Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma
Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma
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DOI：
10.1007/s00262-016-1905-7
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发表时间：
2016-12-01
影响因子：
5.8
通讯作者：
Murayama, Yuichi
中科院分区：
文献类型：
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作者：
Akasaki, Yasuharu;Kikuchi, Tetsuro;Murayama, Yuichi
本试验旨在评估替莫唑胺（TMZ）化疗和免疫治疗与DC和胶质瘤细胞融合的组合在胶质母细胞瘤（GBM）患者中的安全性和临床反应。GBM患者被分配到两组：TMZ化疗对最初诊断的胶质瘤失败后复发的GBMs（R组）或新诊断的GBM（N组）。从手术标本中获得的自体培养的胶质瘤细胞与自体DC使用聚乙二醇融合。将融合细胞（FC）皮内接种于颈部区域。评价本试验的毒性、无进展生存期（PFS）和总生存期（OS）。WT-1，gp-100和MAGE-A3的表达，被认为是化疗耐药相关肽（CAP），通过石蜡包埋的肿瘤样品的免疫组织化学证实。通过四聚体和ELISPOT测定法评估了患者接种疫苗前后的PBMC。所有患者对FC免疫治疗均耐受良好。R组（n = 10）的中位PFS和OS分别为10.3和18.0个月，N组（n = 22）的中位PFS和OS分别为18.3和30.5个月。与最初切除的肿瘤相比，在R组患者的复发肿瘤中观察到CAP的上调和/或细胞质积聚。在四聚体和ELISPOT测定中观察到针对CAP的特异性免疫应答。导致CAP上调和/或细胞质积累的TMZ治疗与作为产生针对CAP的特异性免疫的手段的FC免疫治疗的组合可以安全地在GBM患者中诱导抗肿瘤作用。
This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM).GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient's PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays.FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays.The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.