[0067] As used herein, the term "pharmaceutical composition of the present invention" refers to a composition comprising or containing a first active ingredient (or a first preparation containing the first active ingredient), a second active ingredient (or a second preparation containing the second active ingredient), and a third active ingredient (or a third preparation containing the third active ingredient). In the present invention, the first preparation, the second preparation, and the third preparation may be the same or different preparations. In addition, the first preparation, the second preparation, and the third preparation may be the same preparation, or each independent preparation.

[0068] Oncolytic virus of the present invention

[0069] The active ingredient combination of the present invention includes a first active ingredient oncolytic virus, and the oncolytic virus is preferably a recombinant human adenovirus type 5. The recombinant human adenovirus type 5 injection used in the present invention, with a trade name of Ankorui, is the first oncolytic virus therapeutic drug approved by the Food and Drug Administration in China and launched in 2006. It is an oncolytic adenovirus obtained by genetically recombining human adenovirus type 5 (Ad5) using genetic engineering technology, mainly deleting the E1B-55kDa (i.e., 55kD in the E1B region of adenovirus type 5, encoded by the E1B-55k gene) and E3 region gene fragments of human adenovirus type 5, and has the characteristics of specific replication in tumor cells and ultimately leading to oncolysis.

[0070] The oncolytic mechanism of oncolytic viruses is constantly updated with the progress of tumor immunity research. It was previously believed that because some viruses are naturally tropistic for tumors, they can selectively infect tumor cells and lyse tumor cells to kill the tumor. As the research continues to deepen, it has been found that oncolytic viruses not only have the ability to directly lyse tumors, but also can improve the tumor microenvironment in an immunosuppressive state, turning "cold" tumors into "hot" tumors, thereby activating innate immunity and adaptive immunity, so that the body's immune system that was originally evaded by the tumor is mobilized to attack the tumor.

[0071] Adenovirus is a type of pathogen that has been studied in depth. Since the 1960s, adenovirus has been used as a gene expression vector and has been widely used in the field of molecular biology. It is the most commonly used viral vector for gene therapy. Adenovirus vectors have many characteristics that other vectors do not have. Various types of adenovirus vectors have been successfully constructed and applied in engineering.

[0072] Adenovirus is a DNA virus without an envelope. It is composed of 252 capsomers arranged in an icosahedral pattern and is a particle of 70 to 90 nm. The capsid contains a linear double-stranded DNA molecule with an inverted repeat sequence of about 100 bp at each end. Since the 5' end of each DNA chain has a relative molecular mass of 55×10 3 The protein molecules of Da are covalently bound to form a circular structure of double-stranded DNA.

[0073] The adenovirus E3 region gene is an early transcription unit of the adenovirus genome. Its promoter is activated by the E1A protein and then transcribed into protein. The E3 protein mainly destroys the host's immune defense mechanism, protecting the adenovirus from attack by the immune system in the host.

[0074] The recombinant human adenovirus type 5 used in the present invention has been modified, and after the E3 region gene is deleted, it only has the ability to replicate in the host cell without damaging the host's immune system.

[0075] The chemotherapeutic drug of the present invention

[0076] The active ingredient combination of the present invention further comprises a second active ingredient, a chemotherapeutic drug, which includes (but is not limited to): oxaliplatin, S-1, irinotecan, calcium folinate, and 5-fluorouracil.

[0077] In a preferred embodiment of the present invention, the chemotherapy drug is SOX regimen: oxaliplatin (130 mg / m 2 )d1+ S-1 (40 mg / m 2 )bid d1-14 q3w;.

[0078] In another preferred embodiment of the present invention, the chemotherapy drug is the FOLFIRI regimen: irinotecan (180 mg / m 2 )d1+calcium folinate (400mg / m 2 )d1+5-fluorouracil (400mg / m 2 )d1+5-fluorouracil (2400mg / m 2 )civ 46h(Q2w).

[0079] Anti-PD-1 monoclonal antibody of the present invention

[0080] The active ingredient combination of the present invention may further include a third active ingredient, an anti-PD-1 monoclonal antibody, which is selected from the group consisting of sintilimab, carrelizumab, tislelizumab, toripalimab, nivolumab, pembrolizumab or a combination thereof. In a preferred embodiment of the present invention, the anti-PD-1 monoclonal antibody is sintilimab.

[0081] Pharmaceutical composition and administration method

[0082] The present invention also provides a composition which can be used for the synergistic treatment of gastric cancer liver metastasis.

[0083] The pharmaceutical composition of the present invention comprises: an effective amount of recombinant human adenovirus type 5, an effective amount of a chemotherapeutic drug, an optional effective amount of an anti-PD-1 monoclonal antibody, and a pharmaceutically acceptable carrier.

[0084] Typically, the recombinant human adenovirus type 5, or chemotherapeutic drug, or anti-PD-1 monoclonal antibody of the present invention can be formulated in a non-toxic, inert and pharmaceutically acceptable carrier medium, wherein the pH is generally about 5-8, preferably, about 6-8.

[0085] As used herein, "pharmaceutically acceptable carrier" refers to a carrier used for administration of therapeutic agents, including various excipients and diluents.

[0086] The term refers to pharmaceutical carriers that are not essential active ingredients and are not overly toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers in the composition may contain liquids such as water, saline, buffer. In addition, auxiliary substances such as fillers, lubricants, glidants, wetting agents or emulsifiers, pH buffer substances, etc. may also be present in these carriers. The carriers may also contain cell transfection reagents.

[0087] As used herein, the term "effective amount" or "effective dose" refers to an amount that can produce a function or activity on humans and / or animals and / or cells and can be accepted by humans and / or animals.

[0088] As used herein, "pharmaceutically acceptable" ingredients are suitable for use in humans and / or mammals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, substances with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable carrier" refers to a carrier used for the administration of therapeutic agents, including various excipients and diluents. Such carriers include (but are not limited to): saline, buffer, glucose, water, glycerol, polysorbate, ethanol, and combinations thereof. Generally, the pharmaceutical preparation should match the mode of administration. The pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants. The pharmaceutical composition is preferably manufactured under sterile conditions. The amount of active ingredient administered is a therapeutically effective amount. The pharmaceutical preparation of the present invention can also be prepared as a sustained-release preparation.

[0089] Furthermore, the active ingredient combination of the present invention may also be used together with other therapeutic agents (such as anti-tumor agents or chemotherapeutic agents).

[0090] When using a pharmaceutical composition, a safe and effective amount of a combination of active ingredients (including a first active ingredient (or its preparation), a second active ingredient (or its preparation) and a third active ingredient (or its preparation)) is administered to a mammal.

[0091] It should be understood that the effective amount of the first active ingredient (or its preparation) and / or the second active ingredient (or its preparation) and / or the third active ingredient (or its preparation) in the active ingredient combination of the present invention may vary with the mode of administration and the severity of the tumor. The selection of the preferred effective amount can be determined by a person of ordinary skill in the art based on various factors (e.g., through clinical trials). The factors include, but are not limited to: pharmacokinetic parameters such as bioavailability, metabolism, half-life, etc.; the severity of the tumor, the patient's weight, the patient's immune status, the route of administration, etc.

[0092] Typically, for the first active ingredient, the therapeutically effective amount is usually at least 0.5×10 12 VP to 2.5×10 12 VP, of course, the specific dose should also take into account factors such as tumor volume and patient health status, which are all within the skills of a skilled physician.

[0093] For the third active ingredient, its safe and effective amount is usually at least about 1 mg / kg body weight, and in most cases does not exceed about 20 mg / kg body weight, preferably the dose is about 2 mg / kg body weight to 10 mg / kg body weight. Of course, the specific dose should also take into account factors such as the type of drug used, dosage form, route of administration, and patient health status, which are all within the skill range of skilled physicians.

[0094] There is no particular limitation on the administration method of the pharmaceutical composition of the present invention. Representative examples include (but are not limited to): intratumor injection, intraperitoneal injection, intravenous injection, intravenous infusion, and oral administration.

[0095] Pill Box

[0096] The present invention provides a medicine box, comprising:

[0097] Component (1): a preparation containing recombinant human adenovirus type 5;

[0098] Component (2): a preparation containing a chemotherapeutic agent;

[0099] Component (3): a preparation containing an anti-PD-1 monoclonal antibody; and

[0100] Component (4): instructions.

[0101] The preparation containing recombinant human adenovirus type 5 includes (but is not limited to): a lyophilized preparation, a liquid preparation or an injection.

[0102] The preparation containing the chemotherapy drug includes (but is not limited to): a lyophilized preparation, a liquid preparation, or an injection.

[0103] The preparation containing anti-PD-1 monoclonal antibody includes (but is not limited to): lyophilized preparation, liquid preparation, or injection.

[0104] Typically, the kit contains one or more (such as at least two) unit dosage forms containing recombinant human adenovirus type 5 and one or more (such as at least two) unit dosage forms containing chemotherapeutic drugs, and one or more (such as at least two) unit dosage forms containing anti-PD-1 monoclonal antibodies; preferably 4-10 of each.

[0105] As used herein, the term "unit dosage form" means that for the convenience of administration, a composition is prepared into a dosage form required for a single administration, including but not limited to various solid doses (such as tablets), liquid doses, capsules, and sustained-release preparations.

[0106] In the present invention, the unit dosage form of the recombinant human adenovirus type 5 is usually a liquid dosage form.

[0107] The instructions provided by the present invention may include the following description: the method of using the drug kit is to simultaneously use a unit dosage form containing a recombinant human adenovirus type 5, a unit dosage form containing a chemotherapy drug, and a unit dosage form containing an anti-PD-1 monoclonal antibody.

[0108] The instructions provided by the present invention may include the following description: the method of using the drug kit is to simultaneously use a unit dosage form containing a recombinant human adenovirus type 5 and a unit dosage form containing a chemotherapeutic drug, and optionally use a unit dosage form containing an anti-PD-1 monoclonal antibody.

[0109] The medicine kit provided by the present invention is prepared by the following steps: placing a preparation containing recombinant human adenovirus type 5, a preparation containing a chemotherapy drug, and a preparation containing an anti-PD-1 monoclonal antibody and instructions together to form a medicine kit.

[0110] The preparation containing recombinant human adenovirus type 5 preferably contains a unit dosage form of recombinant human adenovirus type 5, the preparation containing chemotherapy drugs preferably contains a unit dosage form of chemotherapy drugs, and the preparation containing anti-PD-1 monoclonal antibody preferably contains a unit dosage form of anti-PD-1 monoclonal antibody.

[0111] The step preferably comprises placing at least one unit dosage form containing a recombinant human adenovirus type 5, at least one unit dosage form containing a chemotherapy drug, and at least one unit dosage form containing an anti-PD-1 monoclonal antibody, as well as instructions, together to form a medicine box.

[0112] The main advantages of the present invention include:

[0113] The combination of recombinant human adenovirus type 5, chemotherapy drugs and anti-PD-1 monoclonal antibodies can synergistically and more efficiently inhibit gastric cancer liver metastasis.

[0114] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art. Unless otherwise specified, the materials and reagents used in the embodiments of the present invention are all commercially available products. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions, such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989) The conditions described, or according to the conditions recommended by the manufacturer.

[0115] Unless otherwise indicated, percentages and parts are by weight.

[0116] The efficacy evaluation criteria of the present invention are:

[0117]

[0118]

[0119] Example 1

[0120] Clinical trial of case 1

[0121] (1) Case introduction:

[0122] Diagnosis: Gastric malignancy (poorly differentiated adenocarcinoma pT4N2M1 stage IV)

[0123] Medical history before treatment / treatment history: Laparoscopic-assisted total gastrectomy with esophagojejunostomy, laparoscopic abdominal lymph node dissection, laparoscopic omental adhesion lysis under general anesthesia on May 21, 2021. Postoperative pathology: infiltrative ulcerative type, tumor size: 6*4*1 cm. Histological type: tubular adenocarcinoma, moderately poorly differentiated, infiltrating into extraserosa fibrofatty tissue, intravascular cancer thrombus.

[0124] Baseline liver MR examination before treatment: liver metastases in S8 and S7 segments.

[0125] Physical examination before treatment: clear consciousness, spirit, flat abdomen, no exposed abdominal wall veins, abdominal breathing, no gastrointestinal peristaltic waves, no intestinal type. Palpation: soft abdominal muscles, no tenderness, no rebound pain, liver and spleen are not palpable under the ribs, Murphys' (-). Percussion: no mobile dullness, no percussion pain in the kidney area, no percussion pain in the liver area. Auscultation: normal bowel sounds, 4 times / min.

[0126] Reason for inclusion: The patient met the inclusion criteria of the project "Clinical study on the efficacy and safety of (Ancore) recombinant human adenovirus type 5 injection combined with standard treatment for liver metastasis of gastrointestinal malignancies". After communication with the patient, the patient signed the informed consent form for inclusion.

[0127] (2) Treatment options

[0128] First cycle (starting from 2021-06-30): SOX scheme;

[0129] The second cycle (2021-07-29) and the third cycle (2021-08-26): Ankorui 1ml + Sintilimab + SOX regimen.

[0130]

[0131]

[0132] (3) Treatment effect

[0133] The target lesion volume before and after treatment was reduced from 17.7 mm ( Figure 1 Left) is reduced to 9.1mm ( Figure 1 Right), imaging examination showed that the tumor was reduced and the efficacy was evaluated as PR (partial response).

[0134] Adverse reaction description: None

[0135] Example 2

[0136] Clinical trial of case 2

[0137] (1) Case presentation Diagnosis: Gastric malignancy (adenocarcinoma rT0N0M0 stage IV liver)

[0138] Medical history and treatment history before treatment: In June 2020, the patient's abdominal distension symptoms worsened compared with before. Gastroscopy was performed: an ulcer was seen in the gastric angle, which was eroded, pale, dirty, and vertically infiltrated into the gastric body. On June 17, 2020, laparoscopic radical gastrectomy (RY anastomosis) was performed, and pathology showed: tubular adenocarcinoma (lesser curvature of gastric body and gastric antrum), moderately differentiated, ulcerative type.

[0139] Baseline examination before treatment: Upper abdominal CT scan on September 29, 2020: 1. Postoperative changes of gastric tumor; multiple metastatic tumors in the liver are possible, combined with clinical follow-up reexamination. 2. Small nodule in the left adrenal gland, combined with clinical follow-up. 3. Multiple cysts in the liver and both kidneys.

[0140] Physical examination before treatment: clear mind, calm breath, pupils of equal size and round, light reflex, no superficial lymph node enlargement, clear breath sounds in both lungs, no rales. Heart (-), flat abdomen, old surgical scars can be seen, no gastrointestinal pattern and peristaltic waves, soft abdomen, no masses, no tenderness and rebound pain, liver and spleen are not below the ribs. No percussion pain in the kidney area, normal bowel sounds, negative shifting dullness. NS (-).

[0141] Reason for inclusion: The patient met the inclusion criteria of the project "Clinical study on the efficacy and safety of (Ancore) recombinant human adenovirus type 5 injection combined with standard treatment for liver metastasis of gastrointestinal malignancies". After communication with the patient, the patient signed the informed consent form for inclusion.

[0142] (2) Treatment options

[0143] The first cycle (2020.10.12), the second cycle (2020.10.28): Ankorui (1ml) + FOLFIRI regimen.

[0144]

[0145] (3) Treatment effect

[0146] The target lesion volume before and after treatment was reduced from 30.8 mm ( Figure 2 Left) is reduced to 29.6mm ( Figure 2 Right), imaging examination showed that the tumor had shrunk, and the efficacy was evaluated as SD (stable disease).

[0147] Adverse reaction description: None

[0148] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. Use of an active ingredient combination, characterized in that: The active ingredient combination includes: The first active ingredient is oncolytic virus, the second active ingredient is chemotherapeutic drug, and the optional third active ingredient is anti-PD-1 monoclonal antibody, and the combination is used to prepare a pharmaceutical composition or a drug kit for the synergistic treatment of gastric cancer liver metastasis.

2. The use according to claim 1, characterized in that The oncolytic virus refers to a recombinant human adenovirus type 5 or a derivative having the same function, preferably, a recombinant human adenovirus type 5.

3. The use according to claim 1, characterized in that In the genome of the oncolytic virus, the E1B-55kDa and E3 region gene fragments of human adenovirus type 5 are deleted.

4. The use according to claim 1, characterized in that The chemotherapy drug is selected from the following group: oxaliplatin, S-1, irinotecan, folinic acid, 5-fluorouracil or a combination thereof.

5. The use according to claim 1, characterized in that The anti-PD-1 monoclonal antibody is selected from the following group: sintilimab, carrelizumab, tilelizumab, toripalimab, nivolumab, pembrolizumab or a combination thereof.

6. An active ingredient combination, characterized in that The combination comprises an oncolytic virus, a chemotherapeutic drug and optionally an anti-PD-1 monoclonal antibody.

7. The active ingredient combination according to claim 6, characterized in that The active ingredient combination consists of oncolytic virus, chemotherapy drug and anti-PD-1 monoclonal antibody.

8. A pharmaceutical composition for treating gastric cancer liver metastasis, characterized in that: The pharmaceutical composition comprises (a) an oncolytic virus, (b) a chemotherapeutic drug, (c) an anti-PD-1 monoclonal antibody and (d) a pharmaceutically acceptable carrier.

9. A medicine box, comprising: (a) a first preparation, wherein the first preparation contains an oncolytic virus and a pharmaceutically acceptable carrier; (b) a second preparation, the second preparation comprising a chemotherapeutic drug and a pharmaceutically acceptable carrier; (c) a third preparation, comprising an anti-PD-1 monoclonal antibody and a pharmaceutically acceptable carrier; and (d) instructions, which describe a method for treating gastric cancer liver metastasis by combining oncolytic virus, chemotherapy drug and anti-PD-1 monoclonal antibody.

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