Parney Ian F, Anderson S Keith, Gustafson Michael P, Steinmetz Susan, Peterson Timothy E, Kroneman Trynda N, Raghunathan Aditya, O'Neill Brian P, Buckner Jan C, Solseth Mary, Dietz Allan B
Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA.
Department of Quantitative Health Sciences, Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
Neurooncol Adv. 2022 Jun 24;4(1):vdac089. doi: 10.1093/noajnl/vdac089. eCollection 2022 Jan-Dec.
Glioblastoma (GBM) has poor prognosis despite aggressive treatment. Dendritic cell (DC) vaccines are promising, but widespread clinical use has not been achieved, possibly reflecting manufacturing issues of antigen choice and DC potency. We previously optimized vaccine manufacture utilizing allogeneic human GBM tumor cell lysate and potent, mature autologous DCs. Here, we report a phase I study using this optimized DC vaccine in combination with standard therapy.
Following surgical resection and radiation with concurrent temozolomide (TMZ), newly diagnosed adult GBM patients received intradermal DC vaccines plus TMZ. Primary endpoints were safety and feasibility. Immune and treatment responses were recorded.
Twenty-one patients were enrolled in this study. One progressed between leukapheresis and vaccine manufacture. Twenty patients received treatment per protocol. Vaccine doses (≥15) were generated following a single leukapheresis for each patient. No dose-limiting vaccine toxicities were encountered. One patient had symptomatic, histologically proven pseudoprogression. Median progression-free survival was 9.7 months. Median overall survival was 19 months. Overall survival was 25% at 2 years and 10% at 4 years. One patient remains progression-free 5 years after enrollment. Specific CD8 T-cell responses for the tumor-associated antigen gp100 were seen post-vaccination. Patients entered the trial with a leukocyte deficit compared to healthy donors which partly normalized over the course of therapy.
This vaccine platform is safe and highly feasible in combination with standard therapy for newly diagnosed patients. Imaging, histological, survival, and immunological data suggest a positive biological response to therapy that warrants further investigation.
尽管进行了积极治疗，胶质母细胞瘤（GBM）的预后仍然很差。树突状细胞（DC）疫苗前景广阔，但尚未实现广泛的临床应用，这可能反映了抗原选择和DC效力的制造问题。我们之前利用同种异体人GBM肿瘤细胞裂解物和高效、成熟的自体DC优化了疫苗生产。在此，我们报告一项使用这种优化的DC疫苗联合标准治疗的I期研究。
在手术切除并同步使用替莫唑胺（TMZ）进行放疗后，新诊断的成年GBM患者接受皮内DC疫苗加TMZ治疗。主要终点是安全性和可行性。记录免疫和治疗反应。
本研究共纳入21例患者。1例在白细胞分离术和疫苗生产之间病情进展。20例患者按方案接受治疗。每位患者单次白细胞分离术后可产生疫苗剂量（≥15）。未遇到剂量限制性疫苗毒性。1例患者出现有症状的、经组织学证实的假性进展。无进展生存期的中位数为9.7个月。总生存期的中位数为19个月。2年总生存率为25%，4年为10%。1例患者入组5年后仍无进展。接种疫苗后观察到针对肿瘤相关抗原gp100的特异性CD8 T细胞反应。与健康供体相比，患者入组时存在白细胞缺乏，在治疗过程中部分恢复正常。
对于新诊断的患者，该疫苗平台与标准治疗联合使用是安全且高度可行的。影像学、组织学、生存和免疫学数据表明对治疗有积极的生物学反应，值得进一步研究。
