CN110833622A

CN110833622A - Combination for treating cancer and therapeutic use thereof

Info

Publication number: CN110833622A
Application number: CN201810939987.1A
Authority: CN
Inventors: 刘华涛; 肖子男
Original assignee: BEIJING ORIENGENE BIOTECHNOLOGY Ltd
Current assignee: BEIJING ORIENGENE BIOTECHNOLOGY Ltd
Priority date: 2018-08-17
Filing date: 2018-08-17
Publication date: 2020-02-25
Also published as: CN116870165A

Abstract

The present invention relates to a combination of an effective amount of herpes simplex virus and an effective amount of a PD-L/PD-1 axis antagonist for use in the treatment of cancer, and the use of such a combination in the treatment of cancer.

Description

Combination for treating cancer and therapeutic use thereof

Technical Field

The present invention relates to a combination for use in the treatment of cancer. The invention also relates to the use of said combination for the treatment of diseases such as cancer.

Background

Herpes Simplex Virus (HSV) is spherical in shape, and the complete Virus consists of a core, a capsid, a capsule (term) and a capsula. The viral core contains double-stranded DNA, wound into a fibril spool. The capsid is icosahedral symmetric, has a diameter of about 100 nm, and consists of 162 capsid particles. The outside of the shell is covered by a film with uneven thickness. The outermost layer of the virus is a typical lipid bilayer envelope. The diameter of the virus including the envelope was 150-200 nm. The surface of the envelope contains viral glycoprotein B (gB), viral glycoprotein C (gC), viral glycoprotein D (gD), viral glycoprotein G (gG) and viral glycoprotein M (gM). Herpes Simplex viruses include Herpes Simplex Virus Type I (HSV-1) and Herpes Simplex Virus Type II. The infectivity of the virus to the host cell is related to the three-dimensional structure of the envelope glycoprotein of the herpes simplex virus, namely, the three-dimensional structure of the envelope glycoprotein determines whether the virus can enter the host cell and the virus titer of the virus which can enter the host cell.

Herpes simplex virus has been used in gene therapy for tumor or nervous system degenerative diseases because it has the ability to use human cells as host cells, and it has the ability to infect a wide range of human cell types, has a low risk of accidental proliferation, and has no integration of host cell genome insertional mutation during the arrest, lytic and latent phases of anti-herpes drugs. For example, herpes simplex virus type I strain HSV1716 is used in the treatment of brain gliomas (see "HSV 1716 infection in the mouth of the brain and mouth-term survival of high-grade glioma", S.Harrow et al, Gene Therapy,11,1648-1658, 2004); herpes simplex virus type I17 + strains infect tumor cells and lyse the tumor cells by lytic replication of the virus to treat cancer.

Programmed cell death 1(PD-1) is a member of the CD28 family of receptors and is an immunosuppressive receptor expressed on the surface of activated T and B cells. The receptor can effectively reduce immune response involved by immune T cells by combining with ligands PD-L1 and PD-L2. Tumor cells escape the host immune system by overexpressing PD-L1. In the analysis of tumor specimens from patients with renal cell carcinoma, it was found that high expression of PD-L1 in tumors was associated with a 4.5-fold increase in tumor invasiveness and mortality risk. Ovarian cancer patients with higher PD-L1 expression had a significantly poorer prognosis than those with low PD-L1 expression. PD-L1 expression was negatively correlated with intraepithelial CD8+ T-lymphocyte counts, suggesting that PD-L1 on tumor cells may inhibit anti-tumor CD8+ T cells. Therefore, blocking the interaction of PD-1 with PD-L1 can significantly increase the activity of CD8+ T cells to kill tumor cells.

Disclosure of Invention

In one aspect, the present invention provides a combination for use in the treatment of cancer, comprising: (i) an effective amount of a PD-L/PD-1 axis antagonist; and (ii) an effective amount of herpes simplex virus; wherein the PD-L/PD-1 axis antagonist is selected from: a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist; the herpes simplex virus is a type I herpes simplex virus.

In some embodiments, the PD-L/PD-1 axis antagonist is a PD-1 binding antagonist. In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to its ligand binding partner. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to both PD-L1 and PD-L2. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody selected from the group consisting of: MDX-1106, Merck 3745, CT-011, AMP-224, AMP-514, and JS 001.

In some embodiments, the PD-L/PD-1 axis antagonist is a PD-L1 binding antagonist. In some embodiments, the PD-L1 binding antagonist inhibits PD-L1 from binding to PD-1. In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to B7-1. In some embodiments, the PD-L1 binding antagonist inhibits PD-L1 from binding to both PD-1 and B7-1. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody selected from the group consisting of: YW243.55.S70, MPDL3280A, MDX-1105, MEDI-4736 and MSB 0010718C.

In some embodiments, the PD-L/PD-1 axis antagonist is a PD-L2 binding antagonist. In some embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

In some embodiments, the type I herpes simplex virus is a herpes simplex virus with a accession number of CGMCC No. 1736.

In some embodiments, the combination of the invention further comprises: an effective amount of an additional therapeutic agent. The additional therapeutic agent is an anti-cancer agent and/or a complementary potentiating agent. The anti-cancer agent comprises an anti-metabolite drug, an inhibitor of topoisomerase I and topoisomerase II, an alkylating agent, a microtubule inhibitor, an anti-androgenic agent, a GNRh modulator, or a mixture thereof.The supplementary synergist comprises tricyclic antidepressant, non-tricyclic antidepressant and Ca²⁺Antagonists, amphotericin, triphenyl alcohol analogs, antiarrhythmic agents, antihypertensive agents, thiol consumables and calcium formyltetrahydrofolate.

In another aspect, the present invention provides the use of a combination as described above in the manufacture of a medicament for the treatment of cancer. The cancer is selected from: colorectal cancer, liver cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematologic malignancies, and renal cell carcinoma.

In some embodiments, the cancer is metastatic or non-metastatic melanoma. In a specific embodiment, the cancer is melanoma that is liver metastases.

In yet another aspect, the invention provides a method of treating cancer in an individual, the method comprising administering to the individual an effective amount of a PD-L/PD-1 axis antagonist in combination with an effective amount of herpes simplex virus. In general, in such combination therapy, the PD-L/PD-1 axis antagonist and the herpes simplex virus can be administered at the same time point or at different time points using the same route of administration or using different routes of administration. The PD-L/PD-1 axis antagonist and the herpes simplex virus are as defined above.

In a specific embodiment of the present invention, the injection JS001 (please refer to Chinese patent application 201610628048.6) of the PD-1 monoclonal antibody and the injection JS001 of the recombinant human herpes simplex virus are used for treating patients with melanoma with liver metastasis by the combined administration of intratumoral injection and intravenous injection, respectively.

Detailed Description

Various aspects of the present invention will be described in detail with reference to examples, which are intended to be illustrative only. It will be appreciated by those of ordinary skill in the art that the present invention is not limited by the specific operating procedures described in the examples.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "about" or "approximately" herein means that the particular value determined by one of ordinary skill in the art is within an acceptable error range that depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 standard deviation or more than one standard deviation per operation in the art. Alternatively, "about" may mean a range of up to 20% of a given value, preferably up to 10% of a given value, more preferably up to 5% of a given value and more preferably up to 1% of a given value. Alternatively, especially for biological systems or processes, the term may mean within an order of magnitude of a certain value, preferably within 5 times a certain value, more preferably within 2 times a certain value. Where particular values are described in the application and claims, unless otherwise stated, it should be assumed that the term "about" means within an acceptable error range for the particular value.

I. Combinations for the treatment of cancer

In one aspect, provided herein is a combination for treating cancer, comprising: (i) an effective amount of a PD-L/PD-1 axis antagonist; and (ii) an effective amount of herpes simplex virus.

"PD-L/PD-1 axis antagonist" herein refers to the following molecules: which inhibits the interaction of the PD-L/PD-1 axis binding partner with one or more of its binding partners, thereby eliminating T cell dysfunction resulting from signal transduction on the PD-L/PD-1 signaling axis, restoring or increasing T cell function (e.g., proliferation, cytokine production, target cell killing). PD-L/PD-1 axis antagonists as used herein include PD-1 binding antagonists, PD-L1 binding antagonists and PD-L2 binding antagonists.

As used herein, "PD-1 binding antagonist" refers to the following molecule: which reduces, blocks, inhibits, cancels, or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners (e.g., PD-L1, PD-L2). In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to its ligand binding partner. In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to PD-L1. In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to PD-L2. In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to both PD-L1 and PD-L2. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with the signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of: MDX-1106, Merck 3745, CT-011, AMP-224, AMP-514, and JS001 (see Chinese patent application 201310258289.2).

As used herein, "PD-L1 binding antagonist" refers to the following molecule: which reduces, blocks, inhibits, cancels, or interferes with the signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1, B7-1). In some embodiments, the PD-L1 binding antagonist inhibits PD-L1 from binding to PD-1. In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to B7-1. In some embodiments, the PD-L1 binding antagonist inhibits PD-L1 from binding to both PD-1 and B7-1. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody, antigen binding fragment thereof, immunoadhesin, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with the signaling produced by the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1, B7-1). In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of: YW243.55.S70, MPDL3280A, MDX-1105, MEDI-4736 and MSB 0010718C.

Herein, "PD-L2 binding antagonist" refers to the following molecule: which reduces, blocks, inhibits, cancels, or interferes with the signal transduction resulting from the interaction of PD-L2 with one or more of its binding partners (e.g., PD-1). In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partner. In some embodiments, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antibody, antigen binding fragment thereof, immunoadhesin, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with the signaling produced by the interaction of PD-L2 and one or more of its binding partners (e.g., PD-1). In one embodiment, PD-L2 binding antagonists attenuate negative costimulatory signals mediated by signal transduction through PD-L2 mediated by or through cell surface proteins expressed on T lymphocytes, thereby causing dysfunctional T cells to develop less dysfunction (e.g., increase effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

In some embodiments, the combinations described herein for treating cancer may further comprise additional anti-cancer agents and/or complementary potentiators. The anti-cancer agents include, for example, antimetabolites, inhibitors of topoisomerase I and topoisomerase II, alkylating agents, microtubule inhibitors, anti-androgens, GNRh modulators, or mixtures thereof. Such supplementary potentiating agents include, for example, tricyclic antidepressants (e.g., imipramine (imipramine), desipramine (desipramine), amitriptyline (amitriptyline), clomipramine (clomipramine), trimipramine (trimipramine), doxepin (doxepin), nortriptyline (nortriptyline), protriptyline (protriptyline), amoxapine (amoxapine), and maprotiline (maprotiline)), non-tricyclic antidepressants (e.g., sertraline (sertraline), trazodone (trazodone), and citalopram (citalopram)), Ca2+ antagonists (e.g., verapamil (verapamil), nifedipine (nifedipine), nitrendipine (nitrendipine) and carvediline (carbapenem), amphotericin (tamoxifen)), and tamoxifen (tamoxifen)), amphoterine (tamoxifen)), and analogs thereof (e), such as, for example, as antihypertension (norfloxacin, e (e), and drugs (e), such as tetrahydroxydine (e), and (e.g., drugs (tetrahydroxydine, e, e.g., drugs (tetrahydroxydine, and a.

anti-PD-1 antibodies

In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody.

Programmed death-1 ("PD-1") is a receptor for PD-L1 (also known as CD274, B7-H1 or B7-DC). PD-1 is a member of the approximately 31kD type I membrane protein in the large family of T cell regulatory factors CD28/CTLA4 (Ishida, Y.et al. (1992) EMBO J.11: 3887-3895; U.S. patent application publication No. 2007/0202100; No. 2008/0311117; No. 2009/00110667; U.S. patent No. 6,808,710; No.7,101,550; No.7,488,802; No.7,635,757; No.7,722,868; PCT publication WO 01/14557). PD-1 negatively regulates the immune response more broadly than CTLA 4.

PD-1 is expressed on activated T cells, B cells and monocytes (Agata, Y.et al. (1996) int. Immunol.8(5): 765-772; Yamazaki, T.et al. (2002J.Immunol.169:5538-5545) and at low levels in Natural Killer (NK) T cells (Nishimura, H.et al. (2000) J.exp.Med.191: 891-898; Martin-Orozco, N.et al. (2007), Semin.cancer biol.17(4): 288-298).

The extracellular region of PD-1 consists of an immunoglobulin (Ig) V domain alone, which is 23% identical to the corresponding domain in CTLA4 (Martin-Orozco, N.et al (2007) Semin. cancer biol.17(4): 288-298). The extracellular IgV domain is followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switching motif, which suggests that PD-1 negatively regulates TCR signaling (Ishida, Y.et al. (1992EMBO J.11: 3887-3895; Blank, C.et al. (Epub2006Dec.29) immunological. immunother.56(5): 739-745).

Antibodies capable of immunospecifically binding murine PD-1 have been reported (see, e.g., Agata, T.et al (1996) int. Immunol.8(5): 765-772).

anti-PD-1 antibodies bind to PD-1 and increase T cell function, thereby upregulating cell-mediated immune responses and are useful in the treatment of T cell dysfunctional diseases, e.g., tumor immunity.

In some embodiments, the anti-PD-1 antibody is MK-3475 (previously referred to as lambrolizumab, Merck), AMP-514, AMP-224(MedImmune/AstraZeneca, which is an anti-programmed cell death 1(PD-1) monoclonal antibody (mAb) developed by Amplimmune), MDX-1106(Bristol-Myers Squibb), or CT-011 (Curetech).

In some embodiments, the anti-PD-1 antibody is one of the antibodies disclosed in US8,354,509 and US8,168,757, the entire contents of which are incorporated herein by reference.

In some embodiments, the anti-PD-1 antibody is one of the antibodies disclosed in WO2004/056875, US7,488,802, and US8,008,449, the entire contents of which are incorporated herein by reference.

In some embodiments, the anti-PD-1 antibody is an antibody (JS001) capable of binding programmed death factor 1(PD-1) disclosed in chinese patent application 201310258289.2, the entire contents of which are incorporated herein by reference, or a functional fragment thereof.

Herpes simplex virus

The term "herpes simplex virus" as used herein has an envelope protein, wherein the envelope protein comprises an amino acid sequence having the function of promoting viral infection of a host cell, said amino acid sequence being disclosed in chinese patent application 200710062939.0 (the entire contents of which are incorporated herein by reference) selected from the group consisting of: SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.7, SEQ ID NO.9, and one or more amino acid sequences obtained by performing one or more amino acid substitutions, additions or deletions on the amino acid sequences of SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.7 and SEQ ID NO.9 to promote the function of virus-infected host cells to be unchanged. In some embodiments, the "Herpes Simplex Virus" herein is a Herpes Simplex Virus isolated from adult chinese kosher (classified under the name of Herpes Simplex Virus Type I, latin literature name of Herpes Simplex Virus Type I, deposited at 2006, 6/14 to china general microbiological culture collection center (CGMCC) located in north one of guancun, hai lake, beijing, under the accession number CGMCC No.1736) disclosed in chinese patent application 200710062939.0 (the entire content of which is incorporated herein by reference).

Combination therapy with PD-L/PD-1 axis antagonists and herpes simplex virus

In another aspect, the invention provides a method of treating cancer in an individual, comprising administering to the individual an effective amount of a PD-L/PD-1 axis antagonist in combination with an effective amount of herpes simplex virus. In general, in such combination therapy, the PD-L/PD-1 axis antagonist and the herpes simplex virus can be administered at the same time point or at different time points using the same route of administration or using different routes of administration.

In some embodiments, the PD-L/PD-1 axis antagonist is selected from: PD-1 binding antagonists, PD-L1 binding antagonists and PD-L2 binding antagonists.

In some embodiments, the PD-L/PD-1 axis antagonist is a PD-1 binding antagonist.

In some embodiments, the PD-1 binding antagonist inhibits binding of PD-1 to its ligand binding partner.

In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to PD-L1.

In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to PD-L2.

In some embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to both PD-L1 and PD-L2.

In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody, e.g., MDX-1106, Merck 3745, CT-011, AMP-224, AMP-514, or JS 001.

In some embodiments, the PD-L/PD-1 axis antagonist is a PD-L1 binding antagonist.

In some embodiments, the PD-L1 binding antagonist inhibits PD-L1 from binding to PD-1.

In some embodiments, the PD-L1 binding antagonist inhibits binding of PD-L1 to B7-1.

In some embodiments, the PD-L1 binding antagonist inhibits PD-L1 from binding to both PD-1 and B7-1.

In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody, e.g., yw243.55.s70, MPDL3280A, MDX-1105, MEDI-4736, or MSB 0010718C.

In some embodiments, the PD-L/PD-1 axis antagonist is a PD-L2 binding antagonist.

In some embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antibody.

In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

In some embodiments, the herpes simplex virus is a type I herpes simplex virus.

In some embodiments, the individual has colorectal cancer, liver cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma.

Mode and route of administration

The term "administering" as used herein is intended to include all manner of delivering a compound, both directly and indirectly, to the desired site of action.

In some embodiments, the herpes simplex virus is administered prior to the PD-L/PD-1 axis antagonist.

In some embodiments, the herpes simplex virus is administered concurrently with a PD-L/PD-1 axis antagonist.

In some embodiments, the herpes simplex virus is administered after the PD-L/PD-1 axis antagonist.

In some embodiments, the herpes simplex virus and the PD-L/PD-1 axis antagonist can be administered continuously or intermittently.

In some embodiments, the PD-L/PD-1 axis antagonist is administered intravenously, intratumorally, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intracamerally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.

In some embodiments, the herpes simplex virus is administered intravenously, intratumorally, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intracamerally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.

In some embodiments, the PD-L/PD-1 axis antagonist and the herpes simplex virus can be administered in the same manner or can be administered in different manners.

The co-administered PD-L/PD-1 axis antagonist and herpes simplex virus may further be administered in combination with additional anti-cancer agents and/or supplementary potentiating agents when administered to a patient undergoing cancer treatment.

Anticancer agents which may be further co-administered with co-administered PD-L/PD-1 axis antagonists and herpes simplex virus include antimetabolites, inhibitors of topoisomerase I and topoisomerase II, alkylating agents, microtubule inhibitors, antiandrogenic agents, GNRh modulators, or mixtures thereof.

Supplementary potentiating agents which can be further co-administered with co-administered PD-L/PD-1 axis antagonists and herpes simplex viruses include, for example, tricyclic antidepressants (e.g., imipramine, desipramine, amitriptyline, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine, maprotiline), non-tricyclic antidepressants (e.g., sertraline, trazodone, and citalopram), Ca2+ antagonists (e.g., verapamil, nifedipine, and trinitropine), and citalopram), Ca2+ antagonists (e.g., verapamil, triptonidine, and trinitrocaridine), and analogs of vitamins (e.g., quinidine, and quinidine), such as quinidine, and quinidine), and analogs of arginine, such as quinidine, and analogs of quinidine, such as quinidine, and analogs of the like, antihypertensive drugs (e.g., reserpine), thiol consumables (e.g., buthionine and sulfoximine), and calcium formyltetrahydrofolate.

The anti-cancer agent and/or the complementary potentiating agent may be administered by the same route as or different route from the route of administration of the PD-L/PD-1 axis antagonist and the herpes simplex virus at the same time point as or different from the time point of administration of the PD-L/PD-1 axis antagonist and the herpes simplex virus.

Dosage forms

The PD-L/PD-1 axis antagonists and herpes simplex viruses of the present invention may be formulated in a conventional manner with one or more physiologically acceptable carriers into dosage forms suitable for the chosen route of administration. The physiologically acceptable carrier comprises an excipient and an adjuvant, and the physiologically acceptable carrier is beneficial to processing the PD-L/PD-1 axis antagonist and the herpes simplex virus into a preparation which can be used in pharmacy. Suitable dosage forms depend on the chosen route of administration, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, injectable dosage forms, suppositories, sustained release dosage forms, transdermal patches.

In some embodiments, the PD-L/PD-1 axis antagonist and the herpes simplex virus are formulated for injection, e.g., intravenous injection and intratumoral injection.

Effective dose

In the combinations described herein and in the treatment of cancer, effective amounts of the PD-L/PD-1 axis antagonist and the herpes simplex virus can be determined first by cell culture assays. The target blood concentration is the concentration of the active ingredient that is capable of inhibiting cell growth or division. In a preferred embodiment, at least 25% of the cellular activity is inhibited. Target blood concentrations of active compounds capable of inducing inhibition of cellular activity of at least about 30%, 50%, 75% or even 90% or more are presently preferred. The percentage of inhibition of cellular activity in the patient can be monitored to assess the appropriateness of the achieved blood concentration, and the dosage can be adjusted up or down to achieve the desired percentage of inhibition.

A therapeutically effective amount for use in humans can also be determined by animal models, as is known in the art. For example, a dose for use in humans may be formulated to achieve an effective circulating concentration that has been found in animals. As described above, the dose in humans can be adjusted by monitoring cytostatic and up-or down-regulating the dose.

Therapeutically effective dosages can also be determined by human data for known active ingredients that exhibit similar pharmacological activities. The dosage used may be adjusted based on the relative bioavailability and potency of the administered active ingredient compared to known active ingredients.

It is well within the ability of one of ordinary skill in the art to adjust the dosage to achieve maximum efficacy in the human body based on the methods described above and other methods well known in the art.

In the case of local administration, the systemic circulating concentration of the administered active ingredient is not of particular importance. In such cases, the active ingredient is administered to achieve a concentration effective to achieve the desired result in the local area.

In the case of co-administration of a PD-L/PD-1 axis antagonist and a herpes simplex virus to an individual suffering from cancer to treat the cancer, the dosage and interval of administration of the PD-L/PD-1 axis antagonist and the herpes simplex virus can be separately adjusted to provide a blood concentration effective for the particular clinical indication under treatment. For example, in one embodiment, the PD-L/PD-1 axis antagonist and herpes simplex virus of the present invention may be administered multiple times per day at relatively high concentrations. More desirably, the PD-L/PD-1 axis antagonist of the invention and the herpes simplex virus are administered at minimum effective concentrations and using a less frequent dosing regimen. This would provide a treatment regimen commensurate with the severity of the disease in the individual.

In an exemplary embodiment of the present invention, a recombinant human herpes simplex virus injection (OrienX010, manufactured by Olympic and Living Biotechnology Co., Ltd., Beijing, 1.0 mL/count. indicated amount: titer of 8.0X 10 is used⁷pfu/mL, particle count not higher than 1X 10¹¹VP/mL) and a recombinant humanized anti-PD-1 monoclonal antibody injection (JS001, manufactured by shanghai junshi biomedical science and technology limited, specification: 240mg/6 ml/vial) for use in combination with melanoma patients with liver metastases. In this embodiment, OrienX010 is injected once every two weeks by intratumoral injection, with a total amount of no more than 10mL (8.0X 10)⁷pfu/mL, 1 mL/arm, up to 10 arms), JS001 was administered every two weeks by intravenous administration at a dose of 3 mg/kg. Alternatively, the skilled person can also select the dose of OrienX010 injection according to the size of the tumor (major diameter): when the length of the tumor is more than or equal to 5cm, 10ml of OrienX010 solution is administeredInjecting liquid; when the length of the tumor is 2-5cm, not less than 5ml of OrienX010 injection is administered; when the length and diameter of the tumor are less than 2cm, not less than 3ml of OrienX010 injection is administered. The combination therapy of this embodiment is performed by imaging the tumor in the treated patient at the end of the 12-week treatment cycle for each 12-week treatment period.

While preferred embodiments of the present invention are described and shown herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that alternative embodiments of the invention described herein may be used to practice the invention. The scope of the invention is defined by the appended claims, and methods and structures within the scope of these claims and their equivalents are also intended to be covered by the appended claims.

Claims

1. A combination for treating cancer comprising:

(i) an effective amount of a PD-L/PD-1 axis antagonist; and

(ii) an effective amount of herpes simplex virus.

2. The combination of claim 1, wherein the PD-L/PD-1 axis antagonist is selected from the group consisting of: PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

3. The combination of claim 2, wherein the PD-L/PD-1 axis antagonist is a PD-1 binding antagonist.

4. The combination of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partner.

5. The combination of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1.

6. The combination of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2.

7. The combination of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2.

8. The combination of claim 3, wherein the PD-1 binding antagonist is an anti-PD-1 antibody.

9. The combination of claim 8, wherein the anti-PD-1 antibody is selected from the group consisting of: MDX-1106, Merck 3745, CT-011, AMP-224, AMP-514, and JS 001.

10. The combination of claim 1, wherein the PD-L/PD-1 axis antagonist is a PD-L1 binding antagonist.

11. The combination of claim 10, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1.

12. The combination of claim 10, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1.

13. The combination of claim 10, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1.

14. The combination of claim 10, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

15. The combination of claim 14, wherein the anti-PD-L1 antibody is selected from the group consisting of: YW243.55.S70, MPDL3280A, MDX-1105, MEDI-4736 and MSB 0010718C.

16. The combination of claim 1, wherein the PD-L/PD-1 axis antagonist is a PD-L2 binding antagonist.

17. The combination of claim 16, wherein the PD-L2 binding antagonist is an anti-PD-L2 antibody.

18. The combination of claim 16, wherein the PD-L2 binding antagonist is an immunoadhesin.

19. The combination according to claim 1, wherein the herpes simplex virus is herpes simplex virus type I.

20. The combination according to claim 19, wherein the herpes simplex virus type I is a herpes simplex virus with a accession number of CGMCC No. 1736.

21. The combination of claim 1, further comprising: an effective amount of an additional therapeutic agent.

22. The combination of claim 21, wherein the additional therapeutic agent is an anti-cancer agent and/or a complementary potentiating agent.

23. The combination of claim 22, wherein the anti-cancer agent comprises an anti-metabolite, an inhibitor of topoisomerase I and topoisomerase II, an alkylating agent, a microtubule inhibitor, an anti-androgenic agent, a GNRh modulator, or a mixture thereof.

24. The combination of claim 22, wherein the supplemental potentiating agent comprises a tricyclic antidepressant, a non-tricyclic antidepressant, Ca²⁺Antagonists, amphotericin, triphenyl alcohol analogs, antiarrhythmic agents, antihypertensive agents, thiol consumables and calcium formyltetrahydrofolate.

25. Use of a combination according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of cancer.

26. The use of claim 25, wherein the cancer is selected from: colorectal cancer, liver cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematologic malignancies, and renal cell carcinoma.

27. The use of claim 26, wherein the cancer is metastatic or non-metastatic melanoma.