CN116887837A - Combination therapy for the treatment of cancer - Google Patents
Combination therapy for the treatment of cancer Download PDFInfo
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- CN116887837A CN116887837A CN202280013623.5A CN202280013623A CN116887837A CN 116887837 A CN116887837 A CN 116887837A CN 202280013623 A CN202280013623 A CN 202280013623A CN 116887837 A CN116887837 A CN 116887837A
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Abstract
The present application provides a method of treating a tumor/cancer and/or generating a memory immune response against a tumor/cancer in a subject in need thereof, comprising administering to the subject an effective amount of a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, wherein the PI3K inhibitor, oncolytic virus, and PD-1 inhibitor can be administered simultaneously, separately, or sequentially. The application also provides a pharmaceutical composition comprising a PI3K inhibitor, an oncolytic virus and a PD-1 inhibitor, and a pharmaceutically acceptable carrier, and a kit comprising the pharmaceutical composition and instructions for use.
Description
The present application claims priority to chinese patent application 202110791354.2 filed on day 7 and 13 of 2021, entitled "combination therapy for treating cancer" by the chinese national intellectual property agency, the contents of which are incorporated herein by reference in their entirety.
The present application relates to a combination therapeutic method and pharmaceutical composition comprising administering to a subject in need thereof a PI3K inhibitor, an oncolytic virus and a PD-1 inhibitor.
Immune Checkpoint Inhibitors (ICI) using anti-CTLA 4 antibodies and anti-PD (L) 1 antibodies have led to a profound revolution in cancer immunotherapy. Since the first Immune Checkpoint Inhibitor (ICI) in 2001 was approved, this series of drugs has attracted considerable attention due to the long-lasting clinical effects on complex cancers. However, a large number of cancer patients still do not respond to ICI treatment. Up to now, the response rate of cancer patients treated with ICI is about 20%, so it is very necessary to find a more effective immunotherapeutic approach to further treat cancer with the immune system.
Pan I type P13K inhibitors
PI3K-AKT-mTOR signaling pathway disorders occur at a high rate in cancer patients, which primarily regulate critical cellular processes such as cell growth, proliferation, metabolism, etc., and can promote survival, expansion and spread of cancer cells in cancer patients. PI3K isoform p110α, encoded by the PIK3CA gene, is the second most readily mutated proto-oncogene in human cancers.
In the PI3K family, pi3kβ is also involved in tumorigenesis, but pi3kα plays a major role, and in addition, the other two isomers pi3kγ and pi3kδ play an important regulatory role on the immune system. Pi3kδ is capable of modulating and maintaining the function of regulatory T cells (tregs), pi3kγ is capable of not only recruiting suppressive myeloid cells into the cancer microenvironment, but also enhancing their suppressive ability against T cell anti-cancer effects.
The compound (AN 2025) with the structure of the formula I and pharmaceutically acceptable salts thereof are oral pan I type PI3K inhibitors, and the indication is head and neck squamous cell carcinoma at the three clinical research and development stages. It is capable of inhibiting not only wild-type pi3α but also mutant p13kα, the mutation sites including H1047R, E542K and E545K. At the same time, it also has inhibitory activity against other PI3K isomers (pi3kβ, pi3kγ, pi3kδ). AN2025 has been shown clinically to be effective in causing breast cancer by PI3K/PIK3CA mutation, and the highest response patients all had PIK3CA mutation (Campone M et al Eur J cancer 2018; 103:147-154). AN2025 can also down-regulate Tregs and inhibitory myeloid cell function and its ability to enter the tumor microenvironment by inhibiting PI3K delta and PI3K gamma (O' Donnell JS et al Semin Cancer biol.2018;48:91-103.Borazanci et al.The Oncol.2020).
Oncolytic viruses
Oncolytic viruses are a class of tumor-killing viruses with replication capacity. Besides the tumor cell lysis caused by selectively infecting the tumor cell, the oncolytic virus can further kill the tumor by activating immune response. In one aspect, oncolytic virus-infected tumor cells are capable of releasing a large number of inflammatory factors, activating natural killer cells (NK cells), initiating an innate immune response to kill the tumor. The inflammatory environment can promote migration of natural killer cells, dendritic cells, and T cells into the tumor microenvironment, causing "cold" tumors to become "hot". Oncolytic viruses, on the other hand, lyse tumor cells to produce a large amount of tumor-associated antigens, and antigen presenting cells kill tumor cells by processing and presenting tumor-associated antigens and virus-associated antigens to T cells, activating an adaptive immune response.
Pelaroep is a non-pathogenic, naturally occurring unmodified reovirus type 3. At present, the medicine is about to enter a three-stage clinical stage of global multicenter, and the indication is advanced metastatic breast cancer. In previous phase two clinical studies, the combination of pelaroep and paclitaxel has achieved good experimental results for the treatment of advanced/metastatic breast cancer.
anti-PD (L) 1 antibodies
The PD1 and PDL1 signaling pathways play a critical role in regulating T cell activation. PDL1 is expressed mainly in immune cells and most human cancer cells. In the tumor microenvironment, cancer PDL1 interacts with PD1 on T cells, ultimately inhibiting the cancer cell killing activity of T cells. A number of successful cases of anti-PD (L) 1 therapy make it a cornerstone of modern tumor immunotherapy.
The Pelareorep can specifically kill tumor cells in a self-specific mode to generate inflammatory tumor microenvironment and promote immune cell infiltration into tumor tissues so that cold tumors become hot; AN2025 is able to systematically regulate immunosuppressive tumor microenvironment, both of which are complementary to the mechanisms of anti-PD (L) 1 therapy killing cancer. This triple combination provides an ideal treatment option for most patients with advanced solid tumors.
Disclosure of Invention
The invention aims to solve the technical problem of low response rate of cancer patients treated by ICI in the prior art. The object of the present invention is to provide a more effective way of immunotherapy for the further treatment of cancer with the immune system.
In view of the above, the present invention provides a method for treating cancer by combining PI3K inhibitor, oncolytic virus and PD-1 inhibitor, wherein the antitumor activity of the method is significantly superior to any two-two combination.
Specifically, the invention provides the following technical scheme:
a method of treating a tumor/cancer and/or generating a memory immune response against a tumor/cancer in a subject in need thereof, comprising administering to the subject an effective amount of a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, wherein the PI3K inhibitor, oncolytic virus, and PD-1 inhibitor can be administered simultaneously, separately, or sequentially.
In one embodiment of the present invention, wherein the PI3K inhibitor is selected from the group consisting of pi3kα, pi3kβ, pi3kγ, and pi3kδ subtype inhibitors.
In one embodiment of the present invention, wherein said PI3K inhibitor is selected from the group consisting of Idelalisib, copanlisib, duvelisib, alpelisib, seletalisib, gedatolisib, rigosertib sodium, leniolisib, umbralisib, buparlisib (AN 2025), AMG-319, GM-604, acalisib, bimiralisib, GDC-0084, ACP-319, tenalisib, serabelisib, SF-1126, nemiralisib, fimepinostat, LY-3023414, voxtalisib, dactolisib, parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
In one embodiment of the present invention, wherein the PI3K inhibitor is a compound having formula (I) or a pharmaceutically acceptable salt thereof,
In one embodiment of the invention, wherein the oncolytic virus comprises a naturally occurring, modified or recombinant virus having replication-competent, and capable of infecting and lysing tumor cells.
In one embodiment of the present invention, wherein the oncolytic virus is selected from the group consisting of reovirus (reovirus), newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia virus (vaccinia virus), filterable virus (parapox orf virus), sindbis virus (Sindbis virus) and herpes simplex virus (herpes simplex virus).
In one embodiment of the invention, wherein the PD-1 inhibitor is selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, tremelimumab, terlipressin Li Shan, singe Li Shan, tirelimumab, kari Li Zhushan, and any combination thereof.
In one embodiment of the invention, the PI3K inhibitor, oncolytic virus and PD-1 inhibitor may be formulated in a dosage form for oral, buccal or parenteral administration, e.g. the dosage form for oral administration may be a tablet, capsule, powder, pill, granule, suspension, solution and solution preconcentrate, emulsion and emulsion preconcentrate, e.g. the dosage form for parenteral administration may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration, e.g. may be a solution, powder injection or lyophilisate.
In one embodiment of the invention, wherein the PI3K inhibitor is administered in a dosage form that is oral, buccal or parenteral, e.g., the dosage form of the oral route may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g., the dosage form of the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
In one embodiment of the invention, wherein the PI3K inhibitor is administered 1 or 2 times per day; or 1 time every 2, 3, 4, 5, 6, 7, 8, 9, 10 days or every 1, 2 or 3 weeks of administration of the PI3K inhibitor; or the PI3K inhibitor is administered 1 time per day for 5 consecutive days per week, followed by 2 days intervals.
In one embodiment of the present invention, wherein the PI3K inhibitor is administered in an adult human in a dosage range of from about 20 mg/day to about 200 mg/day, from about 30 mg/day to about 160 mg/day, from about 60 mg/day to about 120 mg/day.
In one embodiment of the present invention, wherein said PI3K inhibitor is administered to said subject at an effective dose of about 0.5 to about 250mg/kg, about 1 to about 250mg/kg, about 2 to about 200mg/kg, about 3 to about 120mg/kg, about 5 to about 250mg/kg, about 10 to about 200mg/kg, or about 20 to about 120 mg/kg.
In one embodiment of the invention, wherein the oncolytic virus is administered in a dosage form that is oral, buccal or parenteral, for example the dosage form of the oral route may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, for example the dosage form of the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
In one embodiment of the invention, wherein the oncolytic virus is administered at least once daily, repeatedly on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21 or 28, or for any period of 2-28 days, or longer, the oncolytic virus is administered continuously or intermittently daily for any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 24 hours, or for any period of 1-24 hours; preferably, the duration of administration is 5, 15, 30, 60, 90, 120, 150 or 180 minutes or any time or more of 5-180 minutes.
In one embodiment of the present invention, wherein the dose of the oncolytic virus administered in an adult human varies according to individual differences (age, weight, sex), the virus administered varies, for example at about 10 per person 2 -10 17 PFU (colony forming units) or TCID 50 (half of the tissue culture infection dose). In one embodiment of the present invention, wherein the amount of PFU is about 1.0 to about 10 PFU/kg 15 An effective dose of PFU/kg is administered to the subject.
In one embodiment of the present invention, wherein the PD-1 inhibitor is administered by an parenteral route, for example, the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
In one embodiment of the present invention, the PD-1 inhibitor is formulated as a solution, a freeze-dried preparation, or a powder injection.
In one embodiment of the present invention, wherein said PD-1 inhibitor is administered at an effective dose of 0.05mg/kg, 0.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg or 8 mg/kg.
In one embodiment of the invention, wherein the tumor/cancer comprises a primary tumor/cancer, a recurrent tumor/cancer, or a metastatic tumor/cancer, including solid tumors and hematological tumors.
In one embodiment of the invention, wherein the tumor/cancer is selected from the group consisting of: head and neck squamous cell carcinoma, head and neck carcinoma, brain cancer, glioma, glioblastoma multiforme, neuroblastoma, central nervous system carcinoma, neuroendocrine tumor, laryngeal carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, thyroid carcinoma, malignant pleural mesothelioma, lung carcinoma, breast carcinoma, liver carcinoma, hepatoma, hepatobiliary carcinoma, pancreatic carcinoma, stomach carcinoma, gastrointestinal carcinoma, intestinal carcinoma, colon carcinoma, colorectal carcinoma, renal carcinoma, clear cell renal cell carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, bladder carcinoma, prostate carcinoma, testicular carcinoma, skin carcinoma, melanoma, leukemia, lymphoma, bone carcinoma, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasm, squamous cell carcinoma, ewing's sarcoma, systemic light chain amyloidosis, and merkel cell carcinoma; more preferably, the lymphoma is selected from: hodgkin's lymphoma, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, primary mediastinum large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, T-cell/tissue cell enriched large B-cell lymphoma, and lymphoplasmacytic lymphoma, said lung cancer being selected from the group consisting of: non-small cell lung cancer and small cell lung cancer, said leukemia being selected from the group consisting of: chronic myeloid leukemia, acute myeloid leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and myeloid leukemia.
In addition, the present invention provides a pharmaceutical composition and/or pharmaceutical combination comprising a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
In the pharmaceutical composition and/or pharmaceutical combination of the invention, wherein the PI3K inhibitor is selected from the group consisting of pi3kα, pi3kβ, pi3kγ, pi3kδ subtype inhibitors.
In the pharmaceutical compositions and/or combinations of the present invention, wherein the PI3K inhibitor is selected from the group consisting of Idelalisib, copanlisib, duvelisib, alpelisib, seletalisib, gedatolisib, rigosertib sodium, leniolisib, umbralisib, buparlisib (AN 2025), AMG-319, GM-604, acalisib, bimiralisib, GDC-0084, ACP-319, tenalisib, serabelisib, SF-1126, nemiralisib, fimepinostat, LY-3023414, voxtalisib, dactolisib, parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
In the pharmaceutical composition and/or pharmaceutical combination of the invention, wherein the PI3K inhibitor is a compound having formula (I) or a pharmaceutically acceptable salt thereof,
in the pharmaceutical compositions and/or combinations of the invention, wherein the oncolytic virus comprises a naturally occurring, modified or recombinant virus having replication-competent properties and capable of infecting and lysing tumor cells.
In the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the oncolytic virus is selected from the group consisting of reovirus (reovirus), newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovus), vaccinia virus (vaccinia virus), filterable virus (parapox orf virus), sindbis virus (Sindbis virus) and herpes simplex virus (herpes simplex virus).
In the pharmaceutical composition and/or pharmaceutical combination of the invention, wherein the PD-1 inhibitor is selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, tremelimumab, terlipressin Li Shan, singe Li Shan, tirelimumab, kari Li Zhushan, and any combination thereof.
In the pharmaceutical compositions and/or pharmaceutical combinations of the invention, wherein the PI3K inhibitor, oncolytic virus and PD-1 inhibitor may be in the same and/or separate dosage forms (dosage forms).
In the pharmaceutical compositions and/or pharmaceutical combinations of the invention, wherein the pharmaceutical compositions and/or pharmaceutical combinations may be formulated for oral, buccal or parenteral administration, e.g. the oral route may be in the form of tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. the parenteral route may be in the form of intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration, e.g. solutions, powder injection or lyophilisates.
In the pharmaceutical compositions and/or pharmaceutical combinations of the invention, the PI3K inhibitor may be formulated in a dosage form for oral, buccal or parenteral administration, e.g. the dosage form for oral administration may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. the dosage form for parenteral administration may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration, e.g. may be solutions, powder injection or lyophilisates.
In the pharmaceutical compositions and/or pharmaceutical combinations of the invention, wherein the oncolytic virus may be formulated into a dosage form for oral, buccal or parenteral route, e.g. the dosage form for oral route may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. the dosage form for parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
In the pharmaceutical compositions and/or pharmaceutical combinations of the invention, wherein the PD-1 inhibitor may be formulated into a dosage form for administration by an parenteral route, e.g. the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration, e.g. may be a solution, powder injection or lyophilized formulation.
In the pharmaceutical compositions and/or combinations of the invention, a PI3K inhibitor is included in a dosage of 1-1000mg per unit dosage form (unit dose form), e.g., the dosage is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or a value between any two of the above.
In the pharmaceutical compositions and/or combinations of the present invention, about 10 per unit dosage form (unit dose form) is included 2 PFU to about 10 17 Oncolytic viruses at a PFU dose, e.g., at a dose of 10 2 、10 3 、10 4 、10 5 、10 6 、10 7 、10 8 、10 9 、10 10 、10 11 、10 12 、10 13 、10 14 、10 15 、10 16 、10 17 PFU or TCID 50 Or a value between any two of the above.
In the pharmaceutical compositions and/or combinations of the invention, wherein the PD-1 inhibitor is contained in a dose of 1-5000mg per unit dosage form, e.g., the dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2500, 2600, 2750, 2800, 3000, 3500, 4000, 4500, 5000mg or a value between any two of the above.
The present invention provides a pharmaceutical composition and/or pharmaceutical combination for use in the treatment of a tumor/cancer and/or generating a memory immune response against a tumor/cancer.
The present invention provides the use of a pharmaceutical composition and/or pharmaceutical combination for the manufacture of a medicament for the treatment of a tumor/cancer and/or for the generation of a memory immune response against a tumor/cancer.
In addition, the invention provides a kit comprising the pharmaceutical composition and/or pharmaceutical combination of the invention, and instructions for use, wherein the PI3K inhibitor, oncolytic virus, and PD-1 inhibitor may be in the same and/or separate containers.
FIG. 1 tumor growth curves for single EMT6 tumors treated with different drug combinations of AN2025, pelarorep and anti-PD-1 antibodies. Each group had 10 mice. AN2025 dosing: 30mg/kg, orally administered (PO) once daily. Pelaroep administration: 2X 10 8 TCID 50 Intravenous administration was once daily for 2 consecutive days, followed by discontinuation of the administration for 4 days. anti-PD-1 antibody administration: 10mg/kg, intravenous (IV) every 6 days.
Definition of terms:
Unless otherwise indicated herein, the terms used herein have the conventional meaning in the art to which they pertain.
The term "PI3K inhibitor" refers herein to phosphatidylinositol 3-kinase, a highly conserved family of enzymes, an important component of the intracellular PI3K-Akt-mTOR signaling axis. Examples of PI3K inhibitors include, but are not limited to, PI3kα, PI3kβ, PI3kγ, PI3kδ subtype inhibitors. Specific embodiments include, but are not limited to Idelalisib, copanlisib, duvelisib, alpelisib, seletalisib, gedatolisib, rigosertib sodium, leniolisib, umbralisib, buparlisib (AN 2025), AMG-319, GM-604, acalisib, bimiralisib, GDC-0084, ACP-319, tenalisib, serabelisib, SF-1126, nemiralisib, fimepinostat, LY-3023414, voxtalisib, dactolisib, parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof. Preferred examples include, but are not limited to, compounds of formula I (also referred to herein as AN 2025) as taught herein
The term "oncolytic virus" refers herein to a virus that is capable of replicating in and killing tumor cells. Including reovirus (reovirus), newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia virus (vaccinia virus), filterable virus (parapox orf virus), sindbis virus (Sindbis virus) and herpes simplex virus (herpes simplex virus). Wherein the oncolytic viruses include, but are not limited to, oncolytic viruses of members of the following viral families: myophagidae (myoviridae), longwell (siphoviridae), shortwell (podoviridae), lamivudinae (tecaviridae), coverlay (curtiviridae), blastophaidae (plasmaviridae), lipochaidae (lipothrix viridae), picophagostimulaidae (fuseleviridae), poxviridae (poxyiridae), iridoviridae, alga DNA viridae (phycodnaviridae), baculovirusidae (baculoviridae), herpesviridae (hepeviridae), adenoviridae (adenoviridae), papovaviridae (papovaviridae), polysomyvidae (polynaphaniviridae), filoviridae (inoviridae), picoviridae (picoviridae), bipropvidae (bipropvidae) circular (circoviridae), parvoviridae (parvoviridae), hepadnaviridae (hepadnaviridae), retroviridae (retroviridae), saccharactidae (cicoviridae), reoviridae (reoviridae), birnaviridae (birnaviridae), paramyxoviridae (paramyxoviridae), rhabdoviridae (rhabdariae), filoviridae (filoviridae), orthomyxoviridae (orthomyxoviridae), bunyaviridae (bunyaviridae), arenaviridae (arenaviridae), leiomyoviridae (levoviridae), picoviridae (picoviridae), companion viridae (sequiviridae), comoviridae (oviridae), potyviridae (potyviridae), caliae (calividae), astroviridae (astroviridae), wild Tian Bingdu (nodaviridae), tetraviridae (tetraviridae), tomato family of candidiviridae (tombusviridae), coronaviridae (coronaviridae), flaviviridae (glaaviridae), togaviridae (togaviridae), and baculoviridae (barnaviridae). In addition, methods are provided that include immunoprotecting viruses and recombinant viruses of these viruses. In addition, methods are provided that include the use of a combination of at least two oncolytic viruses. Preferably, the oncolytic virus provided by the present method is reovirus (reovirus). More preferably, the oncolytic virus provided by the present method is a serotype 3 detoxified reovirus (serotype-3-alerting strain). Examples of oncolytic viruses include, but are not limited to, onyx-015, DNX-2401, coloAdl, oncos102, prostAtak, CG0070, pexavec, GLONC, HF10, HSV1716, reolysin, and Cavatak.
The term "PD-1 inhibitor" refers to an "anti-PD 1/PDL1 antibody," which is an antibody directed against programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1). Exemplary antibodies include, but are not limited to, antibodies as shown in patent nos. US7,029,674, US7,488,802, US7,521,051, US8,008,449, US8,354,509, US8,617,546, and US8,709,417. Specific examples of PD-1/PD-L1 inhibitors also include Nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, tremelimumab, terlipressin Li Shan, singeing Li Shan, tirelizumab, kari Li Zhushan, and any combinations thereof.
"treating," "treating" and "treatment" refer to reducing, inhibiting and/or reversing the progression of a disease (e.g., tumor/cancer) in a subject in need thereof. The term "treatment" includes any sign of successful treatment or amelioration of a disease, including any objective or subjective parameter, such as alleviation; moderating; reduced symptoms or greater tolerance to injury, pathology or condition in the subject; delay or slow down the rate of development, etc. Measurement of treatment or improvement may be based on, for example, the results of physical, pathological, and/or diagnostic examinations as known in the art. For example, in one embodiment, reference to "treating" a cancer in accordance with the present invention refers to the use of a PI3K inhibitor, oncolytic virus, and PD-1 inhibitor of the present invention in combination therapy to achieve at least one positive therapeutic outcome, such as a reduction in the number of cancer cells, a reduction in the size of a tumor, a reduction in the rate at which tumor cells infiltrate peripheral organs, or a reduction in the rate of tumor metastasis or tumor growth, in a subject suffering from cancer or diagnosed with cancer.
Treatment may also refer to reducing the risk of onset or onset of disease, or reducing disease recurrence (e.g., extending the time to recurrence) than would occur without such measures. In the medical field, such treatment is also referred to as "prophylaxis".
The term "effective amount" or "therapeutically effective amount" refers to an amount effective to treat a disease as recorded by clinical testing and evaluation, patient observation, and the like. An "effective amount" may further mean an amount that causes a detectable change in biological or chemical activity. The detectable change may be detected and/or further quantified by one of ordinary skill in the relevant mechanisms or methods. Furthermore, an "effective amount" may refer to an amount that maintains a desired physiological state (i.e., reduces or prevents significant decline and/or promotes improvement of the condition). An "effective amount" may further refer to a therapeutically effective amount.
In some embodiments, the PI3K inhibitor is administered to the subject in an effective amount. The effective amount is typically from 0.01mg/kg body weight to 500mg/kg body weight per day. In some embodiments, the pharmaceutically acceptable compositions may be formulated such that a dose of 0.01mg/kg body weight to 200mg/kg body weight or 0.01mg/kg body weight to 100mg/kg body weight of the compound per day (e.g., a dose of 0.75mg to 7.5g or 15g based on 75kg of human) may be administered to a subject receiving these compositions. In certain embodiments, the active pharmaceutical ingredients of the present invention are formulated to provide a dosage of 0.01mg/kg to 70mg/kg (e.g., a dosage of 0.75mg to 5.25g based on 75kg of a human).
In some embodiments, an effective dose of PI3K inhibitor is about 0.5 to about 250mg/kg, about 1 to about 250mg/kg, about 2 to about 200mg/kg, about 3 to about 120mg/kg, about 5 to about 250mg/kg, about 10 to about 200mg/kg, or about 20 to about 120mg/kg. In some embodiments, the effective dose comprises about 0.5mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 8mg/kg, 10mg/kg, 20mg/kg, 25mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg, and 300mg/kg. The dosage form may take a variety of suitable forms, such as a tablet or capsule, and the effective dose may be provided in one or more unit dosage forms (e.g., tablet, capsule) and provided 1,2 or 3 times per day, or at intervals of, for example, 4, 8 or 12 hours throughout the day. The tablet or capsule may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100 or 1,250mg of the compound. For example, in some embodiments, administering a PI3K inhibitor to a human subject may include a daily dose of PI3K inhibitor in the range of 100-1,250, 150-1,000, 200-800, or 250-750mg, which may be administered all once a day, or in multiple portions at intervals throughout the day. Liquid formulations may also be prepared so that any dose may be readily and conveniently dispensed.
In some embodiments, the oncolytic virus is administered to the subject at an effective dose. The effective dose is determined by individual differences and its influencing factors include, but are not limited to, age, sex, weight and the nature of the tumor, such as the type and size of the tumor, etc. For administration to a subject, the effective dose is typically 10 3 -10 12 PFU or TCID 50 . The effective dose may also be 1.0PFU/kg body weight to about 10 15 PFU/kg body weight, e.g. from 10 2 PFU/kg body weight to 10 13 PFU/kg body weight. Preferably, the effective dose is about 1X 10 8 Up to 1X 10 12 PFU or TCID 50 . For example, for administration to a subject, the effective dose is about 10 2 To 10 17 PFU。
In some embodiments, the oncolytic virus may be administered to the subject in a single or multiple administrations, either simultaneously or consecutively. For example, administration may last from days to weeks. Oncolytic viruses can be administered to one or more tumor sites in the same individual. The dosage form may take a variety of suitable forms, such as administration of the oncolytic virus in a dosage form that is oral, buccal or parenteral, and the effective dose may be provided in one or more unit dosage forms (e.g., tablets and capsules) and at least once daily. Tablets and capsules, for example, may contain about 10 2 PFU to about 10 17 PFU doses of oncolytic virus. For example, the dosage is 10 2 、10 3 、10 4 、10 5 、10 6 、10 7 、10 8 、10 9 、10 10 、10 11 、10 12 、10 13 、10 14 、10 15 、10 16 、10 17 PFU or TCID 50 Or a value between any two of the above. The antibodies will typically be admixed with a pharmaceutically acceptable non-toxic carrier substance (e.g., physiological saline or phosphate buffered saline) prior to administration, and may be administered using any medically appropriate procedure, including, for example, but not limited to, intravenous or intra-arterial administration and injection into the cerebrospinal fluid. In some cases, intraperitoneal, intradermal, intracavity, intrathecal or direct administration of the tumor or of the artery supplying the tumor may be advantageous.
In some embodiments, an effective dose of the antibody is about 5 to about 250mg/kg, about 10 to about 200mg/kg, or about 20 to about 120mg/kg. In some embodiments, the effective dose comprises 5mg/kg, 10mg/kg, 20mg/kg, 25mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg, and 300mg/kg. The dosage form may take the form of, for example, a tablet or capsule, and the effective dose may be provided in one or more tablets, capsules, etc., and provided once a day or at intervals of, for example, 4, 8 or 12 hours throughout the day. The tablet or capsule may contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000mg of antibody. Liquid formulations may also be prepared so that any dose may be easily and conveniently dispensed.
In some embodiments, the antibody is administered to the subject in an effective amount. The effective amount is typically from 0.01mg/kg body weight to 500mg/kg body weight per day. In some embodiments, the pharmaceutically acceptable compositions may be formulated such that a dose of 0.01mg/kg body weight to 200mg/kg body weight or 0.01mg/kg body weight to 100mg/kg body weight of the compound per day (e.g., a dose of 0.75mg to 7.5g or 15g based on 75kg of human) may be administered to a patient receiving these compositions. In certain embodiments, the compositions of the present invention are formulated to provide a dose of 0.01mg/kg to 70mg/kg (e.g., a dose of 0.75mg to 5.25g based on 75kg of human).
An effective amount of antibody may be, for example, 0.05mg/kg, 0.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, or 8mg/kg per dose (e.g., doses of 3.75mg to 600mg based on 75kg of human).
The dose of antibody may be administered once a week, twice, three times, four times, five times or more, once a week, once every two weeks, or even once every three weeks during the course of treatment. The administration time may be once daily, once every two days, once every three days, once every four days, once every five days, once weekly, once every two weeks, or once every three weeks. Formulations comprising antibodies can be prepared so that any dose can be easily and conveniently dispensed.
The term "subject" refers to mammalian subjects, and particularly human subjects, including male or female subjects, and includes neonatal, infant, toddler, adolescent, adult or geriatric subjects, and further includes various ethnicities and races, such as caucasian, african and asian. Herein, the subject suffers from a tumor/cancer. In one embodiment, whether the tumor patient expresses PD-L1 is not considered. In another embodiment, the tumor patient is a PD-L1 expression positive tumor patient.
The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid salt of a compound of formula I or formula II of the present invention. These salts may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free form with a suitable organic or inorganic acid, respectively, and isolating the salt so formed. Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclosulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, maritime benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalate (napthylate), 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, gluconate, stearate, succinate, tanninate, tartrate, tosylate, trifluoroacetate and xinafoate. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride/chloride salt.
The terms "tumor" and "cancer" are used interchangeably herein to refer to uncontrolled abnormal proliferation of local tissue of the body. If medical intervention is not performed in time, the tumor/cancer may grow uncontrolled and possibly metastasize to other locations in the body, ultimately leading to death of the body.
The term "cancer" may include cancers caused by genetically inherited mutations. Examples of such cancers include, but are not limited to, breast cancer, cancers that may be associated with lyframine syndrome (e.g., pediatric sarcomas, leukemia, and brain cancer), cancers that may be associated with linqi syndrome such as colon cancer, cholangiocarcinoma, brain cancer, endometrial cancer, renal cancer, ovarian cancer, pancreatic cancer, small intestine cancer, gastric and ureteral cancer, lung cancer, melanoma, prostate cancer, retinoblastoma, thyroid cancer, and uterine cancer.
Furthermore, the cancer may be the result of acquired mutations (e.g., mutations caused by diet, environment, and/or lifestyle) or somatic mutations. Examples of such cancers may include, but are not limited to, adrenal gland cancer, adrenal cortex cancer, bladder cancer, brain cancer, primary brain cancer, glioma, glioblastoma, breast cancer, cervical cancer, colon cancer (non-limiting examples include colorectal cancer, such as colon adenocarcinoma and colon adenoma), endometrial cancer, epithelial cancer, esophageal cancer, gall bladder cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (non-limiting examples include adenocarcinoma, small cell lung cancer and non-small cell lung cancer), lymphoma (non-limiting examples include B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma), melanoma, malignant pancreatic insulinoma, myeloma, multiple myeloma, ovarian cancer, pancreatic cancer (such as exocrine pancreatic cancer), prostate cancer, renal cell carcinoma, skin cancer (in addition to the cancers previously mentioned, for example squamous cell carcinoma), gastric cancer, testicular cancer, thyroid follicular cancer, wilm's tumor, choriocarcinoma, mycosis fungoides, hypercalcemia of malignancy, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell lymphoma, burkitt's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, rhabdomyosarcoma, neurosheath tumor, kaposi's sarcoma, polycythemia vera, primary thrombocythemia, hodgkin's disease, non-hodgkin's lymphoma, soft tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma and retinoblastoma.
"metastatic cancer" refers to cancer in which cancer cells from one organ or body part have spread (by "metastasis") to another non-adjacent organ or body part. Cancers at a non-adjacent organ or body part ("secondary tumor" or "metastatic tumor") include cancer cells derived from an organ or body part from which cancer cells have spread. Sites where secondary tumors may occur include, but are not limited to, lymph nodes, lungs, liver, brain and/or bones.
The terms "pharmaceutically acceptable" and "pharmaceutically acceptable" are used interchangeably herein to refer to the types generally accepted by those skilled in the pharmaceutical arts. Such as pharmaceutically acceptable salts, pharmaceutically acceptable carriers, and the like.
"oral dosage form" refers to a pharmaceutical formulation prepared for use in an individual by the oral route of administration. Examples of known oral dosage forms include, but are not limited to, tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, and the like. In some methods, powders, pills, granules, capsules and tablets may be coated with suitable polymers or common coating materials to achieve, for example, greater stability in the gastrointestinal tract or to achieve a desired release rate. In addition, the capsule shells of the powder, pill or granule are further coated. The tablets may be scored to facilitate drug administration split.
When the compounds of formula I according to the invention are administered as oral formulations, they are preferably coated with a film. Suitable membranes are known in the art and are commercially available or can be manufactured according to known methods. Typically, the film coating material is a hydrophilic polymer such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, and the like. The film coat composition ingredients may include conventional amounts of plasticizers such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin; and opacifiers, such as titanium dioxide and colorants, such as iron oxide, aluminum lakes, and the like. Typically, the film coating material is applied in an amount that provides, for example, a film coating in the range of 1% to 6% of the solid oral dosage form.
When the oncolytic virus of the present invention is administered as an intravenous drip formulation, two commonly used fluids may be selected as follows: crystalline fluids and colloidal fluids. Crystals are aqueous solutions of mineral salts or other water-soluble molecules. Colloids contain larger insoluble molecules, such as gelatin; blood itself is a gel. The most common crystallographic fluid is physiological saline, i.e. 0.9% sodium chloride solution, which approximates the concentration in blood (isotonicity). Ringer's lactic acid or ringer's acetic acid is another isotonic solution commonly used for bulk fluid replacement. Other pharmaceutically acceptable carriers include phosphate buffered saline or other physiologically acceptable buffers, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum powder, calcium phosphate, alginates, scutellaria, gelatin, calcium silicate, microcrystals, cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Pharmaceutical compositions may also include, but are not limited to, lubricants such as talc, magnesium stearate, and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; a sweetener; and (3) a flavoring agent.
The terms "comprising" and "including" as used herein have an open and non-limiting meaning unless otherwise specified. For example, other therapeutic agents, such as "biologic therapeutic agents", "chemotherapeutic agents", may be included in addition to the pharmaceutical combination of PI3K inhibitors, oncolytic viruses, and PD-1 inhibitors of the present invention.
Where "biotherapeutic agent" refers to a biomolecule, such as an antibody or fusion protein, that blocks ligand/receptor activity in any biological pathway that supports tumor maintenance and/or growth or inhibits tumor immune responses. For example, "biotherapeutic agents" include, but are not limited to: alemtuzumab, bevacizumab Shan Kangwei statin, katuzumab, cetuximab, denouzumab, gemtuzumab, ipilimumab, nituzumab, ofatuzumab, panitumumab, rituximab, tositumomab, trastuzumab, nal Wu Liyou mab, actigzumab, dulvacizumab, abamectin.
Wherein "chemotherapeutic agent" is a chemical compound that may be used in the treatment of cancer including, but not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle toxin plant alkaloids, cytotoxic/antitumor biotin, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligonucleotides that inhibit gene expression associated with abnormal cell proliferation or tumor growth. For example, the number of the cells to be processed, examples of chemotherapeutic agents include, but are not limited to, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analog, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, calcium folinic acid, sirolimus, irinotecan sirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabotinib, cerulolanib, crizotinib, darafatinib, dacatinib, danarotinib, dasatinib, povtinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinatinib, everatinib, imatinib, inipa, lapatinib, lenvatinib, linifanib, linsitinib, martetinib, momelotinib, mo Tisha, lenatinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, piciliib, prantinib, quintinib, regtinib, rigosertib, rucaparib, ruxolitinib, celecoxib, soridegabib, sorafenib, sunitinib, tiratinib, tivantinib, tofacitinib, vanadulteb, vanadzutinib, vanadzuatib.
The choice of the dosage regimen for the combination therapy of the invention depends on a number of factors, such as: the rate of turnover of solid serum or tissue, the level of symptoms, the overall immunogenicity, and the accessibility of the target cells, tissues, or organs in the subject. Preferably, the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient, consistent with acceptable levels of side effects. Thus, the dosage and frequency of administration of each of the biologic and chemotherapeutic agents in combination therapy depends in part on the particular therapeutic agent, the severity of the cancer being treated, and the patient's characterization.
The combination therapy of the invention may be administered either pre-operatively or post-operatively to remove the tumor, or may be administered before, during, or after the radiation treatment.
WO2007084786 specifically sets forth the compounds of formula I of the present invention, which compounds or pharmaceutically acceptable salts thereof and processes for their preparation are disclosed in the examples of WO2007084786, which are incorporated herein by reference in their entirety.
The invention is further illustrated by the following examples, which are not meant to limit the scope of the invention in any way.
In some embodiments, administration of a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor in combination results in an enhancement of the PD-1 inhibitor such that, for example, a smaller dose or longer time interval of the PD-1 inhibitor may be effective for treatment.
"antibodies" include all types of immunoglobulins, including IgG, igM, igA, igD and IgE or fragments thereof, which are suitable for use in the medical uses disclosed herein. Antibodies may be monoclonal or polyclonal, and may be of any species origin, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that remain specifically bound to a protein or epitope (PDL 1 or PD 1) to which an antibody used in the present invention binds are included within the scope of the term "antibody". Such fragments can be generated by known techniques. Antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes. Antibodies can be obtained or prepared using methods known in the art.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1: combination therapy of a compound of formula I (AN 2025), oncolytic virus (Pelareorp) and AN anti-PD-1 antibody for the treatment of mouse EMT6 tumors
Materials and methods
Reagents and instrumentation: pelaroep is offered by the company; AN2025 is purchased from MedChem Express. Antibodies to mouse PD-1 (clone number: RMP 1-14) were purchased from BioXcell.
Cell line: mouse breast cancer EMT6 cells (CRL-2755) were purchased from the tissue culture center of the United states. Cells were cultured in DMEM medium supplemented with 10% fetal bovine serum at 37 ℃ and 5% carbon dioxide in an incubator and subcultured twice a week until the necessary number of cells for inoculation of mice were obtained.
Animals: balB/c female mice were purchased from The Jackson Laboratory for 6-8 weeks. Animals were housed in mini-isolation cages and 12h light/dark cycles were performed. The cages were replaced twice a week. Animals were observed once a week and clinical signs were recorded.
Animal study: harvesting EMT6 cells cultured in vitro at 2X 10 6 Cell/ml cell concentration was suspended in 100 μl of serum-free medium and injected into mice subcutaneously (sc) on the right lower back using a syringe. After several days of cell implantation, the mice were randomly allocated based on tumor size such that the average tumor volume of each group of mice was 76.82mm 3 . AN2025 dosing: 30mg/kg, orally administered (PO) once daily. Pelaroep administration: 2X 10 8 TCID 50 Intravenous administration was performed once daily for 2 consecutive days, followed by discontinuation of the administration for 4 days, which was taken as a dosing cycle for subsequent administration. anti-PD-1 antibody administration: 10mg/kg, administered as Intravenous (IV) every 6 days. Tumor size was measured 2-3 times per week with a digital caliper and using the formula (l×w) 2 )/2=mm 3 Calculating a volume, whereinl and w refer to the larger and smaller orthogonal dimensions collected in each measurement. Group tumor size (mean ± SEM) versus time was plotted using GraphPad Prism 9 software. Statistical analysis was performed using the Repeated Measure (RM) two-way ANOVA test.
Experimental results
As shown in fig. 1, although the combination of pelaroep, anti-PD-1 antibody, AN2025, all of which were two by two, exhibited some antitumor activity on the mouse breast cancer EMT6 model. However, the combination of the Pelareorep, the anti-PD-1 antibody and the AN2025 brings about AN anti-tumor activity which is superior to any two combinations and is remarkably superior to the combination activity of the AN2025 and the anti-PD-1 antibody (G5 Vs G3, p < 0.05).
Claims (37)
- A method of treating a tumor/cancer and/or generating a memory immune response against a tumor/cancer in a subject in need thereof, comprising administering to the subject a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, wherein the PI3K inhibitor, oncolytic virus, and PD-1 inhibitor can be administered simultaneously, separately, or sequentially.
- The method of claim 1, wherein the PI3K inhibitor is selected from the group consisting of pi3kα, pi3kβ, pi3kγ, pi3kδ subtype inhibitors.
- The method of claim 1 or 2, wherein the PI3K inhibitor is selected from Idelalisib, copanlisib, duvelisib, alpelisib, seletalisib, gedatolisib, rigosertib sodium, leniolisib, umbralisib, buparlisib (AN 2025), AMG-319, GM-604, acalisib, bimiralisib, GDC-0084, ACP-319, tenalisib, serabelisib, SF-1126, nemiralisib, fimepinostat, LY-3023414, voxtalisib, dactolisib, parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
- The method of any one of claim 1 to 3, wherein the PI3K inhibitor is a compound having formula (I) or a pharmaceutically acceptable salt thereof,
- the method of any one of claims 1-4, wherein the oncolytic virus comprises a naturally occurring, modified or recombinant virus that is replication competent and capable of infecting and lysing tumor cells.
- The method of any one of claims 1-5, wherein the oncolytic virus is selected from the group consisting of reovirus (reovirus), newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovrus), vaccinia virus (vaccinia virus), filterable virus (parapox orf virus), sindbis virus (Sindbis virus) and herpes simplex virus (herpes simplex virus).
- The method of any one of claims 1-6, wherein the PD-1 inhibitor is selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, tremelimumab, terlipressin Li Shan, singe Li Shan, tirelimumab, kari Li Zhushan, and any combination thereof.
- The method of any one of claims 1-7, wherein the PI3K inhibitor is administered in a dosage form that is oral, buccal or parenteral, e.g., the dosage form of the oral route may be a tablet, capsule, powder, pill, granule, suspension, solution and solution preconcentrate, emulsion and emulsion preconcentrate, e.g., the dosage form of the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
- The method of any one of claims 1-8, wherein the PI3K inhibitor is administered 1 or 2 times per day; or 1 time every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or every 1, 2 or 3 weeks of administration of the PI3K inhibitor; or 1 time per day for 1, 2, 3, 4, 5 or 6 days per week followed by 6, 5, 4, 3, 2 or 1 day intervals.
- The method of any one of claims 1-9, wherein the PI3K inhibitor is administered in an adult human at a dosage range of about 20 mg/day to about 200 mg/day, about 30 mg/day to about 160 mg/day, about 60 mg/day to about 120 mg/day.
- The method of any one of claims 1-10, wherein the PI3K inhibitor is administered to the subject at an effective dose of about 0.5 to about 250mg/kg, about 1 to about 250mg/kg, about 2 to about 200mg/kg, about 3 to about 120mg/kg, about 5 to about 250mg/kg, about 10 to about 200mg/kg, or about 20 to about 120 mg/kg.
- The method of any one of claims 1-11, wherein the oncolytic virus is administered in a dosage form that is oral, buccal or parenteral, e.g., the dosage form of the oral route may be a tablet, capsule, powder, pill, granule, suspension, solution and solution preconcentrate, emulsion and emulsion preconcentrate, e.g., the dosage form of the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
- The method of any one of claims 1-12, wherein the oncolytic virus is administered at least once daily, repeatedly on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, or 28, or for any period of 2-28 days, or longer, with continuous or intermittent daily administration of oncolytic virus for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 24 hours, or any period of 1-24 hours; preferably, the duration of administration is 5, 15, 30, 60, 90, 120, 150 or 180 minutes or any time or more of 5-180 minutes.
- The method of any one of claims 1-13, wherein the dose of oncolytic virus administered in an adult human varies according to individual differences (age, weight, sex), such as about 10 per human 2 -10 17 PFU (colony forming units) or TCID 50 (half of the tissue culture infection dose).
- The method of any one of claims 1-14, wherein the amount of PFU is about 1.0PFU/kg to about 10 15 An effective dose of PFU/kg is administered to the subject.
- The method of any one of claims 1-15, wherein the PD-1 inhibitor is administered by an parenteral route, e.g., the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
- The method of any one of claims 1-16, wherein the PD-1 inhibitor is formulated as a solution, a lyophilized formulation, a powder for injection.
- The method of any one of claims 1-17, wherein the PD-1 inhibitor is administered at an effective dose of 0.05mg/kg, 0.1mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, or 8 mg/kg.
- The method of any one of claims 1-18, wherein the tumor/cancer comprises a primary tumor/cancer, a recurrent tumor/cancer or a metastatic tumor/cancer, including solid tumors and hematological tumors.
- The method of any one of claims 1-19, wherein the tumor/cancer is selected from the group consisting of: head and neck squamous cell carcinoma, head and neck carcinoma, brain cancer, glioma, glioblastoma multiforme, neuroblastoma, central nervous system carcinoma, neuroendocrine tumor, laryngeal carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, thyroid carcinoma, malignant pleural mesothelioma, lung carcinoma, breast carcinoma, liver carcinoma, hepatoma, hepatobiliary carcinoma, pancreatic carcinoma, stomach carcinoma, gastrointestinal carcinoma, intestinal carcinoma, colon carcinoma, colorectal carcinoma, renal carcinoma, clear cell renal cell carcinoma, ovarian carcinoma, endometrial carcinoma, cervical carcinoma, bladder carcinoma, prostate carcinoma, testicular carcinoma, skin carcinoma, melanoma, leukemia, lymphoma, bone carcinoma, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome, myeloproliferative neoplasm, squamous cell carcinoma, ewing's sarcoma, systemic light chain amyloidosis, and merkel cell carcinoma; more preferably, the lymphoma is selected from: hodgkin's lymphoma, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, primary mediastinum large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, T-cell/tissue cell enriched large B-cell lymphoma, and lymphoplasmacytic lymphoma, said lung cancer being selected from the group consisting of: non-small cell lung cancer and small cell lung cancer, said leukemia being selected from the group consisting of: chronic myeloid leukemia, acute myeloid leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and myeloid leukemia.
- A pharmaceutical composition and/or pharmaceutical combination comprising a PI3K inhibitor, an oncolytic virus, and a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
- The pharmaceutical composition and/or pharmaceutical combination of claim 21, wherein the PI3K inhibitor is selected from the group consisting of pi3kα, pi3kβ, pi3kγ, and pi3kδ subtype inhibitors.
- The pharmaceutical composition and/or pharmaceutical combination of claim 21 or 22, wherein the PI3K inhibitor is selected from Idelalisib, copanlisib, duvelisib, alpelisib, seletalisib, gedatolisib, rigosertib sodium, leniolisib, umbralisib, buparlisib (AN 2025), AMG-319, GM-604, acalisib, bimiralisib, GDC-0084, ACP-319, tenalisib, serabelisib, SF-1126, nemiralisib, fimepinostat, LY-3023414, voxtalisib, dactolisib, parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof.
- The pharmaceutical composition and/or pharmaceutical combination according to any one of claim 21-23, wherein the PI3K inhibitor is a compound having formula (I) or a pharmaceutically acceptable salt thereof,
- the pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-24, wherein the oncolytic virus comprises a naturally occurring, modified and recombinant replication competent virus capable of infecting and lysing tumor cells.
- The pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-25, wherein the oncolytic virus is selected from the group consisting of reovirus (reovirus), newcastle disease virus (Newcastle disease virus), vesicular stomatitis virus (vesicular stomatitis virus), adenovirus (adenovirus), vaccinia virus (vaccinia virus), filterable virus (parapox orf virus), sindbis virus (Sindbis virus) and herpes simplex virus (herpes simplex virus).
- The pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-26, wherein the PD-1 inhibitor is selected from the group consisting of: anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, tremelimumab, terlipressin Li Shan, singe Li Shan, tirelimumab, kari Li Zhushan, and any combination thereof.
- The pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-27, wherein the PI3K inhibitor, oncolytic virus, and PD-1 inhibitor may be in the same and/or separate dosage forms (dosage forms).
- The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-28, wherein the PI3K inhibitor is formulated for oral, buccal or parenteral administration, e.g. the oral route is in the form of tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. the parenteral route is in the form of intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration, e.g. solutions, powder injection or lyophilisates.
- The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-29, wherein the oncolytic virus is administered in a dosage form that is oral, buccal or parenteral, e.g. the dosage form of the oral route may be tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, e.g. the dosage form of the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration.
- The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-30, wherein the PD-1 inhibitor may be formulated for administration by an parenteral route, e.g. the parenteral route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal penetration, transmucosal administration, e.g. as a solution, powder injection or lyophilized formulation.
- The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-31, wherein the PI3K inhibitor is contained in a dose of 1-1000mg per unit dosage form (unit dose form), e.g. the dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or a value between any two of the above.
- The pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-32, wherein about 10 per unit dosage form (unit dose form) 2 PFU to about 10 17 Oncolytic viruses at a PFU dose, e.g., at a dose of 10 2 、10 3 、10 4 、10 5 、10 6 、10 7 、10 8 、10 9 、10 10 、10 11 、10 12 、10 13 、10 14 、10 15 、10 16 、10 17 PFU or a value between any two of the above.
- The pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-33, wherein the PD-1 inhibitor is contained in a dose of 1-5000mg per unit dosage form, e.g., the dose is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4500, 5000mg, or a value between any two of the above.
- The pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-34 for use in the treatment of a tumor/cancer and/or generating a memory immune response against a tumor/cancer.
- Use of a pharmaceutical composition and/or pharmaceutical combination according to any one of claims 21-34 for the manufacture of a medicament for the treatment of a tumor/cancer and/or for the generation of a memory immune response against a tumor/cancer.
- A kit comprising the pharmaceutical composition and/or pharmaceutical combination of any one of claims 21-35, and instructions for use, wherein the PI3K inhibitor, oncolytic virus, and PD-1 inhibitor may be in the same and/or separate containers.
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