Dendritic cell-based immunotherapy for malignant glioma

The immunotherapy for malignant glioma faces unique difficult, due to some anatomical and immunological characteristics including the existence of blood brain barrier, the absence of lymphatic tissues and dendritic cells （DCs） in the central nervous system （CNS） parenchyma, and the presence of an immunosuppressive microenvironment. Therefore, immunothera-peutic approaches will not be beneficial unless the compromised immune status in malignant glioma patients is overcome. DC-based immunotherapy, vaccinating cancer patients with DCs pulsed with various tumor antigens, is one of the most promising immunotherapeutic approaches for treatment of malignantglioma because it seems able to overcome, at least partially, the immunosuppressive state associated with primary malignancies. The preparation of DCs, choice of antigen, and route and schedule of administration are improving and optimizing with rapid development of molecular biology and gene engineering technology. DC vaccination in humans, after a number of pre-clinical models and clinical trials, would increase the clinical benefits for malignant glioma immunotherapy.     

Dendritic cell-based immunotherapy for malignant gliomas

Despite dramatic advances in surgical techniques, imaging and adjuvant radiotherapy or chemotherapy, the prognosis for patients with malignant glial tumors remains dismal. Based on the current knowledge regarding immune responses in the healthy CNS and glioma-bearing hosts, this review discusses dendritic cell-based immunotherapeutic approaches for malignant gliomas and the relevance of recent clinical trials and their outcomes. It is now recognized that the CNS is not an immunologically tolerated site and clearance of arising glioma cells is a routine physiologic function of the normal, noncompromised immune system. To escape from immune surveillance, however, clinically apparent gliomas develop complex mechanisms that suppress tumoricidal immune responses. Although the use of dendritic cells for the treatment of glioma patients may be the most appropriate approach, an effective treatment paradigm for these tumors may eventually require the use of several types of treatment. Additionally, given the heterogeneity of this disease process and an immune-refractory tumor cell population, the series use of rational multiple modalities that target disparate tumor characteristics may be the most effective therapeutic strategy to treat malignant gliomas.     

免疫治疗在胶质瘤的研究进展

胶质瘤是中枢神经系统常见的肿瘤之一,其治疗方法（手术、放疗和药物化疗）缺乏特异性,预后较差。随着免疫学、细胞生物学和基因组学的发展,肿瘤免疫治疗开创了肿瘤治疗的新时代,在其他侵袭性癌症如晚期黑色素瘤和晚期非小细胞肺癌中的取得了显著效果,目前免疫治疗在胶质瘤方面的基础及临床试验研究也进展得如火如荼。在此,该综述总结近年来有前景的免疫治疗方法,回顾临床前和临床试验的现状,并讨论胶质瘤免疫治疗的挑战和未来的前景。 [国际神经病学神经外科学杂志, 2023, 50(3): 73-77]     

PHA、CD3、与IL-2协同诱导PBMC过继免疫治疗恶性脑胶质瘤的实验研究

目的 提高人脑胶质瘤过继免疫治疗的效果,探索治疗脑胶质瘤的新途径。方法 用植物血凝素（PHA）、抗CD3单抗（CD3）和IL－2共同诱导人外周血单个核细胞（PBMC）,诱导,扩增新型抗胶质瘤效应细胞PHA－CD3AK细胞,并与CD3AK细胞在某些生物学方面进行了比较。结果 两组效应细胞增殖曲线均于第6天达高峰,峰值可见,PHA－CD3AK细胞＞CD3AK（P＜0．05）;PHA－CD3AK细胞扩增倍数明显高于CD3AK细胞（P＜0．05）;两组效应细胞于培养的第6、8、10天所测得的杀伤胶质瘤细胞BT325活性可见,PHA－CD3AK细胞＞CD3AK细胞（P＜0．05）。结论 PHA、CD3和IL－2具有协同增强作用,使PHA－CD3AK细胞成为较CD3AK细胞增殖能力、杀伤活性更强的免疫效应细胞、且IL－2用量减少,为胶质瘤的过继免疫治疗打下了理论基础。     

Characterization of four human malignant glioma cell lines

Summary In this paper, the characterization of four human malignant glioma cell lines is described. The four lines are positive for glial fibrillary acidic protein (GFAP) in variable amounts. One of them, LN 992, is positive for S-100 protein. Myelin basic protein could not be detected in any of the four lines. The four lines had high levels of CNPase activity. The karyotype shows polyploidy for all lines, with modal numbers ranging from 80 to 120 and various numbers of marker chromosomes. Particular attention has been paid to the surface phenotype and a panel of three antiglioma monoclonal antibodies (Mabs), five antimelanoma Mabs, one anti-CALLA Mab, and two anti-HLA-DR Mabs has been used in an antibody-binding radioimmunoassay for the four cell lines. Lines LN 215 and LN 235 are positive with two antiglioma Mabs, LN 992 is negative. The four lines are positive with all five antimelanoma Mabs, except for LN 992 which ist negative with Mab D5. LN 992 and LN 215 are positive with the anti-CALLA Mab N2A12. LN 308 and LN 992 are positive with anti-HLA-DR Mab D4-22. There was no correlation between the in vitro morphology of the lines and the expression of the various biochemical or surface markers. These results stress the heterogeneity of the phenotype of human malignant glioma lines. These lines will be useful tools for further immunologic studies.Supported by grant no. 3.314-082 from the Swiss National Foundation for Scientific Research and in part by grant no. 3.176.82 from the Swiss National Science Foundation and Multiple Sclerosis Society of Switzerland     

肿瘤浸润淋巴细胞过继性免疫治疗人脑胶质瘤实验研究

观察了人脑胶质瘤肿瘤浸润淋巴细胞（ＴＩＬ）体外抗瘤活性及在人脑胶质瘤裸鼠模型体内，ＴＩＬ的抗瘤作用和瘤内分布。ＴＩＬ体外增殖能力和抗瘤活性均在培养３０天达高峰。肿瘤局部转输ＴＩＬ对肿瘤生长具有明显的抑制作用。ＩＬ－２可以提高ＴＩＬ的抗瘤作用，同时可增进ＴＩＬ向肿瘤内的集聚。     

Establishment and partial characterization of five malignant glioma cell lines

Five malignant glioma cell lines (YMG1, 2, 3, 4, and 5) were established from surgical specimens obtained from patients with glioblastoma or anaplastic astrocytoma, and these lines were partially characterized. Three glioma cell lines (YMG1, 3, and 5) were weakly positive for GFAP by Western blot analysis and two cell lines were negative. S‐100 protein was positive in all glioma cell lines. The expression of p53, p16, p15, cyclin‐dependent kinase 4 (CDK4), and EGF receptor (EGFR) proteins was examined by Western blotting. YMG1 and 2 cell lines showed accumulation of p53 protein and loss of p16 and p15 expression. YMG3 and 4 showed accumulation of p53 protein and expression of p16 and p15 proteins. YMG5 revealed weak expression of p53 protein, suggesting wild‐type p53, and loss of p16 and p15 expression. All cell lines expressed various levels of CDK4 protein. YMG1, 2, and 3 showed higher EGFR protein expression and YMG4 and 5 showed lower EGFR expression compared to U251 glioblastoma cells, which express high levels of EGFR. Fluorescence in situ hybridization analysis for EGFR gene expression did not show any amplification in the glioma cell lines. Immunohistochemical studies revealed that the patterns of p53 and EGFR expressions in the original tumor tissues were mostly correlated with those in the malignant glioma cell lines. These results suggest that the characteristics of p53 and EGFR expression in the malignant glioma cell lines were passed over from the original tumor tissues. These newly established malignant glioma cell lines can be used for further analysis of the mechanisms of tumor growth and progression.     

手术联合125I粒子植入治疗复发性脑胶质瘤

目的探讨手术联合125I粒子植入治疗复发性脑胶质瘤的临床效果。方法2007年2月至2009年12月收治49例复发脑胶质瘤患者,采用显微手术联合125I粒子植入治疗26例（观察组）,显微手术切除联合常规外放射治疗23例（对照组）,术后长期随访直至死亡,记录和分析两组患者的生存时间和并发症。结果全部病例随访22～158周,平均55．8周。观察组术后平均生存时间为（62．8±5．6）周,中位生存时间为55周;对照组平均生存时间为（46．9±4．8）周,中位生存时间为39周;两组生存期差异有统计学意义（P〈0．05）。观察组术后出现放射性脑病5例,癫痫7例;对照组术后出现放射性脑病6例,癫痫5例;两组并发症发生率分别为46．2％和47．8％,差异没有统计学意义（P〉0．05）。结论手术联合125I粒子植入治疗复发性脑胶质瘤疗效优于手术后补充外放射治疗,能安全有效地延长患者的生存时间。     

125I近距离放疗联合热疗对人胶质瘤细胞毒性的研究

目的研究125I近距离放疗联合热疗对人胶质瘤细胞的治疗效果。方法收集临床胶质瘤手术肿瘤标本进行体外细胞培养,分为热疗联合放疗组,放疗组,热疗组,空白对照组,MTT法测定各组细胞经处理后的抑制率,transwell侵袭小室测定各组细胞侵袭力变化。结果与对照组相比,各处理组的细胞抑制率显著增加,侵袭力显著降低,且随着温度的升高,热疗联合125I近距离放疗对细胞的抑制率和侵袭力影响也有显著变化。结论125I近距离放疗联合热疗对胶质瘤细胞具有一定杀伤作用。