CN117338793A - 一种药物及其应用、用于肝癌患者的免疫联合治疗方法 - Google Patents
一种药物及其应用、用于肝癌患者的免疫联合治疗方法 Download PDFInfo
- Publication number
- CN117338793A CN117338793A CN202311230493.3A CN202311230493A CN117338793A CN 117338793 A CN117338793 A CN 117338793A CN 202311230493 A CN202311230493 A CN 202311230493A CN 117338793 A CN117338793 A CN 117338793A
- Authority
- CN
- China
- Prior art keywords
- liver cancer
- tumor
- patient
- medicament
- immune
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 201000007270 liver cancer Diseases 0.000 title claims abstract description 39
- 208000014018 liver neoplasm Diseases 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 9
- 238000011282 treatment Methods 0.000 title abstract description 20
- 229940079593 drug Drugs 0.000 title abstract description 9
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960004276 zoledronic acid Drugs 0.000 claims abstract description 43
- 238000002648 combination therapy Methods 0.000 claims abstract description 14
- 206010027476 Metastases Diseases 0.000 claims abstract description 13
- 230000009401 metastasis Effects 0.000 claims abstract description 11
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 9
- 206010027452 Metastases to bone Diseases 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 230000001900 immune effect Effects 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 45
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 abstract description 6
- 230000002195 synergetic effect Effects 0.000 abstract description 5
- 210000004369 blood Anatomy 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 108091007744 Programmed cell death receptors Proteins 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 22
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 11
- 238000011580 nude mouse model Methods 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 8
- 230000003902 lesion Effects 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 5
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 210000004322 M2 macrophage Anatomy 0.000 description 4
- 108010063628 acarboxyprothrombin Proteins 0.000 description 4
- 210000003690 classically activated macrophage Anatomy 0.000 description 4
- 230000005847 immunogenicity Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 3
- 102100022338 Integrin alpha-M Human genes 0.000 description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 3
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 210000001991 scapula Anatomy 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000010109 chemoembolization Effects 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- -1 small molecule compounds Chemical class 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 1
- 238000012752 Hepatectomy Methods 0.000 description 1
- 101100341519 Homo sapiens ITGAX gene Proteins 0.000 description 1
- 208000034767 Hypoproteinaemia Diseases 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 241000249820 Lipotes vexillifer Species 0.000 description 1
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940124605 anti-osteoporosis drug Drugs 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 210000005266 circulating tumour cell Anatomy 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 208000024829 digestive system symptom Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 238000012148 non-surgical treatment Methods 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明提供了一种药物、上述药物在制备用于肝癌患者的免疫联合治疗药物中的应用以及一种用于肝癌患者的免疫联合治疗方法。药物包括唑来膦酸和抗PD‑1单克隆抗体。肝癌患者为不可手术切除肝癌患者,和/或存在骨转移的肝癌患者。本发明首次发现唑来膦酸的新用途,即唑来膦酸能够与程序性死亡受体1抑制剂起到协同抗肿瘤作用,作为不可切除肝癌免疫联合治疗的药物,能够有效减小肝癌患者的原发灶和骨转移灶,血中肿瘤标志物和循环肿瘤细胞等指标均得到有效改善,能够提高临床上不可切除肝癌患者的疗效,相比于现有不可切除肝癌治疗手段,本发明是一种全新的更为可靠、有效的方法。
Description
技术领域
本发明涉及医学生物检测领域,具体是一种用于临床不可切除肝癌免疫联合治疗的药物及其应用。
背景技术
肝细胞癌(Hepatocellular carcinoma,HCC)是我国高发的恶性肿瘤之一,肝切除术仍是目前HCC治疗最常用的根治性治疗手段,但术后5年复发率>70%。对于不可手术切除肝癌患者,经导管动脉化疗栓塞(Transcatheter arterial chemoembolization,TACE)术、分子靶向治疗和免疫检查点抑制的应用使肝癌疗效较过去有了明显提高。其中免疫治疗在晚期不可切除肝癌的临床治疗中更是取得了突破性进展,如程序性死亡受体1(Programmeddeath-1,PD-1)抑制剂是近年来最热门的肿瘤免疫治疗方法,不过免疫检查点抑制剂单药治疗的疗效仍然有限。为了进一步提高患者的疗效,联合治疗方案已经在全球范围内展开。
发明内容
为了克服上述技术缺陷,本发明的第一个方面提供一种药物,其包括:唑来膦酸(Zoledronic acid,ZA)。
进一步地,药物进一步包括:抗PD-1单克隆抗体。
进一步地,所述抗PD-1单克隆抗体为百济神州的替雷利珠单抗。
本发明的第二个方面提供上述药物在制备用于肝癌患者的免疫联合治疗药物中的应用。
进一步地,所述肝癌患者为不可手术切除肝癌患者,和/或,存在骨转移的肝癌患者。
本发明的第三个方面提供一种用于肝癌患者的免疫联合治疗方法,其包括以下步骤:
1)评估患者是否为不可切除肝癌,和/或,肝癌合并骨转移,即病人全身情况不能承受手术创伤、肝功能不能耐受、剩余肝体积(FLR)不足等无法行手术切除,或技术可切除,但切除以后不能获得比非手术治疗更好的疗效。如果患者为不可切除肝癌,和/或,肝癌合并存在骨转移,则判断该患者适合于免疫联合治疗;
2)对适合于免疫联合治疗的患者实施唑来膦酸联合抗PD-1单克隆抗体的免疫联合治疗。
采用了上述技术方案后,与现有技术相比,具有以下有益效果:
在现有技术中,唑来膦酸是一种经典的抗骨质疏松的药物。本发明首次发现唑来膦酸的新用途,即唑来膦酸(ZA)能够与程序性死亡受体1(Programmed death-1,PD-1)抑制剂(即抗PD-1+ZA)起到协同抗肿瘤作用,抗PD-1+ZA作为不可切除肝癌免疫联合治疗的药物,能够有效减小肝癌患者的原发灶和骨转移灶,血中肿瘤标志物和循环肿瘤细胞等指标均得到有效改善,能够提高临床上不可切除肝癌患者的疗效,相比于现有不可切除肝癌治疗手段,本发明是一种全新的更为可靠、有效的方法。
附图说明
图1是入组肝癌患者治疗前原发病灶的磁共振(MRI)图像。
图2是患者诊疗时间轴。诊断为原发性肝细胞癌后第一个月内给予抗病毒治疗。分别在第1、2个月接受了两次TACE治疗。在第6个月时,对患者进行了放射刀治疗。第10个月时发现骨转移。在第10、11和12个月分别实施了抗PD-1+ZA治疗。
图3是发现该患者有骨转移后,肝脏和左肩胛骨的典型MRI图像。在第11个月,左肩胛骨损伤已经显著减轻。12个月时,肝右叶病变稳定,左肩胛骨转移明显减少。14个月时,肝内病变没有进展,肝外转移几乎消失。
图4,图5是肝癌患者血清甲胎蛋白(Alpha-fetoprotein,AFP)和血清异常凝血酶原(Protein Induced by Vitamin K Absence or Antagonist-II,PIVKA-II)在治疗过程中的水平变化。患者AFP和PIVKA-II在治疗第5个月时水平开始显著升高,随后在观察到骨转移之前达到最大值。经抗PD-1+ZA治疗后,二者均逐渐下降。
图6是肝癌患者血清糖类抗原19-9(Carbohydrate antigen 19-9,CA19-9)治疗过程中的水平变化。该患者在诊断时具有高水平的CA19-9。从开始到第10周,CA19-9水平逐渐下降,但仍高于正常水平,而且下降的速度逐渐放缓甚至略有上升。经第三次给予抗PD-1+ZA后,CA19-9降至正常范围(<37mAU/ml)。
图7是肝癌患者血循环肿瘤细胞(Cycle tumor cell,CTC)和循环肿瘤微栓子(Cycle tumor microemboli,CTM)在经三次给予抗PD-1+ZA治疗的数量。随着联合治疗的进展,CTC和CTM逐渐降至0。
图8是在裸鼠荷瘤模型中对小鼠联合应用ZA+抗PD-1的实验过程示意图,ZA-1和ZA-2组是按照给药频率分的组别,ZA-1组小鼠给药频率为每天一次,ZA-2组小鼠给药频率为每隔一天一次。
图9是裸鼠荷瘤模型在实验结束后的小鼠肿瘤组织体积对比图。
图10是在ZA-2组的裸鼠荷瘤模型中,小鼠肿瘤体积随着时间变化的曲线图,组内小鼠给药频率为每隔一天一次,每一个图中的每一条曲线分别代表单只小鼠的肿瘤重量变化。
图11是在裸鼠荷瘤模型中,实验结束终点小鼠肿瘤体积的柱状图。
图12是在ZA-1组的裸鼠荷瘤模型中,小鼠肿瘤体积随着时间变化的曲线图,组内小鼠ZA给药频率为每天一次,每一个图中的每一条曲线分别代表单只小鼠的肿瘤重量随着时间的变化曲线图。
图13是通过免疫组织化学染色检测肿瘤增殖标志物Ki-67的表达图。
图14是在裸鼠荷瘤模型中,小鼠体重变化曲线图。
图15是肝、肾和肺等组织病理切片图。
图16是通过流式细胞术检测上述荷瘤小鼠肿瘤组织中的免疫细胞数量和比例图。
图17是M2巨噬细胞含量柱状图。
图18是T细胞含量柱状图。
图19是中性粒细胞含量柱状图。
图20是M1巨噬细胞含量柱状图。
图21是基于GDSC2药物预测数据库评估三个队列样本对198个小分子化合物或药物单体的IC50的流程示意图,图中的n代表样本数。
图22是TCGA-LIHC的ESTIMATE评分和肿瘤纯度。
图23是TCGA-LIHC队列、ICGC-JP队列和ICGC-FR队列中的高免疫原性组和低免疫原性的组中ZA的IC50值的柱状图。
图24是通过肿瘤TNM分期对TCGA-LIHC的样本进行分组后的各组的ZA的IC50值。
具体实施方式
以下结合附图与具体实施例进一步阐述本发明的优点。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1:一例肝癌患者实施ZA+抗PD-1免疫联合治疗
该肝癌患者是一名61岁的中国女性,临床分期为巴塞罗那(BCLC)a期,中国癌症分期(CNLC)I a期,Child-Pugh评分为7,B级。患者临床表现包括门静脉高压、腹水和低蛋白血症。患者拒绝肝移植,并分别在入院前两个月接受了TACE,整体治疗效果不佳(图1,2)。
由于患者出现严重的消化系统症状,停用了乐伐替尼,后续开展免疫治疗。患者在第10个月出现骨转移,对患者进行了PD-1抗体(替雷利珠单抗注射液)+唑来膦酸(ZA)的联合治疗,为期三个月,共三个疗程,如图2所示。利用MRI观察患者原发性肿瘤和转移性肿瘤的大小。检测血清中肿瘤标志物,如AFP、PIVKA和CA19-9等,检测血中CTC和CTM数量,作为肿瘤转移的指标。
MRI结果显示在经三次抗PD-1+ZA治疗后,患者肝内病变无明显进展,肝外转移几乎消失(图3),血清中AFP、PIVKA和CA19-9逐渐下降并恢复正常水平(图4-6),血中未检测到CTC和CTM(图7),以上结果提示患者在接受抗PD-1+ZA联合治疗后,肿瘤进展得到了有效控制。
实施例2:裸鼠荷瘤模型中ZA+抗PD-1联合应用具有协同抗肿瘤作用
我们通过皮下注射Hepa1-6肝癌细胞系建立了裸鼠荷瘤模型(图8)。8周龄的裸鼠随机分组,每组11只,共6组,即vehicle+lgG组(对照组)、Anti-PD-1组(即抗PD-1组)、ZA-1组、ZA-1+Anti-PD-1组、ZA-2组和ZA-2+Anti-PD-1组。药物处理方法如下:分别在皮下接种肝癌细胞后第5、7和10天腹腔注射PD-1单抗(剂量1mg/kg),每天(ZA-1组)或每隔一天(ZA-2组)腹腔注射ZA(剂量100ug/kg)。在20天的实验期内,每天测量各组小鼠的肿瘤体积。实验结束对小鼠实施安乐死,收集各组的肿瘤组织(图9)。如图10中结果显示,对照组小鼠肿瘤体积显著增加,ZA-2组小鼠肿瘤体积相比对照组增长减缓(P<0.001),表明单独ZA具有一定的抗肿瘤作用。Anti-PD-1组和ZA-2+Anti-PD-1组的肿瘤体积均明显小于对照组(P<0.001)(图11),尽管两组的肿瘤重量无显著差异(P=0.32),但从肿瘤生长曲线上看,ZA-2+PD-1组起效时间更短(P<0.05)(图10)。这些结果表明ZA和抗PD-1单克隆抗体具有协同抗肿瘤效应。
与对照组相比,ZA给药频率的增加(即每天一次,剂量不变)导致ZA-1组小鼠肿瘤体积增长相对缓慢(P<0.001)(图12),然而,ZA-1+Anti-PD-1组的肿瘤体积却显著大于Anti-PD-1组(P<0.01)。此外,在观察20天后,ZA-1+Anti-PD-1组小鼠的肿瘤重量大于ZA-2+Anti-PD--1组(P<0.05)(图11),以上结果表明,增加ZA给药频率反而减弱了ZA与Anti-PD-1单克隆抗体之间潜在的协同抗肿瘤作用。通过免疫组织化学染色检测肿瘤增殖标志物Ki-67的表达(图13),结果显示联合治疗组的Ki-67表达水平显著降低。为了评估治疗的安全性,在20天的观察期内监测小鼠的体重和行为,结果显示小鼠体重无明显变化(图14),给药方案耐受性良好,没有严重副作用。此外,肝、肾和肺等组织病理切片中未观察到明显损伤和转移性肿瘤灶(图15)。
我们通过流式细胞术检测上述荷瘤小鼠肿瘤组织中的免疫细胞数量和比例(图16),其中M1巨噬细胞记为CD11b+F4/80+CD11C+,M2巨噬细胞记为CD11b+F4/80+CD206+,T细胞标记为CD45+CD3+,中性粒细胞标记为CD45+CD11b+Ly6G+。结果显示,对照组M2巨噬细胞比例显著高于其余组(图17),表明M2巨噬细胞具有一定促肿瘤作用,T细胞和中性粒细胞的比例无明显差异(图18-19)。与Anti-PD-1组相比,ZA-2+Anti-PD-1组中M1巨噬细胞比例增加(P<0.001)(图20),这表明ZA和抗PD-1单克隆抗体的协同抗肿瘤作用可能与ZA诱导巨噬细胞向M1表型极化有关。此外,与Anti-PD-1组相比,ZA-1+Anti-PD-1组的M1巨噬细胞比例下降,这表明增加ZA给药频率反而削弱了抗PD-1单克隆抗体的抗肿瘤作用。
实施例3:TCGA和ICGC数据库中ZA对HCC患者具有敏感性
我们收集了三个HCC队列,包括TCGA-LIHC、ICGC-JP和ICGC-FR(图21),基于GDSC2药物预测数据库,评估了来自三个队列总共765个肿瘤样本对198个小分子化合物或药物单体的IC50。索拉非尼是治疗HCC的一线药物,三个队列中索拉非尼和ZA的IC50值和排名接近,表明ZA具有治疗HCC的潜力。接着我们通过ESTIMATE算法和肿瘤纯度来评估肿瘤样本的免疫浸润程度,并将中位数设为临界值,据此将所有样本分为两组,即高、低免疫原性组。TCGA-LIHC的ESTIMATE评分和肿瘤纯度如图22所示。结果显示高免疫原性组中ZA的IC50值显著低于低免疫原性的组(图23),表明前者的疗效更好。此外,我们通过肿瘤TNM分期对TCGA-LIHC的样本进行了分组,结果显示I期ZA的IC50值明显较低(图24),表明在HCC早期给予ZA比中晚期将可能获得更好的疗效。综上结果我们认为,ZA在免疫浸润程度较高的肿瘤免疫微环境中可能发挥了较好的抗肿瘤作用。
应当注意的是,本发明的实施例有较佳的实施性,且并非对本发明作任何形式的限制,任何熟悉该领域的技术人员可能利用上述揭示的技术内容变更或修饰为等同的有效实施例,但凡未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何修改或等同变化及修饰,均仍属于本发明技术方案的范围内。
Claims (6)
1.一种药物,其特征在于,包括:唑来膦酸。
2.如权利要求1所述的药物,其特征在于,进一步包括:抗PD-1单克隆抗体。
3.如权利要求2所述的药物,其特征在于,所述抗PD-1单克隆抗体为替雷利珠单抗。
4.权利要求1~3中任一项所述的药物在制备用于肝癌患者的免疫联合治疗药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述肝癌患者为不可手术切除肝癌患者,和/或,存在骨转移的肝癌患者。
6.一种用于肝癌患者的免疫联合治疗方法,其特征在于,包括以下步骤:
1)评估患者是否为不可切除肝癌,和/或,肝癌合并骨转移;如果患者为不可切除肝癌,和/或,肝癌合并存在骨转移,则判断该患者适合于免疫联合治疗;
2)对适合于免疫联合治疗的患者实施唑来膦酸联合抗PD-1单克隆抗体的免疫联合治疗。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311230493.3A CN117338793A (zh) | 2023-09-22 | 2023-09-22 | 一种药物及其应用、用于肝癌患者的免疫联合治疗方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311230493.3A CN117338793A (zh) | 2023-09-22 | 2023-09-22 | 一种药物及其应用、用于肝癌患者的免疫联合治疗方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117338793A true CN117338793A (zh) | 2024-01-05 |
Family
ID=89364154
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311230493.3A Pending CN117338793A (zh) | 2023-09-22 | 2023-09-22 | 一种药物及其应用、用于肝癌患者的免疫联合治疗方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117338793A (zh) |
-
2023
- 2023-09-22 CN CN202311230493.3A patent/CN117338793A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Raoul et al. | Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support | |
US10350275B2 (en) | Methods of cytotoxic gene therapy to treat tumors | |
JP7316120B2 (ja) | 腫瘍性疾患のための治療 | |
Bisogno et al. | Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma | |
Zhang et al. | Effects of thalidomide on angiogenesis and tumor growth and metastasis of human hepatocellular carcinoma in nude mice | |
Tanaka et al. | Debulking surgery followed by intraarterial 5-fluorouracil chemotherapy plus subcutaneous interferon alfa for massive hepatocellular carcinoma with multiple intrahepatic metastases: a pilot study | |
WO2021143799A1 (zh) | 抗pd-1抗体和呋喹替尼联合在制备治疗癌症的药物中的用途 | |
CN109793892B (zh) | 一种抗pd-1抗体在制备治疗食管癌的药物中的用途 | |
TWI817958B (zh) | 用於治療肝癌之組合物及方法 | |
Sun et al. | Effects of mFOLFOX6 regimen combined with carrelizumab on immune function and prognosis in patients with microsatellite instability colorectal cancer | |
CN117338793A (zh) | 一种药物及其应用、用于肝癌患者的免疫联合治疗方法 | |
US20230172882A1 (en) | Method For Treating Pancreatic Cancer | |
CN110585429B (zh) | 酪氨酸激酶抑制剂联合单克隆抗体以及紫杉醇类药物治疗肿瘤疾病的用途 | |
RU2524309C1 (ru) | Способ выбора тактики лечения местно-распространенного рака предстательной железы | |
CN114159557A (zh) | 一种治疗肿瘤疾病的联合用药组合物及应用 | |
Hodolic et al. | Metastatic prostate cancer proven by 18F-FCH PET/CT staging scan in patient with normal PSA but high PSA doubling time | |
TW202103734A (zh) | 治療克隆氏症(crohn's disease)的方法 | |
WO2019129168A1 (zh) | Pd-1抗体和阿帕替尼联合治疗三阴性乳腺癌的用途 | |
Gözel et al. | P1. 07-010 influence of creatinine clearance on survival parameters in small cell lung cancer treated with Cisplatin-based chemotherapy regimen: Topic: Drug treatment alone and in combination with radiotherapy | |
Frishberg et al. | A phase 1/2 trial of lumasiran (ALN-GO1), an investigational RNAi therapeutic for primary hyperoxaluria type 1 | |
Paszt et al. | Clinical benefits of oral capecitabine over intravenous 5-fluorouracyl regimen in case of neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer | |
WO2023095929A1 (ja) | 悪性腫瘍治療薬 | |
WO2019139583A1 (en) | Methods and combination therapy to treat cancer | |
RU2802962C2 (ru) | Композиции и способы лечения рака печени | |
Tolcher et al. | A phase 1, first in human, open-label, dose escalation and dose expansion study of TST005 in patients with locally advanced or metastatic solid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |