Survivin in brain tumors: an attractive target for immunotherapy

Summary Survivin, a member of the inhibitor of apoptosis proteins gene family, was recently shown to be expressed by tumors originating from different cell lineages. There are also cumulative evidences that spontaneous immune response against survivin derived epitopes may occur. Here, using RT-PCR, Western-blot analysis and immunohistochemistry, we show that survivin is widely expressed by gliomas, meningiomas and schwannomas, bothin vitro andin vivo. These data indicate that survivin may serve as an attractive target for immunotherapies designed for brain tumors.     

Brain Tumor Immunotherapy: An Immunologist's Perspective

Key concepts in brain tumor immunotherapy are reviewed. "Immunotherapy" can refer to a fully-developed, tumor-specific immune response, or to its individual cellular or molecular mediators. The immune response is initiated most efficiently in organized lymphoid tissue. After initiation, antigen-specific T lymphocytes (T cells) survey the tissues – including the brain. If the T cells re-encounter their antigen at a tumor site, they can be triggered to carry out their effector functions. T cells can attack tumor in many ways, directly and indirectly, through cell-cell contact, secreted factors, and attraction and activation of other cells, endogenous or blood-borne. Recent work expands the list of candidate tumor antigens: they are not limited to cell surface proteins and need not be absolutely tumor-specific. Once identified, tumor antigens can be targeted immunologically, or in novel ways. The immune response is under complex regulatory control. Most current work aims to enhance initiation of the response (for example, with tumor vaccines), rather than enhancing the effector phase at the tumor site. The effector phase includes a rich, interactive set of cells and mediators; some that are not usually stressed are of particular interest against tumor in the brain. Within the brain, immune regulation varies from site to site, and local neurochemicals (such as substance P or glutamate) can contribute to local control. Given the complexity of a tumor, the brain, and the immune response, animal models are essential, but more emphasis should be given to their limitations and to step-by-step analysis, rather than animal "cures".     

Survivin expression in ganglioglioma

Summary Gangliogliomas are unusual central nervous system (CNS) neoplasms occurring mainly in children and young adults and inducing chronic pharmacoresistant epilepsy. These are usually well differentiated neuroepithelial tumors composed of neurons in association with neoplastic glial cells. Gangliogliomas present with favorable outcome. However, some may recur and/or progress to anaplasia and be associated with a dismal prognosis. Since histopathological features do not consistently correlate with clinical outcome, reliable prognostic factors have yet to be defined in gangliogliomas. Survivin is an anti-apoptotic protein whose expression has been found to be of prognostic significance in many human cancers, including gliomas. The objective of this study was to assess survivin expression using immunohistochemistry in 15 gangliogliomas. Ten lesions were low-grade neoplasms whereas 5 were high-grade tumors. Survivin expression appeared restricted to the neoplastic glial component and was detected in 6/15 gangliogliomas. Two additional tumors expressed survivin upon relapse. Half survivin expressing lesions displayed less than 1% immunoreactive cells. Survivin expression in more than 5% neoplastic glial cells was detected only in malignant and/or recurrent gangliogliomas. Extended lifespan in survivin expressing cells might enhance aggressive behavior in these tumors through accumulation of mutations, thereby allowing progression to malignant phenotypes. Survivin expression may carry a negative prognostic value in gangliogliomas.     

Dexamethasone Mediated Inhibition of Local IL-2 Immunotherapy is Dose Dependent in Experimental Brain Tumors

Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the role of systemic immunosuppression using dexamethasone on the efficacy of local IL-2 immunotherapy in treating experimental murine CNS tumors.An endothelial cell line secreting hIL-2 (NTC-121) was injected intracranially in C57BL/6 mice (n= 10/group) along with B16/F10 (wild type) melanoma cells. A separate set of animals also received daily injections of either 1 mg/k or 10 mg/kg of dexamethasone. Sixty percent of mice treated with IL-2 (P < 0.001 vs. control) vs. 55%(P < 0.005) of mice treated with IL-2 and 1 mg/kg of dexamethasone were long-term survivors (LTS) of >120 days. There was no difference in survival between control animals that received only wild type cells or animals that were treated with IL-2 and 10 mg/kg of dexamethasone. Histopathological examination of brains from animals sacrificed at different times showed an accumulation of CD8 + T-cells around the site of the injected tumor only in the IL-2 group and the group that received 1 mg/kg of dexamethasone.These results suggest that while high doses of dexamethasone can completely inhibit the immune response observed with IL-2, lower and more likely therapeutic doses of dexamethasone do not inhibit local IL-2 immunotherapy.     

Single Brain Metastases of Carcinoid Tumors

Carcinoid tumors are one among the most uncommon source of metastatic lesion to the brain. Four cases of single brain metastases from carcinoid tumors operated upon and verified by both histology and immunohistochemical staining are reported. The site of the primary carcinoid tumor was the lung in two cases, ileum in one and the left colon in another. The location of the brain metastasis was supratentorial in two cases and cerebellar in two. A high vascular tumor with large blood channels was found at surgery. Immunohistochemical studies showed in all four cases positive staining for synaptophysin, neuron-specific enolase, chromogranine and cytocheratine and negative staining for S-100 and HMB-45. The postoperative survival time ranged from 5 to 18 months. The epidemiological, surgical and pathological features of brain metastases from carcinoid tumors are also discussed from the analysis of 44 well-documented cases reported in the literature.     

Immunotherapy of a Murine T Cell Lymphoma Localized to the Brain

Mouse YC8 T cell lymphoma was used as a model to determine whether an effective immunotherapy procedure could be devised for the treatment of lymphoma localized to the brain. Implantation of 5 × 10⁴ YC8 cells into the left cerebral hemisphere induced rapid loss of the animal's body weight. Severe loss of weight and early deaths were observed in the untreated control group. Although resistance can be conferred to the brain by immunization of naive BALB/c mice, adoptive chemoimmunotherapy procedures were surprisingly not effective in inducing remissions in animals with lymphoma confined to the brain. Even passive transfer of effector cells from immunized, tumor resistant donor animals combined with systemic IL-2 treatment did not impart resistance to recipients with brain tumors. However, regression of the intracranial tumor and apparent cures could be accomplished, when ex vivo cultured effector cells were transferred intravenously.     

Anti-angiogenic Treatment Strategies for Malignant Brain Tumors

The use of angiogenesis inhibitors may offer novel strategies in brain tumor therapy. In contrast to traditional cancer treatments that attack tumor cells directly, angiogenesis inhibitors target at the formation of tumor-feeding blood vessels that provide continuous supply of nutrients and oxygen.With respect to brain tumor therapy, inhibitors of angiogenesis display unique features that are unknown to conventional chemotherapeutic agents. The most important features are independence of the blood–brain barrier, cell type specificity, and reduced resistance. Malignant brain tumors, especially malignant gliomas, are among the most vascularized tumors known. Despite multimodal therapeutic approaches, the prognosis remains dismal. Thus, angiogenesis inhibitors may be highly effective drugs against these tumors. In a clinical setting, they could be applied in the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence.This article provides an overview of current anti-angiogenic treatment strategies with emphasis on substances already in clinical trials or candidate substances for clinical trials. The cellular and molecular basis of these substances is reviewed.     

树突状细胞和脑胶质瘤自体免疫治疗的实验和临床研究(英文)

目的对树突状细胞(DC)肿瘤疫苗进行实验和临床研究并探讨其应用前景。方法从脑胶质瘤患者外周血提取 DC 进行培养并对其进行形态学和免疫学鉴定。采用乳酸脱氢酶(LDH)释放法检测负载不同肿瘤抗原的 DC 诱导细咆毒性 T 细胞(CTL)体外杀伤活性。在实验研究的基础上拟定临床治疗方案:将56例脑胶质瘤术后患者分为3组,实验组19人接受冻融法制备的自体肿瘤抗原 DC 疫苗和卡介苗(BCG)治疗,阳性对照组17人接受全肿瘤组织匀浆和 BCG治疗,阴性对照组20人,术后仪接受放疗。结果采用粒细胞、巨噬细胞集落刺激因子(GM-CSF)及白细胞介素-4(IL-4)培养可获得高纯度的 DC。DC 在负载肿瘤抗原后诱导CTL 杀伤活性大大提高而 DC 与肿瘤细胞共培养对 CTL 杀伤活性无显著影响。临床治疗中实验组中位数生存时间大于38个月,阳性对照组为24个月,二者均高于阴性对照组(13个月)。生存分析示3组间的生存曲线分布差异有显著性意义。结论采用冻融法制备的自体脑胶质瘤抗原 DC 疫苗可抑制脑胶质瘤的复发和进展,从而有效地延长脑胶质瘤患者的生存时间,有良好的临床应用前景。     

Survivin基因siRNA真核表达载体的构建及其对转染膀胱癌细胞Survivin表达的抑制作用

目的构建针对Survivin基因的siRNA(smallinterferenceRNA)真核表达载体,并观察其对转染的膀胱癌细胞中Survivin基因表达和细胞凋亡的影响。方法应用siRNA设计软件设计针对Survivin基因的特异性短链寡核甘酸,化学合成后经退火形成双链siRNA模板,通过克隆到质粒pSilencer1.0-U6构建siRNA真核表达载体并用酶切和测序鉴定;然后将其转染人膀胱癌细胞株BIU-87,以反义Survivin寡核甘酸(ASODN)抑制效果为对照,分别采用噻唑蓝(MTT)比色法和DNA原位末端标记(TUNEL)法检测BIU-87细胞生长抑制率(IR)和凋亡指数(AI),半定量逆转录聚合酶链反应(RT-PCR)和Westernblot检测BIU-87细胞中SurvivinmRNA及其蛋白的表达。结果酶切和测序证实siRNA真核表达载体构建成功。siRNA对BIU-87细胞的IR和AI(62.14%和33.77%)均分别显著高于ASODN(39.33%和23.98%)和空白对照组(1.98%和3.75%),P均<0.05,SurvivinmRNA及其蛋白相对表达水平均显著低于ASODN和空白对照组。结论构建的siRNA真核表达载体能有效地抑制Sur-vivinmRNA的转录和表达,诱导BIU-87细胞凋亡和抑制细胞生长,为膀胱肿瘤的基因治疗提供新的方法和手段。     

树突状细胞和脑胶质瘤自体免疫治疗的实验和临床研究

目的 对树突状细胞(DC)肿瘤疫苗进行实验和临床研究并探讨其应用前景。方法 从脑胶质瘤患者外周血提取DC进行培养并对其进行形态学和免疫学鉴定。采用乳酸脱氢酶(LDH)释放法检测负载不同肿瘤抗原的DC诱导细胞毒性T细胞(CTL)体外杀伤活性。在实验研究的基础上拟定临床治疗方案:将56例脑胶质瘤术后患者分为3组,实验组19人接受冻融法制备的自体肿瘤抗原DC疫苗和卡介苗(BCG)治疗,阳性对照组17人接受全肿瘤组织匀浆和BCG治疗,阴性对照组20人,术后仅接受放疗。结果 采用粒细胞、巨噬细胞集落刺激因子(GM-CSF)及白细胞介素-4(IL-4)培养可获得高纯度的DC。DC在负载肿瘤抗原后诱导CTL杀伤活性大大提高而DC与肿瘤细胞共培养对CTL杀伤活性无显著影响。临床治疗中实验组中位数生存时间大于38个月,阳性对照组为24个月,二者均高于阴性对照组(13个月)。生存分析示3组间的生存曲线分布差异有显著性意义。结论 采用冻融法制备的自体脑胶质瘤抗原DC疫苗可抑制脑胶质瘤的复发和进展,从而有效地延长脑胶质瘤患者的生存时间,有良好的临床应用前景。     

黑色素瘤相关抗原-A:食管癌免疫治疗新靶点

黑色素瘤相关抗原(melanoma-associated antigen,MAGE)-A亚家族是MAGE基因家族成员,属于癌睾丸抗原,包括MAGE-A 1～MAGE-A 12,定位于X染色体.MAGE-A在正常组织中几乎不表达,而在多种肿瘤组织中表达,其在食管癌细胞系和食管癌组织均有较高表达.MAGE-A基因编码的抗原肽可由食管癌细胞MHC Ⅰ分子提呈至细胞毒性T细胞,能够发挥特异性抗肿瘤活性.因此,以MAGE-A抗原为新靶点,对食管癌患者进行免疫治疗有良好的前景.     

浆液性卵巢肿瘤组织中DCR3、Survivin、PDCD5的表达

目的:探讨DCR3、Survivin、PDCD5凋亡相关基因在浆液性卵巢肿瘤组织中的表达。方法:采用免疫组化及Real-time PCR两种方法观察浆液性囊腺瘤16例、交界性浆液性囊腺瘤25例、浆液性囊腺癌48例组织中DCR3、Survivin、PDCD5的蛋白及mRNA表达。结果:DCR3、Survivin、PDCD5在卵巢浆液性囊腺瘤组织的细胞浆或核未见明显的棕黄色颗粒沉着,而在交界性浆液性囊腺瘤组织的细胞浆或核中可见弱的棕黄色颗粒沉着,浆液性囊腺癌可见强的棕黄色颗粒沉着。与卵巢浆液性囊腺瘤组相比,交界性浆液性囊腺瘤、浆液性囊腺癌中DCR3、Survivin、PDCD5 mRNA表达水平显著增高(P＜0.05)。结论:DCR3、Survivin、PDCD5凋亡相关基因在浆液性卵巢肿瘤中的蛋白及mRNA表达变化呈一致升高的趋势,其机制可能与调控凋亡有关,进而参与了卵巢肿瘤的发生发展过程,并可为卵巢肿瘤的防治提供一些新策略。     

持续灌注榄香烯(elemene)治疗恶性脑肿瘤

目的探讨持续灌注榄香烯治疗恶性脑肿瘤的疗效.方法总结分析我院1996年1月～1998年11月间,采用持续灌注榄香烯化疗23例恶性脑肿瘤患者的疗效.恶性胶质瘤13例,脑转移瘤10例.榄香烯400～800mg/d,6～12g/疗程,2～3个疗程,每疗程间隔1～1.5个月.经皮颈内动脉穿刺插管,或经皮锁骨下静脉或肘正中静脉穿刺插管,用泵持续灌注.根据治疗前后肿瘤体积变化,平均生存期,体能状态评分评价疗效.结果1)治疗前后肿瘤体积(cm3)平均缩小62.2%,P＜0.01.2)全组CR3例,PR14例,CR+PR17例,有效率73.9%(95%可信区间±13.4%).对照组29例,CR2例,PR10例,CR+PR12例,有效率40.9%(95%可信区间±17.9%)(P＜0.02).3)治疗前后KPS平均记分差为6.5,P＜0.01.4)治疗组平均生存期25.8个月,对照组平均生存期17.4月(P＜0.01).结论持续灌注榄香烯化疗对恶性脑肿瘤疗效明显,能延长患者高质量的生存期,值得进一步探讨.     

Brain tumor immunotherapy: an immunologist's perspective

Summary Key concepts in brain tumor immunotherapy are reviewed. “Immunotherapy” can refer to a fully-developed, tumor-specific immune response, or to its individual cellular or molecular mediators. The immune response is initiated most efficiently in organized lymphoid tissue. After initiation, antigen-specific T lymphocytes (T cells) survey the tissues — including the brain. If the T cells re-encounter their antigen at a tumor site, they can be triggered to carry out their effector functions. T cells can attack tumor in many ways, directly and indirectly, through cell-cell contact, secreted factors, and attraction and activation of other cells, endogenous or blood-borne. Recent work expands the list of candidate tumor antigens: they are not limited to cell surface proteins and need not be absolutely tumor-specific. Once identified, tumor antigens can be targeted immunologically, or in novel ways. The immune response is under complex regulatory control. Most current work aims to enhance initiation of the response (for example, with tumor vaccines), rather than enhancing the effector phase at the tumor site. The effector phase includes a rich, interactive set of cells and mediators; some that are not usually stressed are of particular interest against tumor in the brain. Within the brain, immune regulation varies from site to site, and local neurochemicals (such as substance P or glutamate) can contribute to local control. Given the complexity of a tumor, the brain, and the immune response, animal models are essential, but more emphasis should be given to their limitations and to step-by-step analysis, rather than animal “cures”.     

单发脑转移瘤的外科治疗

本文报告了５１例单发脑转移瘤，全部为手术和病理检查所证实。５１例中，男性３２例，女性１９例，平均年龄为４６．８岁。这些患者的主要表现为颅内压增高。本研究结果表明年龄较小、身体条件好的单发脑转移瘤患者，如果他们的原发灶经过适当处理，或转移性脑瘤是可切除的，都应尽早地行手术治疗，并同时行减压术。术后患者应行全脑放疗和化疗，以便延长其生命，改善生活质量。     

含替尼泊甙联合化疗同时放疗治疗脑恶性胶质瘤

目的 :评价含替尼泊甙的联合化疗治疗恶性脑神经胶质瘤的治疗效果和毒副作用 ,探讨有效的辅助化疗方案 ,以期提高恶性脑神经胶质瘤的疗效 ,延长患者的生存期。方法 :不能手术、术后残留或复发的恶性脑神经胶质瘤 2 5例 ,其中大脑半球胶质瘤 15例 ,包括星形细胞瘤Ⅲ级 11例 ,Ⅳ级 4例 ;脑干胶质瘤 8例 ;小脑胶质瘤 2例。采用含替尼泊甙的联合化疗方案 :1)TV方案 :紫杉醇 135mg m2 ,静脉滴入d1;替尼泊甙 2 0 0mg m2 ,分 3天静脉滴入 ,(d1～d3) ,3周后可重复。 2 )MV方案 :司莫司汀 10 0mg m2 ,d1晚顿服 ,替尼泊甙 (用法同前 ) ,6周后重复。第 1周期化疗后常规局部外放疗 ,DT5 0～ 60Gy。结果 :2 5例患者有效 17例 ,总有效率 68 0 % ,其中大脑半球胶质瘤有效率 60 0 % (9 15 ) ,脑干胶质瘤有效率 87.5 % (7 8) ,小脑胶质瘤有效率 5 0 0 % (1 2 )。经χ2 检验 ,两种化疗方案有效率差异无显著性。主要毒性为骨髓抑制 ,特别是中性粒细胞减少 ,其中Ⅲ、Ⅳ度毒性反应 5例 ,占 2 0 0 % ,经对症处理均恢复正常。远期疗效正在观察中。结论 :替尼泊甙加紫杉醇或司莫司汀联合化疗同时放疗治疗恶性脑胶质瘤安全、有效 ,为脑瘤辅助化疗提供了新方案     

VEGF in Brain Tumors

Vascular endothelial growth factor (VEGF) is a regulator of angiogenesis, vasculogenesis and vascular permeability. In this contribution, molecular and biological properties of VEGF are described. Furthermore, this article focuses on the evidence that angiogenesis in brain tumors is mediated by VEGF. Among the topics discussed are expression patterns of VEGF and its receptors in different brain tumors, possible regulatory mechanism involved in the VEGF-driven tumor angiogenesis and the involvement of VEGF in the genesis of peritumoral edema. Finally, anti-angiogenesis approaches to target VEGF/VEGF receptors are discussed.     

恶性黑色素瘤的免疫治疗现状与进展

恶性黑色素瘤是一种高度恶性,易转移,预后差,对化疗放疗均不敏感的恶性肿瘤。随着肿瘤免疫学、分子生物学技术的迅速发展,过继免疫治疗、生物化学治疗、肿瘤疫苗、靶向治疗以及佐剂等治疗恶性黑色素瘤的方法显示了良好的应用前景。免疫治疗已逐渐成为肿瘤综合治疗的一个重要组成部分,文章就该方面的研究进展进行综述。     

放射治疗124例原发性脑瘤临床分析

本文回顾124例原发性脑瘤的单纯放疗和术后放疗的5年生存情况。材料与方法：分析经术后病理或CT、MRI证实的124原发性脑瘤。8mv－x线或60Co常规分割全脑照射，中线剂量30～40Gy，局部追加照射DT10－20Gy。全脊髓预防照射DT25～30Gy。结果：5年生存率：全部切除者和部分切除者分别是7／13（53．4％）、8／23（34.8％）；放射剂量50～60Gy者好于低剂量组；胶质瘤、髓母细胞瘤、室管膜瘤分别为10/32（31.2％）、2／6（33．3％）、1／2。结论：病人生存期长短取决于手术切除程度、放射剂量与肿瘤组织学类型。