臨床免疫學(xué)-腫瘤免疫與實(shí)驗(yàn)診斷

1、 腫瘤免疫與實(shí)驗(yàn)診斷腫瘤免疫與實(shí)驗(yàn)診斷 TUMOR IMMUNOLOGY AND IMMUNE DIAGNOSIS 主 要 內(nèi) 容1. 簡(jiǎn)要腫瘤生物學(xué)簡(jiǎn)要腫瘤生物學(xué)2. 腫瘤免疫學(xué)簡(jiǎn)介腫瘤免疫學(xué)簡(jiǎn)介3.目前腫瘤診療現(xiàn)狀與前景目前腫瘤診療現(xiàn)狀與前景 免疫系統(tǒng)與腫瘤免疫系統(tǒng)與腫瘤u 強(qiáng)大的免疫功能強(qiáng)大的免疫功能- 人類(lèi)自然人類(lèi)自然 生存的前提生存的前提u 免疫監(jiān)督是免疫功能之一免疫監(jiān)督是免疫功能之一腫瘤現(xiàn)狀腫瘤現(xiàn)狀l腫瘤是一種生物現(xiàn)象腫瘤是一種生物現(xiàn)象 突變是自然的突變是自然的、必然的進(jìn)化形式、必然的進(jìn)化形式l成瘤也是一種適應(yīng)性進(jìn)化成瘤也是一種適應(yīng)性進(jìn)化l四千多年的歷史，治療無(wú)能為力四千多年的歷史

2、，治療無(wú)能為力 19世紀(jì)至世紀(jì)至20世紀(jì)初的手術(shù)世紀(jì)初的手術(shù) 20世紀(jì)初的放療世紀(jì)初的放療 1947年后的化療年后的化療Concepts of tumor biologyTumor: A cell-clone malignant disease Diseases continuous changing their nature Kinds of specific genetic diseases Cell cycle G 0 M G 1 S G 2 Cell alteration processes: cell benign prolif. being malig. Tumor 1 2 10

3、6 10 9 10 12 Tumor Cell Biology 20771mm, 1mg 1cm, 1g1kgMonths to yearsmonthsdays 腫瘤發(fā)生學(xué)的主要學(xué)說(shuō)腫瘤發(fā)生學(xué)的主要學(xué)說(shuō) Main hypothesis in tumorigenesisuSomatic mutation and gene mutation（突變）（突變）uChromosome abnormalityuEvolution theory（進(jìn)化）（進(jìn)化）uMicro-environment hypothesis （微環(huán)境）（微環(huán)境）uChronic InflammationuStem cells et

4、c.Anti-tumor immunity Yes or no? Yes !lLigation test (腫瘤結(jié)扎實(shí)驗(yàn)?zāi)[瘤結(jié)扎實(shí)驗(yàn)), more than 100 yearslSyngeneic mice (等基因鼠等基因鼠)lClinical dataEvidence for immune surveillance in humanslIncreased incidence of EBV+ B cell lymphomas in transplant patients treated with immunosuppressive drugslIncreased incidence of K

5、aposis sarcoma & EBV+ B cell lymphomas in AIDS patientslGastric cancer associated with H. pylori infectionlCervical cancer caused by HPVlLiver cancer caused by hepatitis B & C No !l HIV infectionl Nudo mice (裸鼠裸鼠)l TSA, TAAImmunological SurveillanceEhrlich, Burnet & ThomasPaul Ehrlich (1

6、909) First to conceive of the concept of Cancer Immunosurveillance. Predicted that cancer would occur at “incredible frequency” if host defenses did not prevent the outgrowth of continuously arising cancer cells.Lewis Thomas (1957) “primary function of cellular immunity.is to protect from neoplastic

7、 disease”Macfarland Burnet (1957) “It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provide an effective immunological reaction with regression of this tumor and no clinical hint of its existence” Ess

8、ences:Tumor is autologous or heterologousOr does exist specific tumor antigen ? Essences: Can tumor stimulate immune system to provoke effective response ? Essences:lHow can tumor escape from the surveillance of immune system (免疫監(jiān)督免疫監(jiān)督)lWhat can we do in dealing with tumor Immune System A well devel

9、oped defense systeml Non specific and specific defense mechanisms(特異與非特異免疫特異與非特異免疫)l Initave immunityl Acquired immunity Humoral, CellularTumor antigensKey molecules between tumor and human bodyu Classificationu Tumor markers and tumor antigensTumor antigen discoveringl TSTA TSA: a long road to look

10、ing forl Three stages: Original McAb TAA T cell clone TSAIs Tumor Antigen Provoke Immune Response(免疫激發(fā)免疫激發(fā)) long time controversial Yes ! Show special features: weak differential antigen embryonic antigen oncoviral antigen mutation genesWhy ? Tumor escaping the Immune System(免疫逃逸免疫逃逸) in many ways 1

11、Low antigenicity (抗原性抗原性): MHC expressing defect TPA Co-stimulating molecules Adhering molecules etc. Pathway of Antigen Presentation by Antigen-Presenting Cells(抗原遞呈)Structures of Class I and Class II Major Histocompatability Complex (MHC) MoleculesRole of Co-stimulation in T-Cell ActivationDendrit

12、ic Cells, the Surface Changes Occurring With MaturationWhy ? Tumor escaping the Immune System in many ways 2n Introcyto-moleculesn antigenic modulationn inhibition factors:n TGF FasL Tsn blocking factors Anti-Tumor Immunology 選擇免疫治療是無(wú)奈之舉選擇免疫治療是無(wú)奈之舉u 一百多年前的腫瘤結(jié)扎試驗(yàn)一百多年前的腫瘤結(jié)扎試驗(yàn)u Coleys toxinu 臨床的提示臨床的提示

13、 免疫的進(jìn)展放大了人們的預(yù)期免疫的進(jìn)展放大了人們的預(yù)期l 單克隆抗體的出現(xiàn)單克隆抗體的出現(xiàn)l 人源性抗體的問(wèn)世人源性抗體的問(wèn)世l 人類(lèi)基因組計(jì)劃的完成人類(lèi)基因組計(jì)劃的完成l 免疫監(jiān)測(cè)點(diǎn)功能的發(fā)現(xiàn)免疫監(jiān)測(cè)點(diǎn)功能的發(fā)現(xiàn)l CAT 細(xì)胞的應(yīng)用細(xì)胞的應(yīng)用腫瘤免疫與與生物治療的關(guān)聯(lián)腫瘤免疫與與生物治療的關(guān)聯(lián) 細(xì)胞因子治療細(xì)胞因子治療 免疫細(xì)胞治療免疫細(xì)胞治療 基因治療基因治療 分子靶向治療分子靶向治療 抗體治療抗體治療腫瘤免疫治療腫瘤免疫治療目前，全球癌癥免疫治療主要包括以下三個(gè)方面：目前，全球癌癥免疫治療主要包括以下三個(gè)方面：1. 針對(duì)新抗原的特異性針對(duì)新抗原的特異性T細(xì)胞治療細(xì)胞治療;2. 以基因修

14、飾為核心的以基因修飾為核心的ACT: CAR-T、TCR-T免疫細(xì)胞治療；免疫細(xì)胞治療；3. 腫瘤相關(guān)靶點(diǎn)抗體與腫瘤相關(guān)靶點(diǎn)抗體與免疫檢查點(diǎn)抗體。免疫檢查點(diǎn)抗體。 重新審視免疫平衡理論重新審視免疫平衡理論l 關(guān)于免疫激發(fā)關(guān)于免疫激發(fā)l 對(duì)腫瘤發(fā)生學(xué)的影響對(duì)腫瘤發(fā)生學(xué)的影響l 已展現(xiàn)一定的臨床效果已展現(xiàn)一定的臨床效果免疫檢驗(yàn)點(diǎn)抗體免疫檢驗(yàn)點(diǎn)抗體 （immunol checkpoint） CAT 腫瘤治療腫瘤治療 (chimeric antigen receptor，CAR)目前受世人關(guān)注，這項(xiàng)技術(shù)最目前受世人關(guān)注，這項(xiàng)技術(shù)最早見(jiàn)于早見(jiàn)于1993年以色列科學(xué)家年以色列科學(xué)家Eshhar Z的報(bào)導(dǎo)。

15、將抗體序列表達(dá)在抗腫瘤的報(bào)導(dǎo)。將抗體序列表達(dá)在抗腫瘤免疫細(xì)胞表面免疫細(xì)胞表面。CAT 的技術(shù)路線的技術(shù)路線（1）靶點(diǎn)，這方面專(zhuān)利多數(shù)己過(guò)期）靶點(diǎn)，這方面專(zhuān)利多數(shù)己過(guò)期（2）與靶點(diǎn)結(jié)合的單鏈抗體與靶點(diǎn)結(jié)合的單鏈抗體（3）跨膜區(qū)與胞內(nèi)區(qū)，所有）跨膜區(qū)與胞內(nèi)區(qū)，所有CAR-T的差別不大，的差別不大，這些都是美國(guó)的專(zhuān)利這些都是美國(guó)的專(zhuān)利（4）剎車(chē)及安全開(kāi)關(guān)剎車(chē)及安全開(kāi)關(guān)（5）轉(zhuǎn)染技術(shù)，國(guó)際上常用的慢病毒載體系統(tǒng)）轉(zhuǎn)染技術(shù)，國(guó)際上常用的慢病毒載體系統(tǒng)腫瘤治療的耐藥腫瘤治療的耐藥 耐藥產(chǎn)生的基本原理耐藥產(chǎn)生的基本原理-生物變異與適應(yīng)生物變異與適應(yīng) 耐藥發(fā)生的必然性耐藥發(fā)生的必然性 抗體耐藥發(fā)生的特點(diǎn)抗體耐

16、藥發(fā)生的特點(diǎn) Immune response -two stagesl Immune excitation recognition, antigen presentationl Immune response non-specific, specific-humoral and cellular The Anti-tumor Immune ResponseAmount Attack to the Tumoru Tumor antigenicity enhancingu Manipulate the immune system i.e tumor vaccinesu Adopted specif

17、ic therapies cellular humoralCellular Tumor killing mechanism:l NK and K (MHC inhibit receptor)l CTLl macrophagesl Ab and humoral moleculesEffector Mechanisms of Tumor Cell Killing by Cytotoxic T Cells (CTLs)ABThe effect models of antibodyl Epitope binding:l Neutralizationl ADCC effectl Induced comp

18、liment functionl Signal transductionl Prevention is not practical by now (with the except of lung cancer)l Early diagnosis is the only effective measurelPathological that is too latelImaging techniques show limited roles because of molecular features in tumor cell lSerological a valuable field to de

19、lving lGenetic method a hopeful field血液血液(體液體液)腫瘤相關(guān)分子檢測(cè)腫瘤相關(guān)分子檢測(cè)1. 1. 多肽與蛋白類(lèi)多肽與蛋白類(lèi)2. 2. 核酸類(lèi)核酸類(lèi)( (基因基因) ) （1 1）內(nèi)源基因的變異：）內(nèi)源基因的變異： 基因結(jié)構(gòu)突變基因結(jié)構(gòu)突變 基因表達(dá)異?；虮磉_(dá)異常 （2 2）外源基因的入侵）外源基因的入侵3. 3. 復(fù)合形式復(fù)合形式 脂蛋白，糖蛋白脂蛋白，糖蛋白, AFP, AFP異質(zhì)體，異質(zhì)體，CACA抗抗原類(lèi)等原類(lèi)等4. 4. 各種修飾形式各種修飾形式 ( (甲級(jí)化、磷酸化、甲級(jí)化、磷酸化、 組氨酸、組氨酸、 乙乙?；?、?；?、 泛素化、糖化等泛素化、

20、糖化等) )l Bens Jones protein AFP, CEA Several dozens l Become more significantl Show hopeful futureHistorical Background 1846 Bence Jones protein 1940 Acid phosphatase 1960 Immunoassay 1963 AFP 1965 CEA 1975 McAb 1980 PSA CA serial 1970-1980 Oncogenes 1990-Characteristics of the “Ideal” Tumor Marker M

21、easured easily sensitivity and specificity. Quantitative level Multiple usagesTypes of Tumor Markers Hormone: hCG calcitonin gastrin prolactin growing hormones Enzymes: acid phosphatase alkaline phosphatase Proteins and Glycoproteins: PSA CA Oncofetal antigens: Receptors: PR ER EGFR Oncogen products

22、: RAS myc bcl Tumor suppressor genes: p53 RbTechniques of Tumor Marker Detection Physic-chemical methods Primary immune methods Amplified immune methods Amplified immune methodsRIA, ELISA, Immune fluorescence, Luminex, Micro-particles etc.Significance and limitations the application of tumor markers

23、 Screening Diagnosis and differencial diagnosis Staging and prognosis Therapy assessments Monitoring RecurrenceLimited value, but:lAFP in ChinalPSA in USA in male more than 50 lCA-125 for ovary tumor Early detectable Tissue specific Significant in Risk populations Marker utilitiesTumor Marker Screening Prog. Monitoring Recurrence Colon CEA n y y yHepto AFP y com n y yOvary CA125 p com n y yOvary CEA n n y yBrea CA153 n n y yPanc CA199 p com y yGastro CA724 p com y yProst PSA p com y y y Non-Hodgk