System for treating biliary tract cancer

Abstract

The invention relates to a system for treating biliary tract cancer, which comprises a device for applying an alternating electric field to a target area of a patient, and is characterized in that the frequency of the alternating electric field is 100-300kHz, and the field intensity is 1-3V / cm; the patient suffers from biliary tract cancer and has, simultaneously or will be subjected to combined treatment of an immune checkpoint inhibitor and a chemical drug. The immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from a group consisting of a duvaleriumab, an averlumab, a suaglizumab and an atelizumab; the chemical drugs comprise chemical drugs based on platinum drugs and / or chemical drugs of anti-metabolic drugs, and the chemical drugs based on the platinum drugs comprise cis-platinum or carboplatin; and / or the chemical drug of the anti-metabolic drug contains gemcitabine. According to the system disclosed by the embodiment of the invention, proliferation of the biliary tract cancer cells can be inhibited, migration of the biliary tract cancer cells is inhibited, mitosis of the biliary tract cancer cells is interfered, and immunogenic death of the biliary tract cancer cells is promoted. The present disclosure also relates to a method of treating biliary tract cancer.

Description

Technical Field

[0001] This application relates to the field of combination therapy, and more particularly to systems and methods for treating biliary tract cancer, as well as the use of combinations of alternating electric fields, immune checkpoint inhibitors and chemical drugs in the formation of drugs for treating biliary tract cancer, and the use of alternating electric fields in the preparation of drugs that promote immunogenic death of biliary tract cancer cells. Background Technology

[0002] Biliary tract cancer (BTC) is a group of malignant tumors originating from the epithelium of the gallbladder and bile ducts, exhibiting high heterogeneity. Surgery is the preferred treatment for biliary tract tumors, but many patients are already at an advanced stage at diagnosis, thus losing the opportunity for surgery. For patients with inoperable biliary tract cancer, chemotherapy and radiotherapy are commonly used treatments. However, these treatments have limited efficacy and may be accompanied by significant side effects. Targeted therapy is a drug therapy that targets specific molecular markers of tumor cells, reducing damage to normal cells. However, the application of targeted therapy in biliary tract cancer is still in its early stages. Immunotherapy attacks tumor cells by activating or enhancing the patient's own immune system. Immune checkpoint inhibitors, such as durvalumab, are a type of immunotherapy that blocks the interaction between PD-L1 and PD-1, thus preventing immune escape by tumor cells.

[0003] Due to the complexity and heterogeneity of biliary tract cancer, single treatment methods often have limited effectiveness. Therefore, there is an urgent need for therapies with better therapeutic effects, such as those used in combination with other treatments, such as chemotherapy, targeted therapy, or immunotherapy. Summary of the Invention

[0004] Tumor therapeutic electric fields (TTFields) are a novel non-invasive treatment method that interferes with the mitosis of tumor cells by applying a specific alternating electric field to the tumor area, leading to cell death.

[0005] This disclosure aims to at least partially address at least one of the technical problems existing in the prior art. To this end, this disclosure provides a system and method for treating biliary tract cancer, as well as the use of a combination of an alternating electric field, an immune checkpoint inhibitor, and a chemical drug in the formation of a medicament for treating biliary tract cancer, and the use of an alternating electric field in the preparation of a medicament that promotes immunogenic death of biliary tract cancer cells.

[0006] This disclosure also provides a system for treating biliary tract cancer, including means for applying an alternating electric field to a target area of ​​a patient, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm; the patient has biliary tract cancer and has received, is receiving or will receive combined treatment with immune checkpoint inhibitors and chemotherapy drugs.

[0007] Preferably, the biliary tract cancer includes unresectable biliary tract cancer, locally advanced biliary tract cancer, or metastatic biliary tract cancer.

[0008] Preferably, the biliary tract cancer includes intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

[0009] Preferably, the electric field is applied for a period of not less than 24 hours.

[0010] Preferably, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab.

[0011] Preferably, the chemical drug comprises a platinum-based chemical drug and / or antimetabolite chemical drug.

[0012] Preferably, the platinum-based chemical drug comprises cisplatin or carboplatin; and / or the antimetabolite chemical drug comprises gemcitabine.

[0013] Preferably, the immune checkpoint inhibitor and / or the chemical drug are administered via intravenous injection.

[0014] Preferably, the immune checkpoint inhibitor and the chemical drug are administered simultaneously or sequentially; and / or the immune checkpoint inhibitor is administered to the patient once every three weeks (Q3W).

[0015] Preferably, the second dose of the chemical drug is administered 7 days after the first dose.

[0016] Preferably, the immune checkpoint inhibitor is administered after the chemotherapy treatment is completed.

[0017] Preferably, the immune checkpoint inhibitor is administered at the end of the patient's last treatment cycle.

[0018] Preferably, the immune checkpoint inhibitor is administered to the patient once every four weeks (Q4W).

[0019] Preferably, the dose of the immune checkpoint inhibitor is 1000-2000 mg.

[0020] Preferably, the dose of the immune checkpoint inhibitor is 1500 mg.

[0021] Preferably, the chemical drug comprises gemcitabine at 1000 mg / m2 and cisplatin at 25 mg / m2 administered intravenously.

[0022] This disclosure also provides the use of a combination of an alternating electric field, an immune checkpoint inhibitor, and a chemical drug in the formation of a medicament for treating biliary tract cancer, wherein the alternating electric field has a frequency of 100-300 kHz and a field strength of 1-3 V / cm.

[0023] Preferably, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

[0024] Preferably, the anti-PD-L1 antibody is selected from: durvalumab, avelumab, sugemalimab, and atezolizumab; and / or the platinum-based chemical drug comprises cisplatin or carboplatin; and / or the antimetabolite chemical drug comprises gemcitabine.

[0025] Preferably, the alternating electric field is applied for no less than 24 hours.

[0026] This disclosure also provides the use of an alternating electric field in the preparation of a drug that promotes immunogenic death of biliary tract cancer cells, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm; wherein the biliary tract cancer patient is receiving drug treatment before, after, or concurrently, the drug including immune checkpoint inhibitors and chemotherapeutic agents.

[0027] Preferably, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

[0028] Preferably, the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab; the platinum-based chemical drug includes cisplatin or carboplatin; and the antimetabolite chemical drug includes gemcitabine.

[0029] This disclosure provides a method for treating biliary tract cancer, the method comprising: applying an alternating electric field to a target area of ​​a patient with biliary tract cancer, the alternating electric field having a frequency of 100-300 kHz and a field strength of 1-3 V / cm; administering an immune checkpoint inhibitor to the patient; and administering a chemical drug to the patient.

[0030] Preferably, the biliary tract cancer includes unresectable biliary tract cancer, locally advanced biliary tract cancer, or metastatic biliary tract cancer.

[0031] Preferably, the biliary tract cancer includes intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

[0032] Preferably, the patient has not previously received treatment for biliary tract cancer.

[0033] Preferably, the patient has experienced a recurrence of the disease more than 6 months after undergoing a surgery aimed at curing the disease or more than 6 months after the end of adjuvant therapy.

[0034] Preferably, the immune checkpoint inhibitor is an anti-PD-L1 antibody; the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab.

[0035] Preferably, the chemical drug comprises a platinum-based chemical drug and / or antimetabolite chemical drug.

[0036] Preferably, the platinum-based chemotherapy comprises cisplatin or carboplatin; and / or the antimetabolite chemotherapy comprises gemcitabine.

[0037] Preferably, the immune checkpoint inhibitor and / or the chemical drug are administered via intravenous injection.

[0038] Preferably, the immune checkpoint inhibitor and the chemical drug are administered simultaneously or sequentially.

[0039] Preferably, the immune checkpoint inhibitor is administered to the patient once every three weeks (Q3W).

[0040] Preferably, the method includes administering a first dose of the chemical drug to the patient and then administering a second dose of the chemical drug 7 days later.

[0041] Preferably, the method includes a treatment cycle lasting 21 days, wherein: (a) the patient is given an immune checkpoint inhibitor and a first dose of the chemical drug on day 1 of the treatment cycle, and (b) the patient is given a second dose of the chemical drug on day 8 of the treatment cycle.

[0042] Preferably, the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7 or 8 times.

[0043] Preferably, the method includes administering an immune checkpoint inhibitor to the patient after chemotherapy.

[0044] Preferably, the method includes administering an immune checkpoint inhibitor to the patient after the last treatment cycle.

[0045] Preferably, the immune checkpoint inhibitor is administered to the patient once every four weeks (Q4W).

[0046] Preferably, the dose of the immune checkpoint inhibitor is 1000-2000 mg.

[0047] Preferably, the dose of the immune checkpoint inhibitor is 1500 mg.

[0048] Preferably, the method comprises administering gemcitabine at a dose of 1000 mg / m² and cisplatin at a dose of 25 mg / m² to the patient via intravenous injection.

[0049] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0050] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0051] Figure 1 This is a schematic block diagram of the device for applying an alternating electric field in the system for treating biliary tract cancer according to this application.

[0052] Figure 2 This figure shows the colony-forming ability of HCCC-9810 cells after 96 hours of TTFields application and without TTFields application, according to embodiments of this application.

[0053] Figure 3 and Figure 2 Similarly, it shows a statistical analysis of the clonogenic capacity of HCCC-9810 cells with and without TTFields applied for 96 hours.

[0054] Figure 4 This is a graph showing the migration ability of HCCC-9810 cells with and without TTFields applied for 24 hours, as described in the embodiments of this application.

[0055] Figure 5 and Figure 4 Similarly, it shows a statistical analysis of the migration ability of HCCC-9810 cells with and without TTFields applied for 24 hours.

[0056] Figure 6 The images show mitosis in HCCC-9810 cells with and without TTFields applied for 96 hours, as described in this application.

[0057] Figure 7 This is an analytical graph showing the LDH release capacity of HCCC-9810 cells after 96 hours of TTFields application and without TTFields application, as described in the embodiments of this application.

[0058] Figure 8 The image shows the expression of calreticulin on the surface of HCCC-9810 cells after 96 hours of TTFields application and without TTFields application, as described in the embodiments of this application.

[0059] Figure 9 This is an analysis graph showing the ATP content secreted by HCCC-9810 cells after 96 hours of TTFields application and without TTFields application, as described in the embodiments of this application.

[0060] Figure 10This is an analytical graph showing the HMGB1 content secreted by HCCC-9810 cells after 96 hours of TTFields application and without TTFields application, as described in the embodiments of this application.

[0061] Figure label:

[0062] The device 100 for applying an alternating electric field, the electric field generating device 10, the switching device 20, and the electric field applying device 30. Detailed Implementation

[0063] The embodiments of this disclosure are described in detail below. The embodiments described below are exemplary and are only used to explain this disclosure, and should not be construed as limiting this disclosure.

[0064] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this disclosure, unless otherwise stated, "a plurality of" means two or more.

[0065] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this disclosure. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0066] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this disclosure, all other technical and scientific terms used in this disclosure shall have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0067] In this disclosure, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this disclosure but do not exclude other contents.

[0068] In this disclosure, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0069] In this disclosure, the term "medicine" refers to any one or more substances (e.g., chemical drugs (e.g., platinum-based chemical drugs (e.g., cisplatin or carboplatin), antimetabolite chemical drugs (e.g., gemcitabine), etc.), biological products (e.g., anti-PD-L1 antibodies), etc.) and / or non-substances (e.g., physical fields (e.g., electric fields)) that can be used to treat a disease or its symptoms. When the medicine as used herein contains multiple substances (e.g., chemical drugs (e.g., platinum-based chemical drugs (e.g., cisplatin or carboplatin), antimetabolite chemical drugs (e.g., gemcitabine), biological products (e.g., anti-PD-L1 antibodies), etc.) and / or non-substances (e.g., physical fields (e.g., electric fields)), the ...) and / or non-substances (e.g., physical fields (e.g., electric fields)) are used to treat a disease or its symptoms. For example, platinum-based drugs (e.g., cisplatin or carboplatin), antimetabolites (e.g., gemcitabine), biologics (e.g., anti-PD-L1 antibodies), and / or non-materials (e.g., physical fields (e.g., electric fields)) may not coexist in a pharmaceutical formulation in physical form. For example, when a drug as used herein comprises a drug, an anti-PD-L1 antibody, and an electric field (e.g., an alternating electric field), the drug may comprise an anti-PD-L1 antibody in physical form and a drug and electric field (e.g., an alternating electric field) in written form; the drug may also comprise a device for generating an electric field (e.g., an alternating electric field) in physical form and a drug and anti-PD-L1 antibody in written form.

[0070] In this disclosure, the term "treatment" refers to reducing, improving, or slowing the progression of a disease or disease-related symptoms. It should be noted that, although not excluded, treating a disease or symptom does not require the complete elimination of the disease or disease-related symptoms. In specific embodiments involving BTC, "treatment" can refer to any form or combination of achieving one or more primary or secondary clinical endpoints. As used herein, "treatment" covers diseases in mammals, particularly humans. As used herein, "treatment" covers administering a drug to an individual to reduce, improve, or slow the progression of a disease or disease-related symptoms. When the drug comprises a device for generating an electric field (e.g., an alternating electric field) in physical form and a chemical drug and an anti-PD-L1 antibody in written form, or comprises an anti-PD-L1 antibody in physical form and a chemical drug and an electric field (e.g., an alternating electric field) in written form, "treatment" as used herein refers to administering the electric field, the chemical drug, and the anti-PD-L1 antibody simultaneously or sequentially to an individual to reduce, improve, or slow the progression of a disease or disease-related symptoms.

[0071] In this disclosure, the term "mitosis" refers to a mode of cell division in an organism, a fundamental process for the growth, development, and tissue repair of multicellular organisms. Mitosis causes a single cell to divide into two daughter cells with identical genetic information. This process occurs continuously throughout the life cycle of an organism to maintain normal tissue function and the overall health of the organism. Mitosis can be divided into the following stages: Prophase: Chromosomes begin to condense, becoming more compact and visible. Each chromosome consists of two identical sister chromatids connected by centromeres. Simultaneously, the nuclear membrane and nucleolus disappear, and the spindle apparatus begins to form. Metaphase: Chromosomes align in the central plane of the cell, forming a structure called the centroplate. Spindle fibers from the spindle apparatus connect to the centromeres of the chromosomes. Anaphase: Sister chromatids are pulled towards the cell poles. In this stage, the two chromatids of each chromosome separate and are pulled towards opposite cell poles. Telophase: Chromosomes reach the cell poles and begin to decondense. The nuclear membrane and nucleolus reform, forming two new nuclei. Cytokinesis: The cytoplasm divides, forming two independent cells. In animal cells, this is usually accomplished by the formation of a contractile ring, while in plant cells, it is the formation of a cell plate. Mitosis is crucial for maintaining genetic stability because it ensures the accurate distribution of genetic material during cell division. However, any abnormality in the mitotic process can lead to genetic errors, such as variations in chromosome number, which are associated with the development of certain genetic diseases and cancers.

[0072] In this disclosure, the term "biliary tract cancer (BTC)" refers to any cancer of the biliary system originating from the bile duct (cholangiocarcinoma), gallbladder, or ampulla of Vater (AoV).

[0073] In this disclosure, the term "inoperable" refers to cancer or tumor that cannot be completely removed by surgery.

[0074] In this disclosure, the term "locally advanced" refers to cancer that has spread beyond its site of origin but has not yet spread to other parts of the body (stage 3).

[0075] In this disclosure, the term "metastasis" refers to the spread of cancer from its origin (primary site) to other parts of the body (stage 4).

[0076] In this disclosure, the term "anti-PD-L1 antibody" refers to an antibody or antigen-binding fragment thereof capable of selectively binding to a PD-L1 peptide. Examples of anti-PD-L1 antibodies can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, the contents of which are incorporated herein by reference. In some embodiments, the anti-PD-L1 antibody may be durvalumab, avelumab, sugemalimab, or atezolizumab. In other embodiments, the anti-PD-L1 antibody is durvalumab, avelumab, or atezolizumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. As described herein, the term "durvalumab" refers to an antibody that selectively binds to PD-L1 and blocks the binding of PD-L1 to PD-1 and CD80 receptors, as disclosed in U.S. Patent No. 9,493,565 (where durvalumab is referred to as "2.14H9OPT"), which is incorporated herein by reference in its entirety. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain, reducing binding to the complement component C1q and the Fc receptor, which mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Durvalumab is able to alleviate PD-L1-mediated human T-cell suppression in vitro and inhibit tumor growth in xenograft models via a T-cell-dependent mechanism.

[0077] This disclosure discloses a system and method for treating biliary tract cancer, as well as the use of a combination of an alternating electric field, an immune checkpoint inhibitor, and a chemical drug in the formation of a drug for treating biliary tract cancer, and the use of an alternating electric field in the preparation of a drug that promotes immunogenic death of biliary tract cancer cells. These will be described in detail below.

[0078] System for treating bile duct cancer

[0079] In a first aspect, this disclosure provides a system for treating biliary tract cancer. According to an embodiment of this disclosure, the system includes: means for applying an alternating electric field to a target region of a patient, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm, and the patient has biliary tract cancer and has been, is, or will be receiving combined therapy with an immune checkpoint inhibitor and a chemotherapy drug. The system according to an embodiment of this disclosure is capable of inhibiting the proliferation of biliary tract cancer cells, inhibiting the migration of biliary tract cancer cells, interfering with the mitosis of biliary tract cancer cells, and promoting immunogenic death of biliary tract cancer cells.

[0080] According to embodiments of this disclosure, the biliary tract cancer includes unresectable biliary tract cancer, locally advanced biliary tract cancer, or metastatic biliary tract cancer.

[0081] According to embodiments of this disclosure, the biliary tract cancer includes intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

[0082] According to embodiments of this disclosure, the electric field is applied for a period of not less than 24 hours, preferably not less than 48 hours, and more preferably 72 to 96 hours.

[0083] According to embodiments of this disclosure, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab.

[0084] According to embodiments of this disclosure, the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

[0085] According to embodiments of this disclosure, the platinum-based drug comprises cisplatin or carboplatin; and / or the antimetabolite comprises gemcitabine.

[0086] According to embodiments of this disclosure, the immune checkpoint inhibitor and / or the chemical drug are administered via intravenous injection.

[0087] According to embodiments of this disclosure, the immune checkpoint inhibitor and the chemical drug are administered simultaneously or sequentially, with the immune checkpoint inhibitor given to the patient once every three weeks (Q3W).

[0088] According to an embodiment of this disclosure, the chemical drug is administered as a second dose 7 days after the first dose.

[0089] According to embodiments of this disclosure, the immune checkpoint inhibitor is administered after the chemotherapy treatment is completed.

[0090] According to an embodiment of this disclosure, the immune checkpoint inhibitor is administered at the end of the patient's last treatment cycle.

[0091] According to an embodiment of this disclosure, the immune checkpoint inhibitor is administered to the patient once every four weeks (Q4W).

[0092] According to embodiments of this disclosure, the dose of the immune checkpoint inhibitor is 1000-2000 mg.

[0093] According to an embodiment of this disclosure, the dose of the immune checkpoint inhibitor is 1500 mg.

[0094] According to embodiments of this disclosure, the chemical drugs include gemcitabine at 1000 mg / m2 and cisplatin at 25 mg / m2 administered intravenously.

[0095] This disclosure also provides a method for inhibiting the proliferation of biliary tract cancer cells, the method comprising applying an alternating electric field of a certain frequency and field strength to the biliary tract of a patient for a period of time using a device for applying an alternating electric field; and administering a recommended dose of durvalumab and gemcitabine / cisplatin to the biliary tract of a patient in need. Specifically, the alternating electric field may be applied before, after, or simultaneously with the administration of durvalumab and / or gemcitabine / cisplatin. Alternatively, durvalumab and / or gemcitabine / cisplatin may be administered before, after, or simultaneously with the application of the alternating electric field. Applying an alternating electric field before administration of durvalumab and / or gemcitabine / cisplatin (GemCis) may take place within seconds, minutes, hours, or days prior to administration. Applying an alternating electric field after administration of durvalumab and / or gemcitabine / cisplatin (GemCis) may take place within seconds, minutes, hours, or days prior to administration. Applying an alternating electric field concurrently with administration of durvalumab and / or gemcitabine / cisplatin (GemCis) may take place within seconds or minutes prior to or after administration. Simultaneous application of an alternating electric field and durvalumab and / or gemcitabine / cisplatin can include administering durvalumab and / or gemcitabine / cisplatin while applying an alternating electric field.

[0096] Preferably, during the initial treatment phase, one cycle consists of 3 weeks (21 days). Durvalumab 1500 mg will be administered intravenously every 3 weeks (Q3W) on day 1 of each cycle for a maximum of 8 cycles. Simultaneously, patients will also receive cisplatin 25 mg / m² and gemcitabine 1000 mg / m² intravenously every 3 weeks (Q3W) on days 1 and 8 of each cycle for a maximum of 8 cycles.

[0097] For subsequent treatment phases, after more than 8 cycles, each cycle will be changed to 4 weeks (28 days). Patients will receive durvalumab 1500 mg monotherapy every 4 weeks (Q4W) on day 1 of each cycle until disease progression (PD) is confirmed or intolerable toxicity occurs.

[0098] The alternating electric field will be used for continuous treatment starting on day 1 of cycle 1 (C1D1) of the entire treatment course, with a daily treatment time of ≥18 hours, throughout the entire course of initial and subsequent treatments, until disease progression (PD) is confirmed or intolerable toxicity occurs. The frequency of the alternating electric field is 100–700 kHz, and the field strength is 1–3 V / cm.

[0099] According to embodiments of this disclosure, the device for applying an alternating electric field is suitable for performing electric field therapy on a patient.

[0100] According to a specific embodiment of this disclosure, see [link to specific implementation]. Figure 1 The device 100 for applying an alternating electric field includes an electric field generating device 10, a switching device 20, and several pairs of electric field applying devices 30. The switching device 20 is electrically connected to the electric field generating device 10 and each electric field applying device 30. The electric field generating device 10 generates an alternating current signal that meets the treatment requirements. The switching device 20 receives the alternating current signal output from the electric field generating device 10 and transmits the alternating current signal to the electric field applying device 30. The electric field applying device 30 is attached to the surface of the patient's body corresponding to the tumor area, applying the alternating current signal to the patient's tumor area for tumor electric field therapy. Specifically, the electric field applying device 30 is an electrode patch. The tumor is biliary tract cancer, which includes unresectable biliary tract cancer, locally advanced biliary tract cancer, or metastatic biliary tract cancer; specifically, biliary tract cancer includes intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

[0101] According to embodiments of this disclosure, the frequency of the device for applying the alternating electric field is in the mid-frequency range, specifically 100–700 kHz, preferably 100–250 kHz, and more preferably 140–160 kHz. According to embodiments of this disclosure, the frequency of the device for applying the alternating electric field can be 100 kHz, 150 kHz, 200 kHz, 300 kHz, 400 kHz, 500 kHz, 600 kHz, 650 kHz, 700 kHz, or a range between these values ​​(100–650 kHz, 100–600 kHz, and 100–500 kHz). A suitable frequency can effectively interfere with the mitosis of biliary tract cancer cells, inhibit their proliferation, inhibit their migration, and promote immunogenic death of biliary tract cancer cells.

[0102] According to embodiments of this disclosure, the electric field strength of the device for applying the alternating electric field is 1-3 V / cm, preferably 1.6-2.5 V / cm, and more preferably 2-2.2 V / cm. According to embodiments of this disclosure, the electric field strength of the device for applying the alternating electric field can be 1 V / cm, 1.1 V / cm, 1.2 V / cm, 1.3 V / cm, 1.4 V / cm, 1.5 V / cm, 1.6 V / cm, 1.7 V / cm, 1.8 V / cm, 1.9 V / cm, 2.0 V / cm, 2.1 V / cm, 2.2 V / cm, 2.3 V / cm, 2.4 V / cm, 2.5 V / cm, 2.6 V / cm, 2.7 V / cm, 2.8 V / cm, 2.9 V / cm, 3 V / cm, or a range between these values, specifically 1-2.9 V / cm, 1-2.8 V / cm, and 1-2.7 V / cm. Moderate field strength can effectively interfere with the mitosis of bile duct cancer cells, inhibit their proliferation, suppress their migration, and promote their immunogenic death.

[0103] According to embodiments of this disclosure, TTFields exhibit field-strength-dependent cytotoxicity against cholangiocarcinoma (HCCC-9810 cells, human cholangiocarcinoma cells). Treatment with an alternating electric field at a frequency of 150 kHz and a field strength of 2.1 V / cm reduced HCCC-9810 cell colony formation and migration, while increasing abnormal mitosis of cancer cells. Furthermore, calreticulin (CRT), a biomarker of immunogenic cell death (ICD), significantly accumulated on the HCCC-9810 cell membrane surface, and the release of high-mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) in the cell culture medium increased.

[0104] Intracellular death (ICD) is a specific form of cell death that can activate a specific immune response in the host against its contained antigens, thus playing an important role in tumor immunotherapy. Cancer cells undergoing ICD express or release damage-associated molecular patterns (DAMPs) in their dying state, promoting the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs). This process can reverse the tumor immunosuppressive microenvironment and enhance the sensitivity to immunotherapy. DAMPs mainly include CRTs exposed on the cell surface, HMGB1 secreted by tumor cells, ATP molecules released by cells, and heat shock proteins (HSP70, HSP90), among others.

[0105] According to embodiments of this disclosure, TTFields can inhibit the proliferation of biliary tract cancer cells and induce immunogenic death of biliary tract cancer cells.

[0106] The use of alternating electric fields in the preparation of drugs that promote immunogenic death of biliary tract cancer cells.

[0107] In a second aspect of this disclosure, the use of an alternating electric field in the preparation of a drug that promotes immunogenic death of biliary tract cancer cells is disclosed, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm, and the biliary tract cancer patient is receiving drug treatment prior to, after, or concurrently with the treatment, the drug comprising immune checkpoint inhibitors and chemotherapeutic agents.

[0108] According to embodiments of this disclosure, the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

[0109] According to embodiments of this disclosure, the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab; the platinum-based chemical drug comprises cisplatin or carboplatin; and the antimetabolite chemical drug comprises gemcitabine.

[0110] A method for treating bile duct cancer

[0111] In a third aspect, this disclosure provides a method for treating biliary tract cancer, the method comprising: applying an alternating electric field to a target region of a patient with biliary tract cancer; administering an immune checkpoint inhibitor to the patient; and administering a chemical drug to the patient. This disclosure also provides the use of a combination of an alternating electric field, an immune checkpoint inhibitor, and a chemical drug in forming a therapy for treating biliary tract cancer.

[0112] In some aspects, the frequency of the alternating electric field is 100-300 kHz. In some aspects, the field strength of the alternating electric field is 1-3 V / cm.

[0113] According to embodiments of this disclosure, the biliary tract cancer includes unresectable biliary tract cancer, locally advanced biliary tract cancer, or metastatic biliary tract cancer.

[0114] According to embodiments of this disclosure, the biliary tract cancer includes intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

[0115] According to an embodiment of this disclosure, the patient has not previously received treatment for biliary tract cancer.

[0116] According to an embodiment of this disclosure, the patient experienced a relapse of the disease more than 6 months after undergoing a curative surgery or more than 6 months after the end of adjuvant therapy. According to an embodiment of this disclosure, the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0117] According to embodiments of this disclosure, the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab.

[0118] According to embodiments of this disclosure, the chemical drug is a concurrent chemoradiotherapy.

[0119] According to embodiments of this disclosure, the chemical drug comprises a platinum-based chemical drug and / or antimetabolite chemical drug.

[0120] According to embodiments of this disclosure, the platinum-based chemotherapy comprises cisplatin or carboplatin.

[0121] According to embodiments of this disclosure, the chemotherapy of the antimetabolite includes gemcitabine.

[0122] According to embodiments of this disclosure, the immune checkpoint inhibitor and / or the chemical drug are administered via intravenous injection. According to embodiments of this disclosure, the immune checkpoint inhibitor and the chemical drug are administered simultaneously or sequentially.

[0123] According to an embodiment of this disclosure, the immune checkpoint inhibitor is administered to the patient once every three weeks (Q3W).

[0124] According to an embodiment of this disclosure, a second dose of the chemical drug is administered to the patient 7 days after the first dose of the chemical drug is given. According to an embodiment of this disclosure, the method or therapy includes a treatment cycle lasting 21 days, wherein: (a) the patient is given an immune checkpoint inhibitor and a first dose of the chemical drug on day 1 of the treatment cycle, and (b) the patient is given a second dose of the chemical drug on day 8 of the treatment cycle.

[0125] According to embodiments of this disclosure, the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7 or 8 times.

[0126] According to an embodiment of this disclosure, an immune checkpoint inhibitor is administered to the patient after chemotherapy. According to an embodiment of this disclosure, an immune checkpoint inhibitor is administered to the patient after the last treatment cycle. According to an embodiment of this disclosure, the immune checkpoint inhibitor is administered to the patient once every four weeks (Q4W).

[0127] According to embodiments of this disclosure, the dose of the immune checkpoint inhibitor is 1000-2000 mg.

[0128] According to an embodiment of this disclosure, the dose of the immune checkpoint inhibitor is 1500 mg.

[0129] According to an embodiment of this disclosure, the patient is given 1000 mg / m2 of gemcitabine and 25 mg / m2 of cisplatin via intravenous injection.

[0130] The implementation methods of this disclosure will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this disclosure. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0131] Example 1: The experimental process of TTFields inhibiting the proliferation of cholangiocarcinoma cells (HCCC-9810 cells, human cholangiocarcinoma cells) and promoting their immunogenic cell death is as follows:

[0132] (1) Cell Culture

[0133] HCCC-9810 cells were purchased from the Cell Bank of the Chinese Academy of Sciences. The growth medium consisted of 10% fetal bovine serum, 1% penicillin-streptomycin solution, and 90% RPMI-1640 (Roswell Park Memorial Institute-1640) medium. All cells were incubated in a humidified cell culture incubator at 37°C with 95% air and 5% CO2.

[0134] (2) In vitro application of TTFields

[0135] HCCC-9810 cells were digested with trypsin containing 0.25% EDTA and seeded onto 20mm circular spreaders in 12-well plates. Each HCCC-9810 cell was seeded onto one 20mm circular spreader in a 12-well plate, for a total of 12 spreaders. After 24 hours of culture, spreaders with good cell condition for each cell type were selected and placed into 12 separate culture dishes, with 15mL of culture medium added to each dish. Each culture dish contained one cell spreader. The control group (no TTFields treatment) had six culture dishes containing HCCC-9810 cells directly placed in a 37°C, 5% CO2 incubator for 96 hours under saturated humidity. In the TTFields group, six culture dishes containing HCCC-9810 cells were placed in an electric field application device. An alternating electric field of 100-300 kHz was applied to the cell samples in both dishes using the device, with the voltage adjusted to maintain the field strength at 1-2.5 V / cm. The device was then placed in a 5% CO2 constant-temperature cell culture incubator at 29-34℃ (the temperature within the culture medium was adjusted according to the electric field strength, controlling it within the range of 36.5-37.5℃), and incubated for 96 hours under saturated humidity.

[0136] (3) Cell counting

[0137] After 96 hours of treatment with TTFields cells, the scaffolds were removed from each group. HCCC-9810 cells were digested with trypsin containing 0.25% EDTA and prepared into single-cell suspensions. The number of cells in each group was measured using a handheld cell counter, Scepter 3.0.

[0138] (4) Cell clone formation

[0139] HCCC-9810 cells from the control group and after 96 hours of TTFields treatment were collected and reseeded in 6-well plates (3.0 × 10³ cells / well), with 3 replicates per group. Cells were cultured until the majority of individual clones had a cell count greater than 50, with medium changes and cell status observation every 3 days. After cloning, cells were fixed with 4% paraformaldehyde for 30 minutes, washed with phosphate-buffered saline (PBS), and stained with 1% crystal violet for 10 minutes per well. Cells were washed several times with PBS, photographed, and counted. Clonal rate = (number of clones / number of seeded cells) × 100%.

[0140] (5) Cell migration experiment

[0141] HCCC-9810 cells were plated according to their growth status, and after overnight incubation, the cells reached a confluence of 70-80%. Wounds were created using a 200 μL pipette tip, and the cells were washed away with PBS. Serum-free culture medium was then added, and after 0 hours, the cells were photographed and placed in an incubator for TTFields treatment. When significant migration was observed in the control group, cell slides from each group were removed for observation and photographing. After 24 hours of TTFields treatment, significant migration was observed in the HCCC-9810 cell control group. ImageJ (image processing software) was used to measure the scratch area and calculate the cell migration rate.

[0142] (6) Immunofluorescence staining

[0143] After 96 hours of TTFields treatment, cell slides from each group were removed and transferred to 12-well plates. Cells were fixed using 4% tissue cell fixative in a fume hood at room temperature. After washing with PBS, cells were blocked in blocking buffer for 60 minutes. After blocking, the blocking buffer was removed, and diluted primary antibody (tubulin, 1:500) was added and incubated overnight at 4°C. The next day, cells were incubated at room temperature in the dark. 488 goat anti-rabbit IgG (H&L) secondary antibody (antibody against the primary antibody, i.e., the main antibody) was incubated for 60 minutes. After washing, it was incubated with DAPI (4',6-diamino-2-phenylpyridine, a fluorescent dye that binds strongly to DNA) in the dark, followed by photography using a fluorescence microscope.

[0144] (7) Lactate dehydrogenase (LDH) assay

[0145] After 96 hours of treatment with TTFields, HCCC-9810 cells (1.0 × 10⁴ cells / well) were evenly seeded in a 96-well cell culture plate. Fresh culture medium was added (using low-serum medium containing 1% serum or appropriate serum-free medium). The wells were divided into the following groups: cell-free culture medium wells (background blank control wells), control cell wells (sample control wells) without TTFields treatment, cell wells for subsequent lysis without TTFields treatment (sample maximum enzyme activity control wells), and TTFields group cell wells (TTFields group treated samples). One hour before the scheduled detection time, the cell culture plate was removed from the incubator. Lactate dehydrogenase (LDH) release reagent provided in the kit was added to the "sample maximum enzyme activity control wells" at 10% of the original culture medium volume. After one hour, the plate was centrifuged (400g for 5 minutes). 120 μL of the supernatant from each well was added to the corresponding well in a new 96-well plate, and the samples were immediately measured. Add 60 μL of LDH detection working solution to each well, mix well, and incubate in the dark at room temperature (approximately 25°C) for 30 minutes. Measure the absorbance at 490 nm. LDH release rate (%) = (Absorbance of treated sample - Absorbance of sample control well) / (Absorbance of maximum enzyme activity in cells - Absorbance of sample control well) × 100.

[0146] (8) Determination of calreticulin expression

[0147] HCCC-9810 cells (control and TTFields treated for 96 hours) were collected. Cells were washed with PBS containing 1% bovine serum albumin (BSA), the supernatant was discarded, and cell particles were briefly vortexed to separate the cells. The cells were resuspended to a concentration of 1×10⁷ / mL. 100 μL of the cell suspension was aliquoted into individual tubes for staining. The cells were incubated at 4°C for 1 hour with primary antibody (CRT, 1 μg / mL) and rabbit IgG isotype control antibody. Secondary antibody was prepared using Alexa... 488 goat anti-rabbit IgG (H&L) was incubated at 4°C for 30 minutes. Cells were washed twice with PBS containing 1% BSA on ice, and then resuspended in 500 μL of PBS containing 1% BSA. Labeled cells were then detected using a BDAccuri C6 flow cytometer. Data were analyzed using FlowJo flow cytometry software.

[0148] (9) ATP assay

[0149] Cell culture medium of HCCC-9810 cells treated with TTFields for 96 hours was collected, centrifuged at 4°C (2000g for 5 minutes), and the supernatant was collected for detection using an ATP assay kit. In short, 100 μL of working solution was added to a black 96-well plate, incubated at room temperature for 5 minutes, then 100 μL of the sample to be tested was added, and the sample was analyzed using a Tecan assay kit. A 20M microplate reader was used to measure chemiluminescence.

[0150] (10) HMGB1 determination

[0151] Cell culture medium of HCCC-9810 cells treated with TTFields for 96 hours was collected, centrifuged at 4°C (3000 rpm for 20 minutes), and the supernatant was collected. HMGB1 (High Mobility Group Box 1 protein) was detected using an enzyme-linked immunosorbent assay (ELISA) kit. 50 μL of the sample was added to each well of the ELISA-coated plate and incubated at 37°C for 30 minutes. After washing, 50 μL of enzyme-labeled reagent was added, and the plate was reacted at 37°C for 30 minutes. After another wash, 50 μL of chromogenic buffer was added, and the plate was incubated at 37°C in the dark for 30 minutes. Finally, stop solution was added, and the plate was processed using Tecan. The OD value was measured at 450 nm using a 20M microplate reader.

[0152] (11) Statistical processing

[0153] Statistical analysis and graphing were performed using GraphPad Prism 9.0 software. Each experiment was repeated at least three times, and data are expressed as mean ± standard deviation. Student's t-test was used for comparisons between two groups, and one-way ANOVA was used for comparisons among multiple groups. P < 0.05 was considered statistically significant and expressed as *P < 0.05; **P < 0.01; and ***P < 0.001.

[0154] The experimental results of this embodiment are as follows:

[0155] (1) TTFields inhibits the proliferation of bile duct cancer cells.

[0156] Cholangiocarcinoma cells from both control and control groups were collected and treated with TTFields at 150 kHz and 2.1 V / cm for 96 hours. Cell colony formation was observed to assess cell proliferation capacity. (See reference...) Figure 2-3 As shown, the colony-forming ability of surviving cells in the TTFields group was significantly reduced. Figure 2The colony-forming ability of HCCC-9810 cells was shown to be significantly reduced after 96 hours of treatment with TTFields at 150 kHz and 2.1 V / cm. Figure 3 The colony formation rate of HCCC-9810 cells after treatment with TTFields at 150 kHz and 2.1 V / cm for 96 hours was 32.6% of that of the control group. This result indicates that TTFields inhibits the proliferation of cholangiocarcinoma cells.

[0157] (2) TTFields inhibits the migration of bile duct cancer cells.

[0158] To test the effect of TTFields treatment on the migration of cholangiocarcinoma cells, a wound healing experiment was conducted in this embodiment. Figure 4 The study showed a reduction in wound area in HCCC-9810 cells after treatment with TTFields at 150 kHz and 2.1 V / cm. Figure 5 Quantitative data showed that after 24 hours of treatment with TTFields at 150 kHz and 2.1 V / cm, the relative migration rate of HCCC-9810 cells was 53.4% ​​compared with the control group. These results indicate that TTFields inhibits the migration of cholangiocarcinoma cells.

[0159] (3) TTFields interfere with the mitosis of bile duct cancer cells.

[0160] Since an electric field with a strength of 2.1 V / cm has a good inhibitory effect, it will result in a small number of cells and make them difficult to observe. Therefore, after applying TTFields at 150 kHz and 1.7 V / cm for 96 hours to HCCC-8910 cells, we performed immunofluorescence staining of microtubules to observe the changes in spindle morphology of dividing cells. Figure 6 The results showed that HCCC-9810 cells treated with TTFields at 150 kHz and 1.7 V / cm exhibited abnormal mitosis, including disordered spindle fiber arrangement and multipolar mitosis. This indicates that TTFields treatment interfered with the normal progression of mitosis in cholangiocarcinoma cells.

[0161] (4) TTFields induce immunogenic death in cholangiocarcinoma cells.

[0162] Cells release LDH into the extracellular space when they are damaged or die. Figure 7The study revealed that after 96 hours of treatment with TTFields at 150 kHz and 2.1 V / cm, the LDH content released by HCCC-9810 cells increased by 3.3-fold, further demonstrating that TTFields cause damage or death in BTC cells. To determine whether TTFields application promotes ICD in BTC cells, several identified ICD biochemical markers were detected in HCCC-9810 cells after 96 hours of treatment with TTFields at 150 kHz and 2.1 V / cm, including exposure of CRT on the cell membrane, and extracellular secretion of ATP and HMGB1. Figure 8 Flow cytometry revealed an increase in CRT expression on the surface of HCCC-9810 cells in the TTFields treatment group. Figure 9 The study revealed that ATP levels in the supernatant of HCCC-9810 cells increased after 96 hours of TTFields treatment at 150 kHz and 2.1 V / cm. Furthermore, Figure 10 The study revealed an increase in extracellular HMGB1 levels in HCCC-9810 cells treated with TTFields at 150 kHz and 2.1 V / cm. These results indicate that TTFields can induce ICD in the BTC cell line, meaning that TTFields induces immunogenic cell death in cholangiocarcinoma cells.

[0163] Example 2: Phase 1b study of TTF in combination with durvalumab, gemcitabine, and cisplatin for the treatment of BTC

[0164] A single-arm phase 1b study was conducted to evaluate the role of tumor therapeutic fields (TTF) in combination with durvalumab and gemcitabine / cisplatin (GemCis) as first-line treatment for unresectable biliary tract cancer (BTC). This study aimed to evaluate the efficacy and safety of adding TTF to the durvalumab plus GemCis regimen for the treatment of previously untreated, unresectable BTC patients.

[0165] Primary objective of the study: To evaluate the preliminary antitumor efficacy, including progression-free survival (PFS), of TTF combined with gemcitabine / cisplatin (GemCis) + durvalumab as first-line treatment for patients with unresectable BTC.

[0166] Secondary objectives of the study: (1) This study also evaluated the safety profile of TTF in combination with GemCis and durvalumab as first-line treatment for patients with unresectable BTC, including adverse events (AEs), time to serious adverse events (SAEs), and treatment-related adverse events (TRAEs); (2) To further evaluate the preliminary efficacy of TTF in combination with GemCis and durvalumab as first-line treatment for patients with unresectable BTC, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS).

[0167] (1) Research plan:

[0168] Approximately 60 patients were enrolled and received TTF in combination with GemCis and durvalumab. The study was conducted in two phases: a safety introductory phase and a main phase. Six patients were initially enrolled in the safety introductory phase, followed by 54 patients in the main phase. The total sample size may be adjusted based on emerging data. Further patient enrollment may be paused until the safety profile of the first six patients is assessed, prior to completion of the first cycle of treatment by the sixth patient. The study will proceed to the main phase only if the safety profile during the safety introductory phase is acceptable, after which patient enrollment will resume.

[0169] This study was conducted in the following stages: screening, treatment, treatment completion, safety follow-up, and survival follow-up.

[0170] (A) Filtering:

[0171] All patients who provide informed consent undergo a screening period of up to 28 days, and qualified patients proceed to the initial treatment phase.

[0172] (B) Treatment:

[0173] During the initial treatment phase, one cycle consisted of 3 weeks (21 days). Durvalumab 1500 mg was administered intravenously on day 1 of each cycle, every 3 weeks, for a maximum of 8 cycles. Concurrently, patients also received cisplatin 25 mg / m² and gemcitabine 1000 mg / m² intravenously on days 1 and 8 of each cycle, every 3 weeks, for a maximum of 8 cycles. Study visits were conducted every 3 weeks, corresponding to the 3-week treatment cycle.

[0174] For subsequent treatment, after more than 8 cycles, each cycle is changed to 4 weeks (28 days). Patients receive durvalumab 1500 mg Q4W monotherapy on day 1 of each cycle until confirmed disease progression (PD) or intolerable toxicity, withdrawal of informed consent, termination of the study, loss to follow-up, death, or study completion (whichever occurs first). Study visits are conducted every 4 weeks, corresponding to the 4-week treatment cycle.

[0175] TTF treatment begins on day 1 of the first cycle (C1D1) with continuous treatment planned for ≥18 hours per day, throughout the entire course of initial and subsequent treatments, until disease progression (PD) is confirmed or intolerable toxicity occurs, informed consent is withdrawn, the study is terminated, the student is lost to follow-up, or the study ends (whichever occurs first).

[0176] Tumor assessments were performed every 6 weeks (Q6W) during the initial 24 weeks, and then every 8 weeks (Q8W) thereafter, until radiographic disease progression (PD) was achieved as defined in the Solid Tumor Efficacy Evaluation Criteria V1.1 and at least one additional follow-up imaging scan was performed.

[0177] For patients who discontinue treatment for reasons other than disease progression (PD), tumor assessment should be performed according to the same plan until (1) imaging confirms disease progression (PD); (2) a new anti-tumor therapy is started; (3) death; or (4) the study ends (whichever occurs first).

[0178] (C) End of treatment:

[0179] End-of-treatment (EOT) visits are conducted after discontinuation of TTF treatment (discontinuation of durvalumab and / or GemCis alone does not constitute an EOT) or before the initiation of a new alternative antitumor therapy.

[0180] (D) Safety follow-up:

[0181] After the EOT visit, a safety follow-up is conducted to collect data on toxicities that occur during treatment.

[0182] (E) Survival follow-up:

[0183] After the above visits are completed, a telephone interview is conducted with the patient or the patient's caregiver every 12 weeks (±14 days) to conduct a survival follow-up assessment.

[0184] This study assessed progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS) as endpoints for efficacy and safety evaluation according to the "Standards for Evaluation of Efficacy in Solid Tumors V1.1".

[0185] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this disclosure. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0186] Although embodiments of the present disclosure have been shown and described above, it is to be understood that the above embodiments are exemplary and should not be construed as limiting the present disclosure. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present disclosure.

Claims

1. A system for treating biliary tract cancer, comprising: A device for applying an alternating electric field to a target area of ​​a patient, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm, and the patient has biliary tract cancer and has been, is, or will be receiving combined treatment with immune checkpoint inhibitors and chemotherapy drugs.

2. The system of claim 1, wherein the biliary tract cancer comprises unresectable biliary tract cancer, locally advanced biliary tract cancer, or metastatic biliary tract cancer.

3. The system according to claim 1, wherein the biliary tract cancer includes intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

4. In the system according to claim 1, the electric field is applied for a period of not less than 24 hours.

5. The system according to claim 1, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab.

6. The system of claim 1, wherein the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

7. The system of claim 6, wherein the platinum-based drug comprises cisplatin or carboplatin; and / or the antimetabolite comprises gemcitabine.

8. The system of claim 1, wherein the immune checkpoint inhibitor and / or the chemical drug are administered by intravenous injection.

9. The system of claim 1, wherein the immune checkpoint inhibitor and the chemical drug are administered simultaneously or sequentially; and / or the immune checkpoint inhibitor is administered to the patient once every three weeks (Q3W).

10. The system of claim 1, wherein the chemical drug is administered as a second dose 7 days after the first dose is administered.

11. The system of claim 1, wherein the immune checkpoint inhibitor is administered after the chemotherapy treatment is completed.

12. The system of claim 1, wherein the immune checkpoint inhibitor is administered at the end of the patient's last treatment cycle.

13. The system of claim 12, wherein the immune checkpoint inhibitor is administered to the patient once every four weeks (Q4W).

14. The system according to claim 1, wherein the dose of the immune checkpoint inhibitor is 1000-2000 mg.

15. The system of claim 1, wherein the dose of the immune checkpoint inhibitor is 1500 mg.

16. The system of claim 1, wherein the chemical agent comprises gemcitabine at 1000 mg / m² and cisplatin at 25 mg / m² administered intravenously.

17. Use of a combination of an alternating electric field, an immune checkpoint inhibitor, and a chemical drug in the formation of a medicament for the treatment of biliary tract cancer, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm.

18. The use according to claim 17, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

19. The use according to claim 18, wherein the anti-PD-L1 antibody is selected from: durvalumab, avelumab, sugemalimab, and atezolizumab; and / or the platinum-based chemical drug comprises cisplatin or carboplatin; and / or the antimetabolite chemical drug comprises gemcitabine.

20. The use according to any one of claims 17-19, wherein the alternating electric field is applied for a period of not less than 24 hours.

21. Use of an alternating electric field in the preparation of a drug that promotes immunogenic death of biliary tract cancer cells, wherein the frequency of the alternating electric field is 100-300 kHz and the field strength is 1-3 V / cm, and the biliary tract cancer patient is receiving drug treatment prior to, after, or concurrently with the treatment, the drug comprising immune checkpoint inhibitors and chemotherapeutic agents.

22. The use according to claim 21, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the chemical drug comprises a platinum-based chemical drug and / or an antimetabolite chemical drug.

23. The use according to claim 22, wherein the anti-PD-L1 antibody is selected from durvalumab, avelumab, sugemalimab, and atezolizumab; the platinum-based chemical drug comprises cisplatin or carboplatin; and the antimetabolite chemical drug comprises gemcitabine.

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