肿瘤学-培训课件
肿瘤学-培训课件,肿瘤,培训,课件
Principle of Chemotherapy, , Target therapy and Cancer ImmunotherapyCancer Center of Guangzhou Medical University 胡晓晔2016.9.13 Chemotherapy is a type of cancer treatment that uses drugs to destroy cancer cells. .HistoryNitrogen mustard19461946HistoryMTX 1941948 8HistoryYEARDRUGS1946Nitrogen mustard1948MTX1957CTX 5-5-FU1970sDDP ADM1990sTAXENS Topo-1 / -1 / G- -CSF 5- 5-HT3 32000sTarget therapyHistory“ “CANCER” Refers to a Malignant neoplasm ( (New growth) )Cancer cells can manifest: : Uncontrolled Proliferation. Loss of function due to lack of ability to differentiate. Invasiveness. The ability to metastasize.Cancer arises as a result of a series of genetic changes in the cell, , the main genetic lesions being: : Inactivation of tumor suppressor genes. The activation of oncogenes.Antineoplastic agents Are cytotoxic not tumoricidal Only kill cells during mitosis, and Not all cancer cells are dividing at the same time. Success Depends On: : Stage of cancer at time of diagnosis Type of cancer Development of drug resistance Overall health of patient. CELL GROWTH CYCLE5 5 DISTINCT PHASES OF MITOSIS 1. G0 - Resting - no mitosis 2. G1 - Postmitotic - first growth 3. S - DNA synthesis phase 4. G2 - Premitotic - second growth 5. M - Mitosis phase GENERATION TIME - one complete cycle different in all tumors, from hours to days11ANTINEOPLASTIC AGENTS 2 MAIN GROUPS OF AGENTS: CELL CYCLE - NONSPECIFIC (CCNS) ALKYLATING AGENTS cytotoxic in any phase of cell cycle effective against slowly growing tumors CELL CYCLE - SPECIFIC (CCS) 3 TYPES ANTIMETABOLITES - cytotoxic is S phase MITOTIC INHIBITORS - cytotoxic in M phase CYTOTOXIC ANTIBIOTICS (some are CCNS) effective against rapidly growing tumorsALKYLATING AGENTSNITROGEN MUSTARDS first developed in 1940s CCNS killing ability mechlorethamine is the prototypical agent USES: Hodgkins disease & lymphomas. CANCERS OF lung, breast, ovary, testes,brain,bladder,Most widely used agent, often in combination with other agents.ALKYLATING AGENTSSELECTED AGENTS: Mechlorethamine (Mustine, Mustargen) IV only (adult use only) Cyclophosphamide (Cytoxan, Neosar) IV and PO, adults and pediatric use Carmustine (BiCNU) IV, adult only, can cross blood-brain barrier, therefore used to tread brain lesionsOTHER AGENTS: Chlorambucil, StreptozotocinANTIMETABOLITESACTIONS: Antagonism of folate, purines, and pyrimidines needed for synthesis of nucleic acids -stops cell replication USES: Solid tumors (breast, lung, liver, brain, colon. Stomach, pancreas) Lymphomas, leukemias. Some agents also immunosuppressive, Useful in treating immune-mediated diseasesANTIMETABOLITESSELECTED AGENTS: (FOLIC ACID ANALOG) METHOTREXATE (Folex, Rheumatrex, MTx) Folic acid antagonist PO & IM, adult and pediatric use Also used to treat immune-mediated diseases, Used incombination with misoprostol for therapeutic abortion Causes profound anemia (folate depletion) Therefore leucovorin “rescue” often used to counteractANTIMETABOLITES SELECTED AGENTS: PURINE ANALOG MERCAPTOPURINE (6-MP, Purinethol) Purine antagonist PO only, adult and pediatric use PYRIMIDINE ANALOG CYTARABINE (Ara-C, Cytosar-U) Pyrimidine antagonist IV and intrathecal (within spinal canal)MITOTIC INHIBITORSACTIONS: Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) Bind to and disrupt mitotic spindles USES: Lymphomas (Hodgkins and non-Hodgkins),Neuroblastoma Kaposis sarcoma,Solid tumors (breast, testicular, etc.)MITOTIC INHIBITORSSELECTED AGENTS: ETOPOSIDE (VP-16, VePesid) IV and PO, adult use only ACLITAZEL (Taxol) IV only, adult use only drug of choice for ovary and breast ca VINCRISTINE (LCR, VCR,Oncovin) IV only, adult and pediatric use drug of choice for acute leukemiaCYTOTOXIC ANTIBIOTICSACTIONS: Source: Streptomyces mold - work by intercalation (insertion of drug molecule between the 2 DNA strands causing it to (“unwind”) Kill some bacteria and viruses but are too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, always used in combination with other agentsCYTOTOXIC ANTIBIOTICSSELECTED AGENTS: DOXORUBICIN (ADR, Rubex, Doxil) IV only, adult use only BLEOMYCIN (BLM, Blenoxane) IM, IV, SQ, adult use only very toxic agents !MISCELLANEOUS ANTINEOPLASTICSVarious actions, Both CCNS and CCS Used in combinations with other agents SELECTED AGENTS: Cisplatin (Platinol) IV, adult and pediatric useALTRETAMINE (Hexalen) PO only, adult use only, primarily used to treat ovarian cancer ASPARAGINASE (Elspar) IV only, adult and pediatric use HYDROXYUREA (Hydrea) PO only, adult use onlyMISCELLANEOUS ANTINEOPLASTICSHORMONES AND ANTAGONISTS. .1. 1. Adrenocortical Suppressant: : Mitotane, , Aminoglutethimide. (. (Adrenal Cortex) )2.2.Adrenocortical Steroids: : Prednisone. (. (Lukemias, , Lymphomas, , Breast) )3.3.Progestins: : Hydroxyprogestrone.( .(Endometrium, (, (Breast) ) Medroprogestrone, , Megesterol acetate. .4.4.Estrogens: : DES, , Ethinylesterdiol.( .(Breast, , Prostate) )5.5.Antiestrogens: :Tamoxifen .( .(Breast) )6.6.Androgens: : Testosterone ( (Breast) )7.7.Antiandrogens: : Flutamide ( (Prostate). ).8.8.Gonadotropin Releasing Hormone Analog: :Leuprolide. (. (Prostate) ) Chemotherapy works by stopping or slowing the growth of cancer cells, which grow and divide quickly. But it can also harm healthy cells that divide quickly, such as those that line your mouth and intestines or cause your hair to grow. Damage to healthy cells may cause side effects. Often, side effects get better or go away after chemotherapy is over.25化疗药物的耐药性化疗药物的耐药性 是是指肿瘤细胞对于化疗药物作用的耐受性。分为:指肿瘤细胞对于化疗药物作用的耐受性。分为: 1.1.天然性耐药(天然性耐药(natural resistancenatural resistance) 或称为或称为原发性耐药(原发性耐药(primary resistanceprimary resistance) 2.2.获得性耐药(获得性耐药(acquired resistanceacquired resistance) 或称为或称为继发性耐药(继发性耐药(secondary resistancesecondary resistance) 多药耐药性(多药耐药性(MDRMDR)是指恶性肿瘤细胞接触一种抗癌药后,继)是指恶性肿瘤细胞接触一种抗癌药后,继而对多种结构不同、作用机制各异的其他抗癌药产生耐药性。而对多种结构不同、作用机制各异的其他抗癌药产生耐药性。(一)(一) 耐药的发生耐药的发生机制机制1.细胞药效学相关的耐药机制 药物作用靶向酶的含量增高或与药物的亲和力改变;肿瘤细胞DNA修复增加;肿瘤细胞代谢替代途径的建立;细胞凋亡途径受阻。2. 细胞药动力学相关的耐药机制肿瘤细胞对化疗药物摄取减少;药物活化酶的量或活性减低;药物去活酶的量或活性增加;细胞对药物的排出增加。( (二二) )克服耐药的策略克服耐药的策略多药联合使用多药联合使用选择不同作用机制的药物序贯使用选择不同作用机制的药物序贯使用提高化疗药物剂量(效果有限)提高化疗药物剂量(效果有限)抑制细胞抑制细胞MDRMDR泵泵合理应用化疗的合理应用化疗的策略策略 联合化疗的概念 原则 单药治疗有效单药治疗有效 作用机制不同作用机制不同 作用时相不同作用时相不同 毒性反应不同毒性反应不同 临床证实有效临床证实有效化疗的临床应用化疗的临床应用 根治性化疗(根治性化疗(Curative ChemotherapyCurative Chemotherapy) 辅助化疗(辅助化疗(Adjuvant ChemotherapyAdjuvant Chemotherapy) 新辅助化疗新辅助化疗( Neoadjuvant ChemotherapyChemotherapy) 姑息性姑息性化疗(化疗(Palliative Chemotherapy Palliative Chemotherapy )化疗的临床应用化疗的临床应用根治性根治性化疗化疗(Curative Chemotherapy)适用于化疗可能治愈的肿瘤In adults, these curable cancers include Hodgkins and non-Hodgkins lymphoma, acute lymphoblastic and myelogenous leukemia, germ cell cancer, ovarian cancer, limited-stage small cell lung cancer, and choriocarcinoma.In pediatric patients, the major curable cancers include the acute leukemias, Burkitt lymphoma, Wilms tumor, and embryonal rhabdomyosarcoma选用公认的标准联合化疗方案足疗程,足剂量不要随意延长化疗间隔加强支持治疗,积极防治化疗合并症化疗的临床应用化疗的临床应用新辅助新辅助化疗化疗( Neoadjuvant Chemotherapy) as the primary treatment in patients who present with localized cancer for which local therapies, such as surgery and/or radiation, exist but are less than completely effective to reduce the size of the primary tumor such that it allows for higher rates of surgical resection while reducing the potential spread of micrometastatic spread. neoadjuvant chemotherapy may allow for preservation of vital organs such as the larynx, anal sphincter, limbs, and bladder. Head and neck cancer,NSCLC, Osteosarcoma,Colorectal cancer化疗的临床应用化疗的临床应用辅助化疗辅助化疗( (Adjuvant Chemotherapy) ) chemotherapy is as an adjuvant to local treatment modalities such as surgery and radiation therapy the goal of adjuvant therapy is to eradicate micrometastases, thereby reducing the incidence of both local and systemic recurrence and improving the overall survival of patientsbreast cancer, colon cancer, gastric cancer, NSCLC, ovarian cancer, head and neck cancer, and cervical cancer, Wilms tumor, and osteogenic sarcoma化疗的临床应用化疗的临床应用姑息性化疗(姑息性化疗(Palliative Chemotherapy ) This approach applies for patients with advanced, metastatic disease. Studies involving a wide range of solid tumor types have shown that chemotherapy confers survival benefit when compared with only supportive care in patients with advanced diseaseThe new era of personalized medicine/Targeted TherapyThe new era of personalized medicine/Targeted TherapyClassical anti cancer treatment Aims at arresting cell proliferation by interfering with cell replication at different stages of mitosis Growth factor self-sufficiencyHanahan D, et al. Cell. 2000;100:57-70. CancerInsensitivity to anti-growth signalsEvading apoptosisTissue invasion and metastasisSustained angiogenesisLimitless replication potentialHallmarks of MalignancyTargeting the Tumor and Its MicroenvironmentCancer cell:Tumor Cell Growth/ReplicationEndothelial cells:Angiogenesis Endothelial CellTumor matrix:Invasion/ metastasisImmune system40Signalling transduction PathwaysProliferation Apoptosis New Strategy - Signalling Pathways as a target for anti cancer treatmentProliferation Apoptosis Proliferation Apoptosis YYMonoclonal AbsTyrosin Kinase InhibitorsTKI 100% Mouse ProteinMouse10% Mouse ProteinHumanized34% Mouse ProteinChimericFully Human100% Human Protein_ximab_zumab_mumabTyrosin Kinase Inhibitors=TKI _nib Monoclonal AbsReceptor Tyrosine Kinase (RTK) FamiliesHER2HER3HER4EGFRTGF-EGFHeregulinEpiregulinNoneHER (erbB) FamilyVEGFR-2 VEGFR-3VEGFR-1VEGF-A VEGF-BVEGF-C VEGF-DVEGFR FamilyFlt-3PDGFRKITFLPDGF SCFPDGFR FamilyPPPPVEGFRs, PDGFR, KIT, Flt-3EGFR/HER2PPPPReceptor Dimerization and ActivationVEGF-A VEGF-CVEGF-DPPPPFGFR1FGF-1FGF-14FGF-16FGF-23FGFR2FGFR3FGFR4IGF-1 IGF-2IGF-1R46Trastuzumab=HerceptinHER2NoneHER (erbB) FamilyMonoclonal anti HER2 AbsImmunohistochemistry (IHC) slides showing intensity of membrane staining for HER2 statusHerceptin for HER2+ breast caMetastaticEarly stagePiccart et al NEJM 2005 Oct 20;353(16):1659-72Receptor Tyrosine Kinase (RTK) FamiliesHER2HER3HER4EGFRTGF-EGFHeregulinEpiregulinHeregulinEpiregulinNoneHER (erbB) FamilyVEGFR-2 VEGFR-3VEGFR-1VEGF-A VEGF-BVEGF-C VEGF-DVEGFR FamilyFlt-3PDGFRKITFLPDGF SCFPDGFR FamilyPPPPVEGFRs, PDGFR, KIT, Flt-3Mutant Flt-3PPPPEGFR/HER2PPPPReceptor Dimerization and ActivationVEGF-A VEGF-CVEGF-DIGF-1RPPPPIGF-1 IGF-2FGFR1FGFR2FGFR3FGFR4FGF-1FGF-14FGF-16FGF-2350Cetuximab=Erbitux Panitumumab=Vectibix Monoclonal anti EGFR AbsEGFRTGF-EGFAmphiregulinEpiregulinRAS Mutant Median Survival monthsPanitumumab + FOLFOX423.9 FOLFOX419.7 Panitumumab/Cetuximab1st line Metastatic CRC Kras WTMonthsSurvival Probability010%20%30%40%50%60%70%80%90%100%0 2 4 6 8 10 12 14 16 18 202224262830323436HR = 0.83 (95% CI: 0.671.02) P-value = 0.07Median Survival monthsCetuximab+FOLFIRI24.9 FOLFIRI21.0HR =0.796 (95% CI: 0.670-0.946P-value = 0.0093OS0.00.51.0180612245430364248MonthsVan Cutsem et al. JCO 28:15s, 2010 (suppl; abstr 3570)Douillard et al. JCO 2010 Nov 1;28(31):4697-705.Erlotinib=TarcevaGefitinib=IressaTKI: EGFREGFRTGF-EGFAmphiregulinEpiregulinChemotharpy for metastaticNon Small Cell Lung CaMonth100806040200010203040Cisplatin and paclitaxelCisplatin and gemcitabineCisplatin and docetaxelCarboplatin and paclitaxelSurvival (%)Schiller JH, et al. N Engl J Med. 2002;346:92-98.55 EGFR mutations 2005 EGFR mutations identified 2008 Gefitinib favorable in Asian, never smoker, Adenoca EGFR mutated patientsMetastatic NSCLCMok et al NEJM 2009 1217 patients randomisedProgression free survival in EGFR mutation positive and negative patientsMok et al, 2008 EGFR Mutation PositiveEGFR Mutation NegativeHR: 0.48 (95% CI: 0.36-0.64; P .0001)Gefitinib events , n (%) 97 (73.5)C/P events, n (%) 111 (86.0)Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)HR: 2.85 (95% CI: 2.05-3.98; P .0001)Gefitinib events, n (%) 88 (96.7)C/P events, n (%) 70 (82.4) 0481216202400.20.40.60.81.0Probability of PFS0481216202400.20.40.60.81.0Probability of PFSGefitinib (n = 91)Carboplatin/paclitaxel (n = 85)MosMosMaemondo , N Engl J Med 2010; 362:2380 Gefitinib in NSCLC with EGFR mutationsEGFRKRASUnknownALKBRAFPIK3CAERBB2MEK1ERBB2 AmplificationMET AmplificationLung Adenocarcinoma: 2012ALK fusion54-yr-old malenever-smoker,adenocaInter-patient Heterogeneity NSCLCPatients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)In 2012: Most oncologists would agree that these patients have very different malignanciesMost oncologists would agree that these patients should receive different therapy39-yr-old femalenever-smokeradenocaEGFR Mt65-yr-old malesmoker,squamousKRAS MtAdvanced-Stage NSCLC & good performance statusEFGR mutation and ALK negative and nonsquamous histologyEFGR mutation and ALK negative and squamous histologyEGFR mutation positiveErlotinib or gefitinibfirst lineConsider crizotinib first or second lineELM4-ALK positiveUpdated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.Proposed Treatment Algorithm for Advanced NSCLC 2012Consider carboplatin/paclitaxel + bevacizumab orcisplatin/pemetrexed bevacizumabConsidercisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxelorcisplatin/vinorelbine cetuximabConsidercisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxelorcisplatin/vinorelbine cetuximabBevacizumab inappropriateBevacizumab appropriateReceptor Tyrosine Kinase (RTK) FamiliesHER2HER3HER4EGFRTGF-EGFHeregulinEpiregulinHeregulinEpiregulinNoneHER (erbB) FamilyVEGFR-2 VEGFR-3VEGFR-1VEGF-A VEGF-BVEGF-C VEGF-DVEGFR FamilyFlt-3PDGFRKITFLPDGF SCFPDGFR FamilyPPPPVEGFRs, PDGFR, KIT, Flt-3Mutant Flt-3PPPPEGFR/HER2PPPPReceptor Dimerization and ActivationVEGF-A VEGF-CVEGF-DIGF-1RPPPPIGF-1 IGF-2FGFR1FGFR2FGFR3FGFR4FGF-1FGF-14FGF-16FGF-2363KITSCFPDGFRPDGFGlivec=Imatinib TKI: c-KIT PDGFRTKI: BCR-Abl fusion proteinGlivec Adjuvant for high risk GIST AngiogenesisContinuously expressed VEGF is a key mediator of angiogenesis and tumour progressionVEGFAngiogenesisControl angiogenesis, control tumour growthRegressionoftumour vasculatureNormalisationofsurviving vasculatureInhibitionof new and recurrentvessel growthVEGFR-3VEGFR-2VEGFR-1Endothelial cellVEGF LigandAnti-VEGF Abs(bevacizumab)Anti-VEGFR2 Abs(ramucirumab)Small-molecule inhibitors (vatalanib, cediranib, motesanib,sunitinib, sorafenib, axitinib, others)SolubleVEGFRs,VEGF Trap(aflibercept)Agents Targeting the VEGF PathwayEndothelial CellVEGFRCancer CellEGFR/HER2TKIMultispecific TKIs: Targeting Multiple Growth Factor Signaling Pathways70TKI: VEGFR, PDGFR, C-Kit, RafSorafenib=NexavarSunitinib=SutentTKI: VEGFR, C-KitPazopanib=VotrientTKI: VEGFR1,2,3, C-Kit, PDFGRTivozanibTKI: VEGFR1,2,3Immune system731. Costimulation via CD28 binding transduces T-cell activating signalsMHCTCRT cellCTLA-4APC3. Blocking CTLA-4 binding enhances T-cell responsesMHCTCRIpilimumabT cellCTLA-4APCT-cell activationMHCTCR2. CTLA-4 binding on activated T cells down-regulates T-cell responsesT cellAPCCD28CTLA-4T-cell inactivationB7B7B7T-cell activationCD28CD28Ipilimumab Immunotherapeutic Ab: AntiCTLA-4 Targeted TherapiesErlotinibGefitinibBevacizumabSunitinibSorafenibSorafenibChemotherapyTrastuzumabT DM1TemsirolimusEverolimusVemurafnibPanitumumabCetuximabLapatinib75 Different pathways “talk” to each other, effecting each otherMore PitfallsPreMSummary Targeted therapies are exciting new treatment option for many cancer types can be more selective and show improved efficacy with minimal toxicity We need more valid biomarkers that define relevant and meaningful targets for treatment肿瘤免疫治疗肿瘤免疫治疗Cancer Immunotherapy1. NEJM. 2015,April 20.ipilimumab (3 mg/kg of body weight) nivolumab (1 mg/kg of body weight)免疫系统(Immune System)基本功能:基本功能:1.免疫防御免疫防御(immunologic defence) 2.免疫稳定免疫稳定(immunologic homeostasis) 3.免疫监视免疫监视(immunologic surveillance)固有免疫:组织屏障、固有免疫细胞及免疫分子固有免疫:组织屏障、固有免疫细胞及免疫分子(非特异性免疫)适应免疫适应免疫 (特异性免疫)体液免疫:产生体液免疫:产生Ab,ADCC细胞免疫细胞免疫80免疫逃逸免疫逃逸是恶性肿是恶性肿瘤的特点瘤的特点之一,也之一,也是治疗的是治疗的靶点。靶点。肿瘤与免疫Hanahan D et al. Cell. 2011 Mar 4;144(5):646-74.免疫治疗是一种新兴的肿瘤治疗模式免疫治疗是一种新兴的肿瘤治疗模式肿瘤免疫治疗是应用免肿瘤免疫治疗是应用免疫学的原理和方法,通疫学的原理和方法,通过调动机体的天然防御过调动机体的天然防御机制或应用生物制剂等机制或应用生物制剂等刺激机体自身的抗肿瘤刺激机体自身的抗肿瘤免疫反应,从而控制和免疫反应,从而控制和杀伤肿瘤细胞。杀伤肿瘤细胞。免疫治疗的策略和现有免疫治疗的策略和现有方法包括:过继性细胞方法包括:过继性细胞治疗、肿瘤疫苗和免疫治疗、肿瘤疫苗和免疫检查点的调节等。检查点的调节等。Matsueda S et al . World J Gastroenterol 2014 February 21; 20(7): 1657-1666靶向免疫检查点治靶向免疫检查点治疗取得重大突疗取得重大突破!破!靶向免疫检查点治疗靶向免疫检查点治疗Mellman I et al. . Nature. . 20112011 Dec 21;480(7378):480-9.21;480(7378):480-9.抗原特异性抗原特异性T细胞反应是由共刺激与共抑制信号共同调节的,靶向免疫检查点治疗可阻细胞反应是由共刺激与共抑制信号共同调节的,靶向免疫检查点治疗可阻断共抑制信号,增强抗肿瘤效应。目前药物研发主要的免疫检查点通路包括断共抑制信号,增强抗肿瘤效应。目前药物研发主要的免疫检查点通路包括PD-1/-1/PD- -L、CTLA-4-4通路。通路。PD-1/PD-L1PD-1/PD-L1PD-L1(programmed death-Ligand 1),程序性死亡受体-配体1,表达于树突状细胞和肿瘤细胞等靶细胞表面。PD-1(programmed death 1):程序性死亡受体1,表达于活化的T细胞、B细胞及髓系细胞表面。Suzanne L et al. . JOURNAL OF CLINICAL ONCOLOGY. . 20112011 Dec 20;29(36):4828-4836. 20;29(36):4828-4836.作用:作用:正常情况正常情况调节免疫介导的组织调节免疫介导的组织 损伤。损伤。肿瘤细胞及组织肿瘤细胞及组织防止肿瘤特异防止肿瘤特异性性T细胞损伤。细胞损伤。A Phase 1b Study of MDX-1106(Nivolumab) in Subjects With Advanced or Recurrent Malignancies(NCT00730639)进展期黑色素进展期黑色素瘤、非小细胞瘤、非小细胞肺癌、前列腺肺癌、前列腺癌、肾癌、结癌、肾癌、结直肠癌直肠癌PD- -L1 1(+ +)肿瘤肿瘤(IHC5%5%细胞)细胞)无活动性脑转无活动性脑转移移MDX-11060.1-10mg/kgq2w8周为一个治疗周期CRPR 或或SDPD 允许停止治疗允许停止治疗a治疗治疗2424个月个月/ /直至直至疾病进展疾病进展/ /不可耐受不可耐受停止治疗停止治疗a 患者进展后若无其他抗肿瘤药物可以接受最多1年的额外MDX-1106治疗。病例数:296例,其中104例为黑色素瘤;疗效评估:根据RECIST v1.0标准每8周评估一次;Suzanne L et al. NEJM. 2012 June 28;366(26):2443-2454.有效人群的临床疗效结果(黑色素瘤组)其中,3.0mg/kg组出现一例CR,客观有效率也较其他浓度组高(41%),结合不良反应发生率等,2014年Nivolumab上市的说明书上建议用量为3mg/kg q2w。2.MDX-11062.MDX-1106治疗效果与肿瘤治疗效果与肿瘤PD-L1PD-L1表达情况相关,表达阴性者疗效较表达情况相关,表达阴性者疗效较差,表达阳性者有一部分效果也较差,具体机制尚待进一步明确。差,表达阳性者有一部分效果也较差,具体机制尚待进一步明确。1.1.抗抗PD-1PD-1抗体抗体MDX-1106MDX-1106对黑色素瘤、对黑色素瘤、NSCLCNSCLC、肾细胞癌具有一定疗效,、肾细胞癌具有一定疗效,而其他肿瘤的疗效尚待进一步研究确定。而其他肿瘤的疗效尚待进一步研究确定。结论3.MDX-11063.MDX-1106药物相关毒性反应发生率较低,且可耐受,提示可于门药物相关毒性反应发生率较低,且可耐受,提示可于门诊应用,临床使用禁忌症较少。诊应用,临床使用禁忌症较少。4.4.关于关于MDX-1106MDX-1106临床临床IIIIII期研究亟需开展,阳性结果将有望为目前肿期研究亟需开展,阳性结果将有望为目前肿瘤治疗提供新方法。瘤治疗提供新方法。靶向靶向PD-1/PD-LPD-1/PD-L及及CTLA-4CTLA-4通路药物通路药物靶点靶点药物药物别名别名厂家厂家类型类型适应症适应症PD-1MEDI0680AMP-514MedImmune/ AstraZenecaNivolumabOpdivo, BMS-936558, MDX-1106, ONO-4538Bristol-Myers Squibb, OnoPharmaceuticalsfully human IgG4FDA批准用于黑色素瘤、肺鳞癌PembrolizumabKeytruda, MK-3475, lambrolizumabMerckhumanized IgG4FDA批准用于黑色素瘤PidilizumabCT-011CureTechhumanized IgG1PD-L1BMS-936559MDX-1105Bristol-Myers Squibbfully human IgG4MEDI4736MedImmune/ AstraZenecaFc-modified human IgG1MPDL3280ARG7446Genentech/ RocheFc-modified human IgG1MSB0010718CEMD Seronofully human IgG1CTLA-4TremelimumabTicilimumab,CP-675206Pfizerfully human IgG2IpilimumabYervoyBristol-Myers Squibbfully human IgG1FDA批准用于黑色素瘤肿瘤突变负荷与免疫治疗疗效的相关性Primary end point: : the immune-related objective response rate (Cohort A, B) and the 20-week immune-related progression-free survival rate (Cohort A, B,C).Le DT et al. N Engl J Med.2015 Jun 25;372(26):2509-20.肿瘤突变负荷与免疫治疗疗效的相关性Pembrolizumab(抗PD-1)治疗dMMR肿瘤疗效显著!肿瘤突变负荷与免疫治疗疗效的相关性dMMR者有更高的肿瘤突变负荷,并且突变负荷的水平与疗效正相关。者有更高的肿瘤突变负荷,并且突变负荷的水平与疗效正相关。Le DT et al. N Engl J Med.2015 Jun 25;372(26):2509-20.治疗模式的选择Anti-VEGF, anti-catinen,TKIs CAR T cellTumor vaccine,trastuzumabRadiotherapyChemotherapy根据各种治疗的作用机制,可能的治疗模式:1、免疫治疗的相互联合:eg. Anti-PD-1 + anti-CTLA-4,过继细胞免疫治疗+靶向免疫检查点,肿瘤疫苗+靶向免疫检查点2、免疫治疗+靶向治疗,eg. Her-2 based tumor vacine+ trastuzumab3、免疫治疗+放疗/化疗/放化疗最佳治疗模式需要漫长的探索免疫治疗的成功取决于以下环节:1、肿瘤中抗肿瘤免疫细胞的浸润2、肿瘤抗原的识别3、T细胞的激活与效应的持久The figure is adopted from Wayteck L et al. Cancer Lett. 2014 Sep 28;352(1):113-25.思考题:思考题: 化疗的临床应用; 化疗药物的作用机制; 化疗药物的常见不良反应; 化疗药物的耐药性的发生机制及克服策略。 分子靶向治疗的机制及代表药物。 免疫治疗的作用机制及代表药物。
收藏