WO2022188850A1 - 包含己酸羟孕酮的抗肿瘤联合制剂及其用途 - Google Patents

包含己酸羟孕酮的抗肿瘤联合制剂及其用途 Download PDF

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WO2022188850A1
WO2022188850A1 PCT/CN2022/080275 CN2022080275W WO2022188850A1 WO 2022188850 A1 WO2022188850 A1 WO 2022188850A1 CN 2022080275 W CN2022080275 W CN 2022080275W WO 2022188850 A1 WO2022188850 A1 WO 2022188850A1
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cancer
therapeutic agent
additional therapeutic
hydroxyprogesterone caproate
tumor
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French (fr)
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杜涛
胡涛
张玉倩
杜新
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深圳埃格林医药有限公司
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Priority to EP22766372.1A priority Critical patent/EP4309658A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

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  • the present invention relates to a pharmaceutical composition for treating tumors and a method for treating tumors, in particular to a pharmaceutical composition comprising enhancing the effect of a tumor therapeutic agent by improving the tumor microenvironment and a method for treating tumors by combining medication.
  • Malignant tumor is a major disease that seriously threatens human health.
  • Conventional treatment methods include surgery, radiotherapy, chemotherapy and targeted therapy, but the effect on advanced tumors is very limited, and there are problems of large toxic side effects and poor tolerance.
  • tumor immunotherapy has achieved remarkable clinical effects. It is a treatment method that activates the body's own immune system to fight tumors. It is currently the most potential treatment method for curing malignant tumors. Therefore, tumor immunotherapy was selected for the Nobel Prize in Physiology or Medicine in 2018.
  • the tumor microenvironment is an important aspect of cancer biology that contributes to tumorigenesis, tumor progression, and response to therapy.
  • the cells and molecules of the immune system are fundamental components of the tumor microenvironment.
  • the composition and characteristics of the tumor microenvironment vary widely and are important for determining anti-tumor immune responses.
  • certain cells of the immune system including natural killer cells, dendritic cells (DCs), and effector T cells, are able to drive powerful antitumor responses.
  • tumor cells often induce an immunosuppressive microenvironment that favors the development of immunosuppressive populations of immune cells, such as myeloid-derived suppressor cells and regulatory T cells.
  • immune checkpoint inhibitors can play an anti-tumor effect by blocking the immunosuppressive signals in the tumor microenvironment and restoring the function of immune cells.
  • the most in-depth and mature immune checkpoints are programmed cell death receptor 1 (PD-1), programmed death ligands 1 and 2 (PD-L1/L2), cytotoxic T cell antigen 4 ( CTLA-4), as well as lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin mucin 3 (TIM-3), T cell immunoglobulin and ITIM domain protein (TIGIT), and T cell activation V region Immunoglobulin Inhibitors (VISTA) et al (Randoph J. Nolle, Science, 2020).
  • PD-1 programmed cell death receptor 1
  • PD-L1/L2 programmed death ligands 1 and 2
  • CTLA-4 cytotoxic T cell antigen 4
  • LAG-3 lymphocyte activation gene 3
  • TIM-3 T cell immunoglobulin mucin 3
  • TAGIT T cell immunoglobulin and
  • PD-1 and/or PD-L1 are highly expressed in the majority of tumor-infiltrating lymphocytes (TILs) from many different tumor types and suppress local effector immune responses including lung, liver, ovarian, cervical, cancer, skin cancer, colon cancer, glioma, bladder, breast, kidney, esophagus, stomach, oral squamous cell carcinoma, urothelial cell carcinoma and pancreatic cancer, and tumors of the head and neck .
  • TILs tumor-infiltrating lymphocytes
  • PD-1 and/or PD-L1 antibodies can block the binding of PD-L1 on tumor cells to the inhibitory receptor PD-1 on the surface of activated T cells, thereby activating tumor-specific T cells and rebuilding the immune system against tumor cells. killing effect.
  • PD-1 antibodies are only about 20% of clinical response rate.
  • PD-1 antibody not only PD-1 antibody, but also other antibodies and even various tumor therapeutic agents have shown great differences in clinical practice from in vitro tests.
  • the microenvironment makes it difficult for drugs to reach the target, and it is difficult for immune cells to enter the tumor tissue to kill cancer cells.
  • 17 ⁇ -Hydroxypregn-4-ene-3,20-dione caproate also known as hydroxyprogesterone caproate, 17-hydroxyprogesterone caproate, 17-HPC, 17-OHPC, OHPC, English name: Hydroxyprogesterone Caproate, CAS No.: 630-56-8, is clinically used to treat habitual abortion, irregular menstruation, endometriosis, functional uterine bleeding, etc.
  • a pharmaceutical composition comprising hydroxyprogesterone caproate and another additional therapeutic agent for treating tumors.
  • another additional therapeutic agent for the treatment of tumors is selected from the group consisting of chemotherapeutic agents, targeted therapy agents, hormone therapy agents, cell therapy agents, oncolytic viral agents or antibodies, especially immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is selected from PD-L1, PD-1, PD-L2, CTLA-4, LAG3, B7-H3, KIR, CD137, PS, TFM3, CD52, CD30, CD20, CD33 , CD27, OX40, GITR, ICOS, BTLA (CD272), CD160, 2B4, LAIR1, TIGHT, LIGHT, DR3, CD226, CD2, SLAM or a combination of inhibitors; preferably, the immune checkpoint inhibitor is a single A cloned antibody, particularly preferably a monoclonal antibody directed against PD-1 or PD-L1.
  • the additional therapeutic agent is selected from atezolizumab, avelumab, durvalumab, camrelizumab, cilimumab, ipilimumab, nivolumab , Pembrolizumab, Sintilimab, Tislelizumab, Toripalimab, Tislimumab, RC98.
  • antineoplastic drug comprising the above-mentioned pharmaceutical composition comprising hydroxyprogesterone caproate and another additional therapeutic agent for treating tumors, and optionally one or more Pharmaceutically acceptable excipients.
  • the dosage form of the antitumor drug is selected from injections, oral preparations or external preparations; injections or oral preparations are preferred; injections are particularly preferred.
  • the injection is selected from injection or powder injection; the oral preparation is selected from tablet, solution, capsule, powder, pill, granule, syrup, suspension or oral sustained and controlled-release preparation; the external preparation is selected from ointment , spray or patch.
  • the additional therapeutic agent is present in amounts ranging from 10% to 100% of the therapeutically effective amount when used alone.
  • the content of each tablet/dose of hydroxyprogesterone caproate is 100-1000 mg
  • the content of each tablet/dose of hydroxyprogesterone caproate is (100-1000 mg)/m
  • the content of each tablet/dose of hydroxyprogesterone caproate is n ⁇ (100-1000 mg).
  • the pharmaceutically acceptable adjuvants are selected from pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents , osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH adjusters, buffers , plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants, deflocculants, filter aids, release retarders, polymer framework materials and film-forming materials at least one of.
  • the invention provides a method of increasing the number of tumor infiltrating lymphocytes (TILs) in need, comprising providing hydroxyprogesterone caproate to a subject.
  • TILs tumor infiltrating lymphocytes
  • its TIL population comprises a population of CD8+ T cells, CD4+ T cells, B cells, natural killer (NK) cells, dendritic cells (DC), M1 macrophages or a combination thereof, preferably expressing a TH1 phenotype of T cells.
  • TILs are increased in the tumor microenvironment (TME) and/or in tumor tissue.
  • the invention provides a method of treating cancer in a subject in need thereof, comprising providing hydroxyprogesterone caproate to the subject.
  • it includes providing the subject with an additional therapeutic agent other than hydroxyprogesterone caproate to treat cancer.
  • its additional therapeutic agent is selected from chemotherapeutic agents, targeted therapy agents, hormone therapy agents, cell therapy agents, oncolytic viral agents or antibodies.
  • the additional therapeutic agent is selected from immunotherapeutic agents.
  • the additional therapeutic agent is selected from immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is selected from PD-L1, PD-1, PD-L2, CTLA-4, LAG3, B7-H3, KIR, CD137, PS, TFM3, CD52, CD30, CD20, CD33, Inhibitors of CD27, OX40, GITR, ICOS, BTLA (CD272), CD160, 2B4, LAIR1, TIGHT, LIGHT, DR3, CD226, CD2, SLAM, preferably against PD-1, PD-L2, CTLA-4, LAG3, B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2,SLAM A monoclonal antibody or a combination thereof, particularly preferably a monoclonal antibody against PD-L1 or PD-1.
  • the additional therapeutic agent is selected from atezolizumab, avelumab, durvalumab, camrelizumab, cilimumab, ipilimumab, nivolumab anti, pembrolizumab, sintilimab, tislelizumab, toripalimab, temslimumab, or RC98.
  • the subject has higher PD-L1 or PD-1 expression.
  • it is administered as a first- or second-line therapy.
  • its hydroxyprogesterone caproate may be administered to the subject prior to, concurrently with, or subsequent to administration of the additional therapeutic agent.
  • the subject thereof has primary or metastatic cancer.
  • the cancer is a solid tumor or metastatic cancer, wherein the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, esophagus cancer, eye cancer, head and neck cancer, kidney cancer, lung cancer, Melanoma, ovarian, pancreatic, prostate or gastric cancer, preferably breast, lung, renal cell carcinoma (RCC), hepatocellular (HCC), melanoma, colorectal or endometrial cancer, particularly preferably primary Metastatic or metastatic non-small cell lung cancer (NSCLC), wherein the metastatic cancer is metastatic melanoma, metastatic colorectal cancer or metastatic endometrial cancer.
  • RRCC renal cell carcinoma
  • HCC hepatocellular
  • NSCLC primary Metastatic or metastatic non-small cell lung cancer
  • the subject thereof has relapsed or refractory cancer.
  • hydroxyprogesterone caproate or the use of hydroxyprogesterone caproate and an additional therapeutic agent to treat cancer reduces tumor cell proliferation in the subject, and/or slows or stabilizes tumor growth in the subject.
  • Figure 1 is a graph showing the growth trend of tumor volume after administration.
  • Figure 2 shows tumor CD8 T cell infiltration (400X) in mice after administration.
  • Figure 3 shows the densitometric analysis of CD8 staining in mouse tumor sections after administration, expressed as integral optical density (IOD)/area, where ** indicates p ⁇ 0.01 compared with the control group in the OHPC group.
  • Anti-PD-L1 antibody was purchased from Rongchang Bio-Pharmaceutical (Yantai) Co., Ltd., batch number: RC98-1-A20170426, the concentration of the stock solution was 6.87 mg/ml, and the solvent was 0.9% sodium chloride solution. Before each administration, 0.9% sodium chloride injection was used to prepare a test drug solution containing Anti-PD-L1 at a concentration of 1 mg/ml.
  • Hydroxyprogesterone caproate was purchased from Xianju County Hongyan Pharmaceutical Chemical Co., Ltd., powder. Before each administration, DMSO was used to dissolve the OHPC powder, and after the powder was completely dissolved, it was diluted with sesame oil to a test drug solution containing 4 mg/ml of OHPC.
  • Mouse breast cancer 4T1 cells were purchased from Beijing Biositu Gene Biology Co., Ltd., and the cells were cultured in an incubator at 37°C with 5% CO 2 , and the medium composition was DMEM medium containing 10% inactivated fetal bovine serum.
  • 4T1 cells were genetically modified by conventional methods to overexpress human PD-L1, and the cells were named 4T1-hPD-1.
  • Balb/c mice SPF grade, female, 6-9 weeks old, weighing 16-22g. 4T1-hPD-1 cells were resuspended in PBS, and then subcutaneously inoculated on the right side of Balb/c mice at a concentration of 5 ⁇ 10 4 cells/0.1 ml in a volume of 0.1 ml/cell.
  • appropriate mice were selected according to the tumor volume and weight of the mice, and they were equally divided into 4 experimental groups, with 8 mice in each group.
  • the table shows:
  • the administration volume is calculated as 10 ⁇ l/g according to the volume of the experimental animal.
  • the body weight and tumor growth state of the experimental animals were continuously observed for 12 days. During the observation period, the tumor volume and the animal body weight were measured every week, and the measured values were recorded. After completing the observation, end the experiment.
  • tumor volume 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • the adaptive feeding period and the experimental period were observed once a day, and the observation contents included but not limited to tumor nodule rupture, animal mental state, diet, etc.
  • T0 the mean tumor volume of the treatment group on the 0th day of administration
  • Vi the mean tumor volume of the solvent control group on the ith day of administration
  • V0 The mean tumor volume of the solvent control group on day 0 of dosing.
  • mice tumors were embedded in paraffin, and sliced for CD staining to compare the infiltration of CD8+ T cells in tumors between groups.
  • Figure 1 shows a graph showing the growth trend of tumor volume after administration.
  • 4T1 breast cancer is resistant to immunotherapy, so the anti-PD-L1 group did not show the effect of inhibiting tumor growth.
  • OHPC alone also had no inhibitory effect.
  • tumor growth was inhibited in the late stage, and the inhibition rate reached 30.7% at the end of the experiment on the 17th day.
  • Table 2 The effect of the test article on the tumor volume of Balb/c mice transplanted with 4T1-hPD-L1 cells
  • b Statistical comparison between the body weight of the administration group and the vehicle control group on the 17th day of group administration, t-test analysis.
  • hydroxyprogesterone caproate can significantly enhance the infiltration of CD8+ T cells.
  • Hydroxyprogesterone caproate can significantly enhance the infiltration of CD8+ T cells and enhance the anti-tumor activity of the monoclonal antibody Anti-PD-L1.

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Abstract

本发明提供包括己酸羟孕酮和另一种治疗肿瘤的额外治疗剂，额外治疗剂优选针对PD-1或PD-L1的单克隆抗体。本发明还提供一种在需要时增加肿瘤浸润淋巴细胞(TIL)数量的方法和一种治疗有需要的受试者癌症的方法，包括向受试者提供己酸羟孕酮。

Description

包含己酸羟孕酮的抗肿瘤联合制剂及其用途
交叉引用
本申请要求在2021年3月11日提交中国专利局、申请号为202110265778.5、发明名称为“包含己酸羟孕酮的抗肿瘤联合制剂及其用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种治疗肿瘤的药物组合物和一种治疗肿瘤的方法，特别涉及一种包括通过改善肿瘤微环境增强肿瘤治疗剂效果的药物组合物和通过联合用药治疗肿瘤的方法。
背景技术
恶性肿瘤(癌症)是严重威胁人类健康的重大疾病，常规的治疗方法有手术、放疗、化疗和靶向治疗，但对于晚期肿瘤的效果非常有限且存在毒副作用大、耐受性差的问题。近几年，肿瘤免疫疗法取得了令人瞩目的临床效果，是一种通过激活人体自身免疫系统以对抗肿瘤的治疗手段，是目前最有潜力治愈恶性肿瘤的治疗手段。因此，肿瘤免疫疗法于2018年入选诺贝尔生理学或医学奖。
肿瘤微环境是癌症生物学的一个重要方面，其促成肿瘤发生、肿瘤进程和对治疗的应答。免疫系统的细胞和分子是肿瘤微环境的基本组成部分。肿瘤微环境的组成和特征变化很大并且对于确定抗肿瘤免疫应答很重要。例如，免疫系统的某些细胞，包括自然杀伤细胞、树突状细胞(DC)和效应T细胞，能够驱动强有力的抗肿瘤应答。然而，肿瘤细胞常常诱导免疫抑制性微环境，其有利于发展免疫细胞的免疫抑制性群体，如髓源性抑制细胞和调节性T细胞。
免疫检查点抑制剂作为肿瘤免疫疗法的代表，可通过阻断肿瘤微环境中的免疫抑制信号，恢复免疫细胞的功能发挥抗肿瘤作用。其中，研究最为深入、应用最成熟的免疫检查点是细胞程序性死亡受体1(PD-1)、程序性死亡配体1和2(PD-L1/L2)、细胞毒性T细胞抗原4(CTLA-4)，以及淋巴细胞激活基因3(LAG-3)、T细胞免疫球蛋白黏蛋白3(TIM-3)、T细胞免疫球蛋白和ITIM结构域蛋白(TIGIT)和T细胞激活V区免疫球蛋白抑制剂(VISTA)等(RandophJ.Nolle，Science，2020)。
在肿瘤微环境中，PD-1和/或PD-L1在来自许多不同肿瘤类型的大部分肿瘤浸润淋巴细胞(TIL)中高度表达，并抑制局部效应免疫应答包括肺癌、肝癌、卵巢癌、宫颈癌、皮肤癌、结肠癌、神经胶质瘤、膀胱癌、乳腺癌、肾癌、食道癌、胃癌、口腔鳞状上皮细胞癌、泌尿道上皮细胞癌和胰腺癌以及头部和颈部的肿瘤。PD-1和/或PD-L1抗体能够阻断肿瘤细胞上的PD-L1与活化T细胞表面的抑制性受体PD-1结合，从而活化肿瘤特异性T细胞，重建免疫系统对肿瘤细胞的杀伤作用。然而，由于肿瘤具有极大的异质性和遗传不稳定性，其发病机制复杂，肿瘤组织中存在多种内源性和外源性的免疫抵抗机制，PD-1抗体只有20％左右的临床反应率。
发明人通过研究发现，不仅PD-1抗体，其他抗体乃至各种肿瘤治疗剂在临床中都表现出了与体外试验较大的差异，一个重要的原因是肿瘤周围具有适合癌细胞存活和增殖的微环境，导致例如药物难以抵达靶点、免疫细胞难以进入肿瘤组织内部杀灭癌细胞等问题。
17α-羟基孕甾-4-烯-3，20-二酮己酸酯，也称己酸羟孕酮、17-羟基孕酮己酸酯、17-HPC、17-OHPC、OHPC，英文名：Hydroxyprogesterone Caproate，CAS No.：630-56-8，临床上用于治疗习惯性流产、月经不调、子宫内膜异位症、功能性子宫出血等。
发明内容
根据本发明的一个方面，提供了一种药物组合物，包括己酸羟孕酮和另一种治疗肿瘤的额外治疗剂。
可选地，另一种治疗肿瘤的额外治疗剂选自：化疗剂、靶向治疗剂、激素治疗剂、细胞治疗剂、溶瘤性病毒剂或抗体，特别是免疫检查点抑制剂。
可选地，所述免疫检查点抑制剂选自PD-L1,PD-1,PD-L2,CTLA-4,LAG3,B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2,SLAM或其组合的抑制剂；优选的，所述免疫检查点抑制剂是单克隆抗体，特别优选针对PD-1或PD-L1的单克隆抗体。
可选地，所述额外治疗剂选自阿特珠单抗，阿维鲁单抗，德瓦鲁单抗，卡瑞利珠单抗，西米单抗，伊匹单抗，纳武单抗，派姆单抗，信迪利单抗，替雷利珠单抗，特瑞普利单抗，替西木单抗、RC98。
根据本发明的另一个方面，还提供一种抗肿瘤药物，其包含上述的包括己酸羟孕酮和另一种治疗肿瘤的额外治疗剂的药物组合物，和任选地一种或者多种药学上可接受的辅料。
可选地，抗肿瘤药物的剂型选自注射剂，口服制剂或外用制剂；优选注射剂或口服制剂；特别优选注射剂。所述注射剂选自注射液或粉针剂；口服制剂选自片剂、溶液剂、胶囊剂、散剂、丸剂、颗粒剂、糖浆剂、混悬剂或者口服缓控释制剂；外用制剂选自软膏剂、喷剂或贴剂。
可选地，额外治疗剂含量为单独使用时治疗有效量的10％-100％。在每日一片/剂的剂型中，每片/剂己酸羟孕酮的含量为100-1000mg，在每日使用m片/剂的剂型中，每片/剂己酸羟孕酮的含量为(100-1000mg)/m，在n日使用一片剂的剂型中，每片/剂己酸羟孕酮的含量为n×(100-1000mg)。
可选地，所述药学上可接受的辅料选自药学上可接受的溶剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂、反絮凝剂、助滤剂、释放阻滞剂、高分子骨架材料和成膜材料中的至少一种。
根据本发明的另一方面，本发明提供了一种在需要时增加肿瘤浸润淋巴细胞(TIL)数量的方法，包括向受试者提供己酸羟孕酮。
可选地，其TIL群体包含CD8+T细胞，CD4+T细胞，B细胞，自然杀伤(NK)细胞，树突细胞(DC)，M1巨噬细胞或其组合的群体，优选表达TH1表型的T细胞。
可选地，其中TIL数量在肿瘤微环境(TME)中增加和/或在肿瘤组织中增加。
根据本发明的另一方面，本发明提供了一种治疗有需要的受试者癌症的方法，包括向受试者提供己酸羟孕酮。
可选地，包括向受试者提供除己酸羟孕酮以外的治疗癌症的额外治疗剂。
可选地，其额外治疗剂选自化疗剂、靶向治疗剂、激素治疗剂、细胞治疗剂、溶瘤性病毒剂或抗体。
可选地，其所述的额外治疗剂选自免疫治疗剂。
可选地，其所述额外治疗剂选自免疫检查点抑制剂。
可选地，其中免疫检查点抑制剂选自PD-L1,PD-1,PD-L2,CTLA-4,LAG3,B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2,SLAM的抑制剂，优选针对PD-1,PD-L2,CTLA-4,LAG3,B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2, SLAM或其组合的单克隆抗体，特别优选针对PD-L1或PD-1的单克隆抗体。
可选地，其中所述额外治疗剂选自阿特珠单抗，阿维鲁单抗，德瓦鲁单抗，卡瑞利珠单抗，西米单抗，伊匹单抗，纳武单抗，派姆单抗，信迪利单抗，替雷利珠单抗，特瑞普利单抗，替西木单抗或RC98。
可选地，其中受试者具有较高的PD-L1或PD-1表达。
可选地，其作为一线或二线治疗方法施用。
可选地，其己酸羟孕酮可以在施用额外治疗剂之前、同时或之后施用于受试者。
可选地，其受试者患有原发性或转移性癌症。其所述癌症为实体瘤或转移癌，其中实体瘤是膀胱癌、骨癌、脑癌、乳腺癌、结直肠癌、子宫内膜癌、食道癌、眼癌、头颈癌、肾癌、肺癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌或胃癌，优选乳腺癌、肺癌、肾细胞癌(RCC)、肝细胞癌(HCC)、黑色素瘤、结直肠癌或子宫内膜癌，特别优选原发性或转移性非小细胞肺癌(NSCLC)，其所述转移癌是转移黑色素瘤，转移结直肠癌或转移性子宫内膜癌。
可选地，其受试者患有复发性癌症或难治性癌症。
可选地，使用己酸羟孕酮或使用己酸羟孕酮和治疗癌症的额外治疗剂降低了受试者中肿瘤细胞的增值，和/或减缓或稳定了受试者的肿瘤生长。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为给药后肿瘤体积增长趋势图。
图2为给药后小鼠肿瘤CD8T细胞浸润(400X)。
图3为给药后小鼠肿瘤切片CD8染色光密度分析，以积分光密度值(IOD)/面积(area)表示，其中**表示OHPC组与对照组相比p<0.01。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品。
实验例1
1、受试药物与试剂
抗体Anti-PD-L1购自荣昌生物制药(烟台)有限公司，批号：RC98-1-A20170426，储存液浓度为6.87mg/ml，溶媒为0.9％氯化钠溶液。每次给药前，采用0.9％的氯化钠注射液配制成含Anti-PD-L1的浓度为1mg/ml的受试药物溶液。
己酸羟孕酮(OHPC)购自仙居县鸿雁医药化工有限公司，粉末。每次给药前，采用DMSO溶解OHPC粉末，待粉末完全溶解后，用芝麻油稀释到含OHPC浓度为4mg/ml的受试药物溶液。
2、动物分组、造模及给药
(1)细胞培养
小鼠乳腺癌4T1细胞购自北京百奥赛图基因生物有限公司，细胞培养在37℃、5％CO 2的培养箱中培养，培养基成分为含有10％灭活胎牛血清的DMEM培养基。本实验使用常规方法对4T1细胞进行基因改造，使其过量表达人源PD-L1，该细胞被命名为4T1-hPD-1。
(2)肿瘤细胞的接种、分组与给药。
Balb/c小鼠，SPF级，雌性，6-9周龄，体重16-22g。采用PBS重悬4T1-hPD-1细胞，然后以5×10 4个/0.1ml浓度，0.1ml/只体积接种于Balb/c小鼠的右侧皮下。当平均肿瘤体积达到约100mm 3时，根据小鼠肿瘤体积和重量选择合适的小鼠入组，平均分配到4个实验组中，每组8只，分别当天开始给药，具体给药方案如下表所示：
表1给药方案
Figure PCTCN2022080275-appb-000001
其中，a：给药体积依实验动物体积按10μl/g计算。
末次给药后，对实验动物体重及肿瘤生长状态继续观察12天，观察期间，每周测量肿瘤体积及动物体重，并记录测量值。完成观察后，结束实验。
3、检测指标
(1)肿瘤体积
分组后每周使用游标卡尺对肿瘤体积进行2次测量，安乐死前测量肿瘤体积，测量肿瘤的长径和短径，其体积计算公式为：肿瘤体积＝0.5×长径×短径 2。
(2)体重检测
接种、分组(即首次给药前)、给药期间每周2次、安乐死前称取动物体重。
(3)一般临床观察
适应性饲养期和实验期间每天观察1次，观察内容包括但不限于肿瘤结节破溃情况、动物精神状态、饮食情况等。
4、药物评价指标
(1)肿瘤体积抑制率(TGl TV)
TGl TV(％)＝[1-(Ti-T0)/(Vi-V0)]×100％；
其中，Ti：治疗组在给药第i天的肿瘤体积均值，T0：治疗组在给药第0天的肿瘤体积均值；Vi：溶剂对照组在给药第i天的肿瘤体积均值，V0：溶剂对照组在给药第0天的肿瘤体积均值。
(2)肿瘤组织CD8+T细胞浸润
实验结束后，取小鼠肿瘤石蜡包埋，切片进行CD染色，比较组间肿瘤中CD8+T细胞浸润。
5、数据采集和统计学分析
测定和观察的原始数据进行记录，基于原始数据进行分析处理，结果分析用平均数和标准误表示(Mean±SEM)。同时对肿瘤体积进行统计学分析，P<0.05认为有显著性差异。结果分析时同时考虑统计学意义和生物学意义。
6、实验结果
(1)肿瘤体积抑制结果
图1示出了给药后肿瘤体积增长趋势图。由图1可以看出，4T1乳腺癌对免疫治疗耐受，因此anti-PD-L1组没有显示出抑制肿瘤生长的效果。OHPC单独给药也没有抑制效果。但在anti-PD-L1和OHPC联用组，肿瘤生长后期受到抑制，第17天实验结束时候抑制率达到30.7％。
各组肿瘤体积和肿瘤肿瘤体积抑制率结果列于表2。
表2受试品对4T1-hPD-L1细胞移植Balb/c小鼠肿瘤体积的影响
Figure PCTCN2022080275-appb-000002
注：a：平均数±标准误差；
b：给药组体重与Vehicle对照组体重在分组给药第17天统计学比较，t-test分析。
(2)肿瘤组织CD8+T细胞浸润
参见说明书附图图2和图3，己酸羟孕酮能够明显增强CD8+T细胞浸润。
7、实验结论
己酸羟孕酮能够明显增强CD8+T细胞浸润，能够增强单抗药物Anti-PD-L1的抗肿瘤活性。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (27)

  1. 一种药物组合物，其特征在于，包括己酸羟孕酮和另一种治疗肿瘤的额外治疗剂。
  2. 根据权利要求1所述的药物组合物，其特征在于，另一种治疗肿瘤的额外治疗剂选自：化疗剂、靶向治疗剂、激素治疗剂、细胞治疗剂、溶瘤性病毒剂或抗体。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述额外治疗剂是免疫检查点抑制剂。
  4. 根据权利要求3所述的药物组合物，其特征在于，所述免疫检查点抑制剂是针对PD-L1,PD-1,PD-L2,CTLA-4,LAG3,B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2,或SLAM的抑制剂，优选针对PD-1或PD-L1的单克隆抗体。
  5. 根据权利要求4所述的药物组合物，其特征在于，所述额外治疗剂选自阿特珠单抗，阿维鲁单抗，德瓦鲁单抗，卡瑞利珠单抗，西米单抗，伊匹单抗，纳武单抗，派姆单抗，信迪利单抗，替雷利珠单抗，特瑞普利单抗，替西木单抗、RC98。
  6. 一种抗肿瘤药物，其包含权利要求1-5中任一项所述的药物组合物，和任选地一种或者多种药学上可接受的辅料。
  7. 根据权利要求6所述的抗肿瘤药物，其特征在于，抗肿瘤药物的剂型选自注射剂，口服制剂或外用制剂；优选注射剂或口服制剂；特别优选注射剂。
  8. 根据权利要求7所述的抗肿瘤药物，其特征在于，所述注射剂选自注射液或者粉针剂；口服制剂选自片剂、溶液剂、胶囊剂、散剂、丸剂、颗粒剂、糖浆剂、混悬剂或者口服缓控释制剂；外用制剂选自软膏剂、喷剂或者贴剂。
  9. 根据权利要求6-8中任一项所述的抗肿瘤药物，其特征在于，额外治疗剂含量为单独使用时治疗有效量的10％-100％。
  10. 根据权利要求6-9中任一项所述的抗肿瘤药物，其特征在于，在每日一片/剂的剂型中，每片/剂己酸羟孕酮的含量为100-1000mg，在每日使用m片/剂的剂型中，每片/剂己酸羟孕酮的含量为(100-1000mg)/m，在n日使用一片剂的剂型中，每片/剂己酸羟孕酮的含量为n×(100-1000)mg。
  11. 一种在需要时增加肿瘤浸润淋巴细胞(TIL)数量的方法，包括向受试者提供己酸羟孕酮。
  12. 根据权利要求11所述的方法，其特征在于，TIL群体包含CD8+T细胞，CD4+T细胞，B细胞，自然杀伤(NK)细胞，树突细胞(DC)，M1巨噬细胞或其组合的群体， 优选表达TH1表型的T细胞。
  13. 根据权利要求11或12所述的方法，其特征在于，其中TIL数量在肿瘤微环境(TME)中增加和/或在肿瘤组织中增加。
  14. 一种治疗有需要的受试者癌症的方法，其特征在于，包括向受试者提供己酸羟孕酮。
  15. 根据权利要求11-14中任一项所述的方法，其特征在于，还包括向受试者提供除己酸羟孕酮以外的治疗癌症的额外治疗剂。
  16. 根据权利要求15所述的方法，其特征在于，所述额外治疗剂选自化疗剂、靶向治疗剂、激素治疗剂、细胞治疗剂、溶瘤性病毒剂或抗体。
  17. 根据权利要求15所述的方法，其特征在于，所述额外治疗剂选自免疫治疗剂。
  18. 根据权利要求17所述的方法，其特征在于，所述额外治疗剂选自免疫检查点抑制剂。
  19. 根据权利要求18所述的方法，其特征在于，所述免疫检查点抑制剂选自PD-L1,PD-1,PD-L2,CTLA-4,LAG3,B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2,SLAM的抑制剂，优选针对PD-1,PD-L2,CTLA-4,LAG3,B7-H3,KIR,CD137,PS,TFM3,CD52,CD30,CD20,CD33,CD27,OX40,GITR,ICOS,BTLA(CD272),CD160,2B4,LAIR1,TIGHT,LIGHT,DR3,CD226,CD2,SLAM或其组合的单克隆抗体，特别优选针对PD-L1或PD-1的单克隆抗体。
  20. 根据权利要求15-19中任一项所述的方法，其特征在于，所述额外治疗剂选自阿特珠单抗，阿维鲁单抗，德瓦鲁单抗，卡瑞利珠单抗，西米单抗，伊匹单抗，纳武单抗，派姆单抗，信迪利单抗，替雷利珠单抗，特瑞普利单抗，替西木单抗或RC98。
  21. 根据权利要求15-20中任一项所述的方法，其特征在于，受试者具有较高的PD-L1或PD-1表达。
  22. 根据权利要求11-21中任一项所述的方法，其作为一线或二线治疗方法施用。
  23. 根据权利要求15-22中任一项所述的方法，其己酸羟孕酮在施用额外治疗剂之前、同时或之后施用于受试者。
  24. 根据权利要求11-23中任一项所述的方法，其受试者患有原发性或转移性癌症。
  25. 根据权利要求24所述的方法，其所述癌症为实体瘤或转移癌，其中实体瘤是膀胱癌、骨癌、脑癌、乳腺癌、结直肠癌、子宫内膜癌、食道癌、眼癌、头颈癌、肾癌、 肺癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌或胃癌，优选乳腺癌、肺癌、肾细胞癌(RCC)、肝细胞癌(HCC)、黑色素瘤、结直肠癌或子宫内膜癌，特别优选原发性或转移性非小细胞肺癌(NSCLC)，其所述转移癌是转移黑色素瘤，转移结直肠癌或转移性子宫内膜癌。
  26. 根据权利要求14-25中任一项所述的方法，其受试者患有复发性癌症或难治性癌症。
  27. 根据权利要求14-26中任一项所述的方法，其使用己酸羟孕酮或使用己酸羟孕酮和治疗癌症的额外治疗剂降低了受试者中肿瘤细胞的增值，和/或减缓或稳定了受试者的肿瘤生长。
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