化疗对肿瘤免疫治疗的增益作用

由全军免疫学专业委员会主办、第二军医大学免疫学研究所承办、河南大学医学院协办的第六届全军免疫学学术交流会将于2007年4月20—23日在河南开封召开。会议将就上一届会议（上海，1999年12月）以来全军基础与临床免疫学研究的进展及国内外免疫学研究现状和发展趋势作充分交流和讨论。会议将特邀国内知名的专家学者作专题报告。[第一段]     

肿瘤免疫治疗和化疗的协同效应及其作用机制

近年来肿瘤治疗领域受到关注的热点之一是免疫治疗与化疗的联合应用,大量基础与临床的研究结果表明,恰当的免疫化疗（chemoimmunotherapy） 能够取得较单一疗法更优的抗肿瘤效果,超越了以往认为化疗对免疫系统具有抑制作用、免疫治疗与化疗难以一起应用的传统观念。免疫化疗具有协同抗肿瘤效果的机制是多方面的,化疗可通过增强肿瘤细胞免疫原性、去除免疫抑制以及调节免疫应答反应等方式增强免疫治疗效果;另外,免疫治疗能够逆转肿瘤细胞的化疗耐药性,从而提高肿瘤细胞对化疗药物的敏感性并降低化疗的毒性作用等。目前,肿瘤免疫治疗与化疗协同作用的机制尚未完全清楚,相信通过其相关机制的不断阐明,将进一步提高免疫化疗的抗肿瘤效果并推动其临床应用。     

肿瘤基因免疫治疗的新动向

肿瘤的治疗方法,主要以外科手术为主,辅以放疗、化疗及免疫治疗等。然而外科手术对早期肿瘤疗效较好,对晚期及有微小灶残余病变的患者效果较差。近年来随着分子免疫学的迅速发展,各种具有抗肿瘤活性的淋巴细胞和细胞因子,粘附分子被广泛应用于恶性肿瘤的临床治疗,成为晚期肿瘤患者有效治疗措施,并取得了良好的效果。肿瘤基因治疗将是人类得以从根本上征眼肿瘤的希望所在。     

肿瘤免疫治疗研究进展

免疫系统的功能状态在肿瘤的发生、发展中起到重要作用,对于肿瘤的发生、发展及预后具有重要的影响.基于肿瘤抗原的存在,机体针对肿瘤抗原具有免疫应答,包括特异性和非特异性免疫.然而,肿瘤抗原具有免疫原性低,肿瘤细胞存在免疫逃逸现象,肿瘤患者机体产生的免疫应答常不能抑制肿瘤生长,例如肿瘤抗原的缺失、主要组织相容性复合体(major histocompatibility complex,MHC)类分子表达低下、共刺激信号异常、肿瘤形成过程中产生或分泌的免疫抑制因子(TGF-β、IL-10、IL-33等)以及肿瘤微环境中各种免疫抑制性细胞,包括骨髓来源的抑制性细胞(myeloid derived suppressor cells,MDSC)和调节性T细胞(regulatory T cells,Treg)等[1].     

肿瘤疫苗与肿瘤免疫治疗研究进展

免疫系统是人体最重要的防御系统之一 ,正常的免疫应答赋予人体抗御感染 ,识别自我与非我 ,及时清除体内衰老、变性的细胞 ,监视突变细胞并将之消灭。肿瘤细胞是人体的变异细胞 ,只要充分调动人体的免疫功能 ,尤其是肿瘤特异性免疫功能 ,就能将肿瘤细胞清除。免疫治疗学的本质就是通过各种手段 ,提高、抑制或调节机体的免疫应答能力 ,最终达到纠正紊乱、治疗疾病的目的 ,其中包括特异性免疫和非特异性免疫。非特异性免疫应答是与生俱来的 ,它的形成并不需要抗原刺激 ,能广泛地针对多种抗原 ,是免疫应答的基础 ,但特异性不强 ,对某种特定抗原…     

肿瘤化疗联合免疫治疗从理论基础到临床实践

在过去的几十年里,化疗是肿瘤内科治疗的基石。尽管化疗疗效显著,但维持病情稳定时间不持久。随着对肿瘤免疫学研究的不断深入,近年来肿瘤免疫治疗再次成为热点。与化疗相比,免疫治疗疗效相对缓和,但更为持久。越来越多的研究表明化疗除了对肿瘤细胞的直接杀伤作用,亦可以增加肿瘤细胞的免疫原性,抑制负性免疫信号,改变肿瘤免疫微环境,从而发挥免疫增强作用,为化疗和免疫治疗的联合应用奠定了理论基础。本文根据已知的肿瘤免疫反应机理和近期发现的化疗免疫调节机制,阐述化疗联合免疫治疗的理论基础,并进一步探讨现有的关于联合治疗的基础和临床研究,从而为后续研究指明方向。      

化学免疫治疗对肝癌患者血液甲胎蛋白 mRNA表达的影响

目的探讨肝动脉化疗栓塞（transcatheter arterial chemoembolization,TACE）联合静脉滴注化学免疫治疗（chemoimmunotherapy,CI）对原发性肝癌患者外周血甲胎蛋白（AFP）mRNA表达的影响及其临床意义。方法应用巢式逆转录聚合酶链反应（nestedRT-PCR）检测36例肝癌患者血液AFPmRNA表达在TACE＋CI前后的变化,并与单纯接受TACE的35例患者比较。结果在治疗后1周和4周,TACE组血AFPmRNA阳性率分别为54.3％和57.1％,与治疗前的51.4％（18/35）比较,差异无显著性（P均>0.05）;而TACE＋CI组血AFPmRNA阳性率各为22.2％和33.3％,分别显著低于治疗前（58.3％,21/36）和TACE组（P<0.01和P<0.05）。经过6～12个月随访,TACE＋CI组平均缓解期为(5.8±2.8)月,有6例出现门脉癌栓或肝外转移（16.7％）,而TACE组为(3.7±2.6)月和13例（37.1％）,差异均有显著性（P<0.001和P<0.05）。结论应用RTPCR技术检测原发性肝癌患者外周血AFPmRNA的动态变化对判断TACE等方法治疗肝癌的疗效有重要参考价值。联合静脉化学免疫治疗能显著降低肝癌患者外周血AFPmRNA的阳性率,可能对防止肝癌细胞的血行播散有积极意义。     

肿瘤微环境对胃癌免疫治疗的影响

胃癌是消化系统死亡率较高的恶性肿瘤,手术切除、放疗、化疗等仍是目前主要的治疗手段,但效果并不理想。随着免疫学研究的发展,免疫治疗成为肿瘤综合治疗中研究的热点,许多新兴的手段如肿瘤疫苗、免疫卡控点治疗等展现出良好的应用前景。由于胃癌发病机制复杂,肿瘤异质性明显,还有很多问题亟待解决,肿瘤微环境是影响肿瘤的发生、发展、转移的重要因素,本文就肿瘤微环境对胃癌免疫治疗的影响方面的研究成果作一综述。     

抗独特型抗体对肿瘤的免疫治疗

1974年Jerne提出网络学说以来,对独特型(Id)、抗独特型(A-Id)、抗抗独特型调节网络进行了大量的研究,其中最受关注的是处于正负调节枢纽的Id环节,Id亦为抗原决定簇,为V基因编码的抗体和TCR表型.根据这一学说认为外在抗原为抗体中Id和T细胞受体所模仿,抗原注射于机体所产生的抗体为Ab1,而Ab1本身具有免疫原性产生A-Id抗体(Ab2),有一部分Ab2在三度空间模仿外在抗原,称     

化疗对肿瘤免疫功能影响的研究进展

肿瘤的发生、发展及转归与机体免疫功能密切相关。化疗是肿瘤常规治疗手段,其在杀伤肿瘤细胞的同时,对机体免疫系统也有不同程度的杀伤和抑制作用。近年来研究发现,化疗对机体免疫格局的调整可能具有双向作用。因此,依据化疗后机体免疫功能的不同变化,调整相应的治疗方案,将化疗和机体免疫功能有机结合,将最终提高肿瘤的治疗效果。     

Beneficial effects of androgen-primed chemotherapy in the Dunning R3327 G model of prostatic cancer

The objective of this study was to test the hypothesis that androgen administration prior to chemotherapy (androgen priming) may potentiate tumor cytotoxicity in hormone-responsive prostate cancer. Accordingly, six groups of Copenhagen rats bearing small (i.e., 40-mm3 median volume) Dunning R3327 G tumors were left untreated or received castration, chemotherapy, or a combination of the two, with or without androgen priming. Groups without priming included: intact untreated, castrate alone, intact plus chemotherapy, and castrate plus chemotherapy (cyclophosphamide, 30 mg/kg/day, for 2 days, with repeat cycle in 24 days) (Cx). To specifically evaluate the effect of androgen priming on Cx cytotoxicity, two additional castrate groups were studied. One received testosterone propionate (4 mg/kg/day) for 2 days prior to Cx and the other after Cx. Treatment effect was evaluated by quantitating tumor volume as well as animal survival to an ethically allowable, maximal tumor burden. As expected, castration and Cx produced a retardation of tumor growth and prolongation of survival when compared to untreated animals. The addition of androgen priming prior to but not after Cx enhanced the degree of tumor suppression. Specifically, 26 days after the second Cx cycle, all androgen-primed tumors had regressed; 70% of tumors had disappeared and those remaining were barely palpable. At this same time point, tumors in all the other groups were actively growing and had volumes greater than initial values (P less than 0.01). Although tumor regrowth occurred, median survival for the androgen-primed group was significantly prolonged, to 186 days versus 39 days (P less than 0.01) for untreated animals and 153 days for the non-primed castrate plus Cx animals (P less than 0.01). These data suggested that androgen priming potentiates the effects of Cx in castrate animals bearing R3327 G tumors.     

Late effects of cancer chemotherapy

Patients with specific types of cancer have achieved substantial prolongation of survival after successful cancer chemotherapy. Furthermore, cancer chemotherapeutic agents are being widely used as immunosuppressive drugs in patients with benign conditions. Both of these patient populations are at risk for development of late complications of treatment. Though the late effects of chemotherapy are less well defined, they are insidious in onset and not manifested clinically until damage have become overt and irreversible. Many reports on the late effects of chemotherapy demonstrate the importance of assessing not only the therapeutic results of various treatment program but also of evaluating the long-term complications of therapy in order to maximize the benefit of the treatment. Thus, skillful and judicious application of chemotherapy produces a minimum of delayed consequences.     

美托洛尔对老年食管癌患者围术期心脏功能的保护作用

背景与目的：老年食管癌手术患者逐渐增多,围术期如何保护心脏功能,减少老年患者围术期心脏并发症的发生率及其死亡率成为目前亟待解决的问题之一。β受体阻滞剂在围术期的预防性应用被逐渐受到重视。本研究拟探讨美托洛尔对老年食管癌患者围术期心脏功能的保护作用。方法：将择期开胸手术的老年食管癌患者随机分为美托洛尔组（患者从麻醉诱导前至术后72h应用美托洛尔调节心率）和对照组（不给予美托洛尔）,每组患者30例。分别记录两组术前、给药后、麻醉诱导后2min、插管、插管后4min、切皮、进胸、手术开始后1h、手术结束前10min、手术结束、拔管及拔管后15min的血流动力学指标和肌钙蛋白水平：并统计围术期发生心脏并发症的患者例数及术后窦性心动过速例数。结果：对照组患者气管插管时收缩压升高．与术前比较差异有显著性（P〈0．05）：气管插管及气管拔管时心率增快,与术前比较差异有显著性（P〈0．05）。而美托洛尔组患者在上述各时间点收缩压、心率与术前相比差异无显著性（P〉0．05）。对照组患者围术期有3例肌钙蛋白阳性,美托洛尔组无阳性病例,两组比较无显著性差异（P=0．237）。对照组有6例患者发生心脏并发症,美托洛尔组患者未发生心脏并发症．两组比较差异有显著性（P=0．024）。对照组中2例患者发生急性心肌缺血,4例患者发生房颤,两组患者围术期均未发生心肌梗塞及死亡。对照组患者术后发生窦性心动过速有15例,美托洛尔组有6例,两组比较差异有显著性（P〈0．05）。结论：美托洛尔能降低老年食管癌患者围术期心脏并发症及术后窦性心动过速的发生率,有效抑制气管插管和气管拔管导致的心率增快或血压升高。     

Combination of adoptive immunotherapy and chemotherapy against advanced cancer with peritoneal dissemination

In a case of advanced gastric cancer with bilateral Krukenberg's tumors and peritonitis carcinomatosa, total gastrectomy, splenectomy and bilateral oophorectomy was performed. Since progressive peritoneal dissemination was recognized, 150 mg of CDDP and 10 mg of MMC which were proved to be effective by chemosensitivity test of anticancer drugs were administered intraperitoneally. After one month, ascites increased. So LAK cells and TIL were transferred intraperitoneally 6 times. With this treatment ascitic collection remarkably decreased, the performance status improved and serum level of IAP and CA125 normalized. Thus, it is clarified that the combination of adoptive immunotherapy and chemotherapy possesses therapeutic efficacy against advanced gastric cancer with peritonitis carcinomatosa.     

Efficacy of combined intravesical immunotherapy and chemotherapy for non-muscle invasive bladder cancer

Intravesical immunotherapy using attenuated bacillus Calmette-Guérin (BCG) strains and intravesical chemotherapy are the modalities most commonly used to treat intermediate- or high-risk patients with non-muscle invasive bladder cancer. BCG has been shown to decrease recurrence rates by up to 67% compared with tumor resection alone, but intensive BCG maintenance regimens are poorly tolerated in a large proportion of patients. Intravesical chemotherapy also decreases the risk of recurrence for these patients, but has diminished efficacy compared with BCG. If BCG dose reduction can be achieved with combined intravesical immunotherapy and chemotherapy, this regimen may improve compliance and thus optimize treatment for these patients by limiting side effects from BCG monotherapy, while at the same time improving oncologic efficacy via the separate anti-tumor mechanisms of these agents. The authors discuss the most recent data regarding combining these agents in an alternating or sequential regimen.     

免疫治疗联合化疗在胃癌治疗中的研究进展

[摘要] 胃癌患者具有相对较高的突变负荷、新抗原基数和肿瘤浸润淋巴细胞,表明其对免疫治疗可能具有潜在应答性,但多项研究显示,免疫检查点程序性死亡受体1（programmed death protein1, PD-1）抑制剂单药治疗应答率仅为10%~26%。近期,人们对化疗对机体免疫系统的影响进行了深入探究,证实化疗药物可通过不同免疫调节机制对肿瘤免疫应答产生影响。多项研究显示,免疫治疗联合化疗药物在提高患者客观缓解率（ORR）和延长生存期方面具有一定成效,联合方案逐渐成为目前晚期胃癌研究的热点。本文主要阐述化疗药物对肿瘤免疫应答的影响、免疫治疗联合化疗在晚期胃癌中的应用及预测疗效的生物标记物的进展,以期为胃癌的临床治疗提供参考。     

Beneficial effects of interleukin-2 on natural killer activity in lung cancer patients

The effects of human interleukin-2 (IL-2) on the growth and natural killer (NK) activities of lymphocytes were evaluated in patients with advanced lung cancer, and compared with age-matched normal subjects. Peripheral blood lymphocytes (PBL) from the patients and the controls were grown exponentially in response to IL-2 and showed no differences in the cell numbers and the proliferative capacities. In both groups, pretreatment for 18 hr with IL-2 was able to augment the NK activity of PBL. Furthermore, PBL propagated in IL-2 over a period of 15 days also demonstrated vigorous NK activity, although there was a relative broad range of NK levels among those from the patient individuals. The present study suggests that the depressed NK activity of PBL from our patients can not be explained by lack of their responsiveness to IL-2, and that human IL-2 can augment the NK activity of PBL and support the growth of PBL-derived cells with high NK levels in patients with lung cancer.