Application of oncolytic virus and anti-PD-1 monoclonal antibody in combined inhibition of liver metastasis of lung cancer

Abstract

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

Description

Technical Field

[0001] The present invention relates to the technical field of anti-tumor drugs, and specifically to the application of oncolytic virus and anti-PD-1 monoclonal antibody in the combined inhibition of liver metastasis of lung cancer and related drugs. Background Art

[0002] The International Association for the Study of Lung Cancer (IASLC) developed the eighth edition of the TNM staging for lung cancer in 2015. The U.S. Medicare Surveillance, Epidemiology, and End Results database shows that about 57% of lung cancer patients have already developed distant metastases at the time of initial diagnosis, among which the liver is a common metastatic site of lung cancer, and about 30% of lung cancer patients will have liver metastases. At present, the treatment of liver metastases of lung cancer mainly focuses on the early diagnosis and examination of liver metastases, and effective treatment options are still needed. In the context of the PD-1 antibody immunotherapy era, most patients still cannot achieve long-term survival, so finding a combined treatment plan to turn "cold tumors" into "hot tumors" and improve the efficacy of immunotherapy is receiving more and more attention. Summary of the invention

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

[0005] The first aspect of the present invention provides a use of an active ingredient combination, wherein the active ingredient combination comprises a first active ingredient oncolytic virus and a second active ingredient anti-PD-1 monoclonal antibody, and the combination is used to prepare a pharmaceutical composition or a medicine kit for the synergistic treatment of liver metastasis of lung cancer.

[0006] 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.

[0007] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0008] 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.

[0009] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: toripalimab (Toyi), durvalumab (Invitrogen), atezolizumab (Tai Shengqi), nivolumab (Opdivo), carrelizumab (Erica), sintilimab (Tyvyt), tilelizumab (Beisel), or a combination thereof.

[0010] In another preferred embodiment, the anti-PD-1 monoclonal antibody is Teplizumab (Toyi).

[0011] 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.

[0012] In a second aspect of the present invention, a pharmaceutical composition for treating liver metastasis of lung cancer is provided, wherein the pharmaceutical composition comprises (a) an oncolytic virus, (b) an anti-PD-1 monoclonal antibody and (c) a pharmaceutically acceptable carrier.

[0013] 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.

[0014] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0015] 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.

[0016] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: toripalimab (Toyi), durvalumab (Invitrogen), atezolizumab (Tai Shengqi), nivolumab (Opdivo), carrelizumab (Erica), sintilimab (Tyvyt), tilelizumab (Beisel), or a combination thereof.

[0017] In another preferred embodiment, the anti-PD-1 monoclonal antibody is Teplizumab (Toyi).

[0018] The third aspect of the present invention provides a drug kit for treating liver metastasis of lung cancer, the drug kit comprising:

[0019] (a) a first preparation, wherein the first preparation contains an oncolytic virus and a pharmaceutically acceptable carrier;

[0020] (b) a second preparation comprising an anti-PD-1 monoclonal antibody and a pharmaceutically acceptable carrier;

[0021] (c) instructions describing a method for treating melanin by combining oncolytic virus and anti-PD-1 monoclonal antibody.

[0022] In another preferred embodiment, the first preparation and the second preparation are independent of each other.

[0023] In another preferred embodiment, the first preparation and the second preparation are freeze-dried preparations or liquid preparations.

[0024] In another preferred embodiment, the first preparation and the second preparation are injections.

[0025] In another preferred embodiment, the first preparation is administered before the second preparation.

[0026] In another preferred embodiment, the first preparation and the second preparation are administered simultaneously.

[0027] In another preferred embodiment, the first preparation is administered after the second preparation.

[0028] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

[0029] 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.

[0030] In another preferred embodiment, the anti-PD-1 monoclonal antibody is selected from the following group: toripalimab (Toyi), durvalumab (Invitrogen), atezolizumab (Tai Shengqi), nivolumab (Opdivo), carrelizumab (Erica), sintilimab (Tyvyt), tilelizumab (Beisel), or a combination thereof.

[0031] In another preferred embodiment, the anti-PD-1 monoclonal antibody is Teplizumab (Toyi).

[0032] The fourth aspect of the present invention provides a method for treating liver metastasis of lung cancer, which comprises administering a therapeutically effective amount of the pharmaceutical composition as described in the fourth aspect of the present invention to a subject in need, thereby treating liver metastasis of lung cancer.

[0033] In another preferred embodiment, the subject in need is a human or a non-human mammal.

[0034] In another preferred embodiment, the non-human mammals include monkeys, gorillas, cows, pigs, dogs, sheep, rabbits or mice.

[0035] In another preferred embodiment, the subject in need thereof suffers from a disease for which the drug is used to treat liver metastasis of lung cancer.

[0036] In another preferred embodiment, the oncolytic virus is a recombinant human adenovirus type 5 with the trade name of Ancore.

[0037] In another preferred embodiment, the anti-PD-1 monoclonal antibody is an anti-PD-1 monoclonal antibody.

[0038] In another preferred embodiment, the recombinant human adenovirus type 5 is administered by intratumoral injection.

[0039] In another preferred embodiment, the anti-PD-1 monoclonal antibody can be administered by intravenous, intraperitoneal or intratumoral injection.

[0040] In another preferred embodiment, the method further comprises administering a chemotherapeutic drug for treating a tumor to a subject in need thereof, wherein the chemotherapeutic drug includes but is not limited to gemcitabine, nedaplatin, cisplatin, and pemetrexed.

[0041] In another preferred embodiment, the method further comprises administering supportive therapeutic drugs for treating tumors to a subject in need thereof.

[0042] In another preferred embodiment, the supportive treatment drugs include: antibiotics, analgesics, nutritional drugs or a combination thereof.

[0043] 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

[0044] Figure 1 Shown is the comparison of tumor volume in Case 1 before and after treatment with Teplizumab combined with oncolytic virus.

[0045] Figure 2 Shown is the comparison of tumor volume in Case 2 before and after treatment with Teplizumab combined with oncolytic virus. DETAILED DESCRIPTION

[0046] After extensive and in-depth research, the inventors unexpectedly discovered for the first time that when a specific recombinant human adenovirus type 5 (Ankorui) is used in combination with an anti-PD-1 monoclonal antibody (such as Teplipril), it has a synergistic therapeutic effect in the treatment of liver metastasis of lung cancer. Clinical experiments have shown that the combined use of recombinant human adenovirus type 5 and anti-PD-1 monoclonal antibodies not only has a significant tumor inhibition effect, but also has good safety. On this basis, the present invention was completed.

[0047] the term

[0048] 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 "Ankorui".

[0049] As used herein, the term "second active ingredient" refers to an anti-PD-1 monoclonal antibody. In a preferred embodiment of the present invention, the "second active ingredient" is toripalimab injection.

[0050] 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 first active ingredient and the second active ingredient described above.

[0051] 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) and a second active ingredient (or a second preparation containing the second active ingredient). In the present invention, the first preparation and the second preparation may be the same or different preparations. In addition, the first preparation and the second preparation may be the same preparation, or separate preparations.

[0052] Recombinant human adenovirus type 5 injection

[0053] The recombinant human adenovirus type 5 injection used in the present invention, with the trade name of Ankorui, is the first oncolytic virus therapeutic drug approved by the China Food and Drug Administration and launched on the market in 2006. It is an oncolytic adenovirus obtained by genetically recombining human adenovirus type 5 (Ad5) using genetic engineering technology. It mainly deletes the E1B-55kDa (i.e., 55kD in the E1B region of type 5 adenovirus, encoded by the E1B-55k gene) and E3 region gene fragments of human adenovirus type 5, and has the characteristic of specific replication in tumor cells, which ultimately leads to oncolysis.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] Anti-PD-1 monoclonal antibodies

[0060] PD-1, programmed death receptor 1, also known as CD279 (cluster of differentiation 279), is an important immunosuppressive molecule. PD-1 regulates the immune system and promotes self-tolerance by down-regulating the immune system's response to human cells and by inhibiting T-cell inflammatory activity. PD-1 is an immune checkpoint that prevents autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T cells in the lymph nodes. Second, it reduces apoptosis of regulatory T cells (anti-inflammatory, suppressive T cells). PD-1 binds to its ligand PD-L1 to initiate programmed cell death of T cells, allowing tumor cells to gain immune escape.

[0061] In a preferred embodiment of the present invention, the anti-PD-1 monoclonal antibody used is toripalimab injection.

[0062] Pharmaceutical composition and administration method

[0063] The present invention also provides a composition which can be used for synergistically treating liver metastasis of lung cancer.

[0064] The pharmaceutical composition of the present invention comprises: an effective amount of recombinant human adenovirus type 5, an effective amount of anti-PD-1 monoclonal antibody, and a pharmaceutically acceptable carrier.

[0065] Generally, the recombinant human adenovirus type 5 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.

[0066] As used herein, "pharmaceutically acceptable carrier" refers to a carrier used for administration of therapeutic agents, including various excipients and diluents.

[0067] The term "pharmaceutically acceptable carrier" 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, and buffers. 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.

[0068] 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.

[0069] 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.

[0070] 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).

[0071] When using a pharmaceutical composition, a safe and effective amount of a combination of active ingredients (including a first active ingredient (or its formulation) and / or a second active ingredient (or its formulation)) is administered to a mammal.

[0072] 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) 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.

[0073] 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.

[0074] For the second 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.

[0075] There is no particular limitation on the administration method of the pharmaceutical composition of the present invention, and representative examples include (but are not limited to): intratumor injection, intraperitoneal injection, and intravenous injection.

[0076] Pill Box

[0077] The present invention provides a medicine kit for treating liver metastasis of lung cancer, the medicine kit comprising:

[0078] Component (1): a preparation containing recombinant human adenovirus type 5;

[0079] Component (2): a preparation comprising an anti-PD-1 monoclonal antibody;

[0080] Component (3): instructions.

[0081] The preparation containing recombinant human adenovirus type 5 includes (but is not limited to): a lyophilized preparation, a liquid preparation or an injection.

[0082] The preparations of the anti-PD-1 monoclonal antibody include (but are not limited to): lyophilized preparations, liquid preparations, or injection solutions.

[0083] 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 anti-PD-1 monoclonal antibodies; preferably 4-10 of each.

[0084] 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.

[0085] In the present invention, the unit dosage form of the recombinant human adenovirus type 5 is usually a liquid dosage form.

[0086] 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 an anti-PD-1 monoclonal antibody.

[0087] The medicine kit provided by the present invention is prepared by the following steps: placing a preparation containing recombinant human adenovirus type 5 and a preparation containing anti-PD-1 monoclonal antibody, as well as instructions, together to form a medicine kit.

[0088] The preparation containing recombinant human adenovirus type 5 preferably contains a unit dosage form of recombinant human adenovirus type 5, and the preparation containing anti-PD-1 monoclonal antibody preferably contains a unit dosage form of anti-PD-1 monoclonal antibody.

[0089] The step preferably places at least one unit dosage form containing recombinant human adenovirus type 5 and at least one unit dosage form containing anti-PD-1 monoclonal antibody, as well as instructions, together to form a drug kit.

[0090] The main advantages of the present invention are:

[0091] (1) The combination of recombinant human adenovirus type 5 and anti-PD-1 monoclonal antibody can synergistically and more efficiently inhibit lung cancer liver metastasis.

[0092] (2) Recombinant human adenovirus type 5 and anti-PD-1 monoclonal antibody can not only achieve better therapeutic effects but also have good safety.

[0093] (3) Combination therapy of recombinant human adenovirus type 5 and anti-PD-1 monoclonal antibody can reduce the risk of drug resistance in antibody therapy.

[0094] 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.

[0095] Unless otherwise indicated, percentages and parts are by weight.

[0096] The efficacy evaluation criteria of the present invention are:

[0097]

[0098]

[0099] Example 1

[0100] Clinical trial of recombinant human adenovirus type 5 combined with anti-PD-1 monoclonal antibody in the treatment of liver metastasis of lung cancer1

[0101] (1) Case introduction:

[0102] Patient, Chen, male, 72 years old

[0103] Physical examination in May 2018: 1. Ground glass miliary and nodular lesions in the posterior segment of both upper lobes, follow-up reexamination is recommended. 2. Miliary lesions in the outer basal segment of the right upper lobe, middle lobe, and lower lobe, follow-up reexamination is recommended. 3. Chronic inflammatory changes in the lower lingual segment of the left upper lobe and the right lower lobe. 4. Multiple low-density lesions in the liver, further examination is recommended. The patient had no cough, hemoptysis, fever, or chest pain.

[0104] On 2020-05-20, the CEA level was 87ng / mL, and on 2020-05-22, he was hospitalized in the respiratory department for treatment.

[0105] [Immunological examination] (2020-05-25): Carcinoembryonic antigen increased (188.00ng / ml);

[0106]

Lung CT

[0107] [PET / CT] (2020-05-28): Nodule in the posterior segment of the apex of the left upper lobe, increased FDG metabolism, peripheral lung cancer considered; lymphangitic carcinomatosis in the left upper lobe; multiple lymph node metastases in the left internal mammary, mediastinal aortic arch, main pulmonary artery window, and left hilar area; metastasis to the left lobe of the liver, multiple bone metastases.

[0108] On 2020-05-29, a CT-guided percutaneous lung puncture biopsy was performed.

[0109] [Pathology] (2020-06-09) (left upper lung puncture biopsy): Combined with morphology and enzyme labeling, it is consistent with non-small cell carcinoma, tending to adenocarcinoma, with some cells having pleomorphism, focal areas with osteoid metaplasia, and puncture tissue is limited; Immunohistochemistry: tumor cells CK-P (+), vimentin (- / +), CK7 (+), TTF-1 (+), p63 (partially +), p40 (-), SYN (-), CGA (-), Ki67 (30% +). 2020-06-09 Supplementary immunohistochemistry: tumor cell PD-L1 (about 80% +); lymphocyte PD-1 (-).

[0110] [FISH genetic testing] (2020.06.16): ALK and ROS1 genes are wild type, and EGFR gene mutation is positive (19Del).

[0111] Treatment history: On 2020-06-24, ametinib targeted therapy was given, with no obvious adverse reactions. On 2021-03-23, 2021-04-21, 2021-05-25, 2021-06-24, and 2021-07-21, bevacizumab 400mg targeted therapy was given, and on 2021-09-25, bevacizumab (Encorta) 400mg d0 (5mg / kg) + ametinib 110mg po qd1-21 targeted therapy was given. 2020-09-18, 2020-10-21, 2020-11-18, 2021-01-20, 2021-02-24, 2021-03-24, 2021-04-22, 2021-05-26, 2021-06-24, 2021-07-22, 2021-09-24, 2021-10-13, 2021-11-05, and 2021-12-03 were treated with ibandronate sodium for bone repair, with no discomfort.

[0112] (2) Treatment options

[0113] Liver puncture biopsy was performed on 2021-10-11.

[0114] Treatment is given according to the following regimen:

[0115]

[0116] (3) Results

[0117] During the treatment, the patient only experienced fever as a side effect.

[0118] Chest CT and upper abdominal MRI were reviewed on 2021-12-04. The results showed that compared with the local injection of Tepli combined with oncolytic virus ( Figure 1 Left), after combined treatment, the maximum diameter of the tumor was significantly reduced ( Figure 1 Right picture), it was reduced from the original 3 cm to 1.59 cm, a reduction of about 50%, and the efficacy evaluation was PR (partial remission).

[0119] Example 2

[0120] Clinical trial of recombinant human adenovirus type 5 combined with anti-PD-1 monoclonal antibody in the treatment of liver metastasis of lung cancer 2

[0121] (1) Case introduction:

[0122] The patient is Xu XX, male, 66 years old.

[0123] The patient developed coughing discomfort without obvious cause on February 2, 2021. On February 23, 2021, chest CT was performed: right lower lung MT, mediastinal and right hilar lymph node metastasis, multiple liver metastasis, hepatogastric lymph node enlargement, and the possibility of metastasis was considered high. On February 26, 2021, bronchoscopy was performed, and tumor cells were seen, considering metastatic poorly differentiated carcinoma, tending to squamous cell carcinoma. PET-CT was performed on March 10, 2021: nodules in the anterior basal segment and posterior basal segment of the right lower lobe with increased FDG metabolism, all of which were considered malignant tumors; multiple liver metastases; multiple bone metastases at the right clavicle sternal end, right scapula, and thoracic 3 vertebrae; multiple lymph node metastases throughout the body (involving bilateral cervical space and supraclavicular area, mediastinal 2R, 4R, 4L, 10R, 7 area, lesser omental sac of the stomach, and retroperitoneum); bilateral adrenal metastasis; a small amount of pleural effusion on the right side. 2021.03.12 Brain MRI: Abnormal signal foci in the left frontal lobe. Considering that the metastasis may be large, please further enhance the examination.

[0124] From March 12, 2021 to July 10, 2021, a total of 6 courses of albumin paclitaxel + carboplatin chemotherapy were performed, and bisphosphonates were used for bone repair treatment until now. In July 2021, the liver metastasis was significantly enlarged, and the efficacy evaluation showed tumor progression. The patient was then enrolled in a clinical study on the safety and efficacy of Ankorui (recombinant human adenovirus injection) combined with PD-1 monoclonal antibody in the treatment of liver metastasis of non-small cell lung cancer, and a liver puncture biopsy was performed.

[0125] Puncture pathology: (Puncture biopsy of liver tumor) showed poorly differentiated carcinoma involvement. Combined with clinical history and immunohistochemistry, the lung origin was first considered. It showed an adenocarcinoma phenotype and was limited to the puncture tissue. The diagnosis was considered comprehensively based on clinical and previous pathological findings.

[0126] Immunohistochemistry: tumor cells CK7 (+), TTF-1 (+), CK5 / 6 (partially +), P40 (-), ARG-1 (-), GPC-3 (-), CD34 (-), PD-1 (-), PD-L 1 (40+), Ki-67 (60%+), (Note: PD-1 clone number, Genentech, 2E5; PD-L 1 clone number, Genentech, ZR3); ALK negative, ROS1 negative, no EGFR gene mutation was found.

[0127] (2) Treatment options

[0128] On August 11, 2021, the patient was given oncolytic virus injection for liver metastases + toripalimab + gemcitabine + nedaplatin chemotherapy.

[0129] Because GP regimen (gemcitabine + cisplatin) chemotherapy caused severe bone marrow suppression, on September 8, 2021, liver metastasis oncolytic virus injection + toripalimab immunotherapy was performed again, and pemetrexed single-agent chemotherapy was used instead.

[0130] Two local injections of recombinant human adenovirus type 5 injection (Ankorui) into the lesion. Dose: 1ml (5*10^11vp / 0.5ml / vial*2 vials).

[0131]

[0132]

[0133] The results showed that compared with the local injection of Teplizumab combined with oncolytic virus ( Figure 2 Left), after combined treatment, the maximum diameter of the tumor was significantly reduced ( Figure 2 Right); efficacy evaluation PR (partial remission).

[0134] The above results show that the use of toripalimab combined with local injection of oncolytic virus is not only effective but also safe.

[0135] 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 comprises a first active ingredient, an oncolytic virus, and a second active ingredient, an anti-PD-1 monoclonal antibody, and the combination is used to prepare a pharmaceutical composition or a medicine kit for synergistically treating liver metastasis of lung cancer.

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 The oncolytic virus is a recombinant human adenovirus type 5 injection with the trade name Ancore.

4. The use according to claim 1, characterized in that The anti-PD-1 monoclonal antibody is selected from the following group: toripalimab (Toyi), durvalumab (Invitrogen), atezolizumab (Tai Shengqi), nivolumab (Opdivo), carrelizumab (Erica), sintilimab (Tyvyt), tilelizumab (Beisel), or a combination thereof.

5. The use according to claim 1, characterized in that The anti-PD-1 monoclonal antibody is Teplizumab (Toyi).

6. The use according to claim 1, characterized in that The oncolytic virus was injected at a rate of 0.5×10 12 VP to 2.5×10 12 VP dosage administration; the anti-PD-1 monoclonal antibody is administered at a dose of 1 to 20 mg / kg (body weight), preferably 2 to 15 mg / kg, and more preferably 3 to 10 mg / kg.

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

8. A medicine kit for treating liver metastasis of lung cancer, the medicine kit comprising: (a) a first preparation, wherein the first preparation contains an oncolytic virus and a pharmaceutically acceptable carrier; (b) a second preparation comprising an anti-PD-1 monoclonal antibody and a pharmaceutically acceptable carrier; (c) instructions describing a method for treating melanin by combining oncolytic virus and anti-PD-1 monoclonal antibody.

9. The medicine box according to claim 8, characterized in that The first formulation and the second formulation are independent of each other.

10. The medicine box according to claim 8, characterized in that The first formulation is administered prior to administering the second formulation.

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