一项在新诊断的成人恶性星形细胞瘤患者中测试多肽 IMA950/聚肌苷酸胞苷酸疫苗安全性和免疫原性的 I/II 期试验。
Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients.
机构信息
Department of Oncology, Clinical Research Unit, Dr Dubois Ferrière Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland.
Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland.
出版信息
Neuro Oncol. 2019 Jul 11;21(7):923-933. doi: 10.1093/neuonc/noz040.
BACKGROUND
Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ glioma patients.
METHODS
Adult patients with newly diagnosed glioblastoma (n = 16) and grade III astrocytoma (n = 3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (n = 7) or i.m. (n = 6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral cluster of differentiation (CD)4 and CD8 T-cell responses.
RESULTS
The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T-cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained T helper 1 CD4 T-cell responses. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.
CONCLUSION
We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients.
TRIAL REGISTRATION
Clinicaltrials.gov NCT01920191.
背景
肽疫苗提供了诱导具有肿瘤杀伤能力的神经胶质瘤特异性 T 细胞的机会。我们使用从神经胶质瘤样本表面洗脱的抗原，设计了一项 I 期/II 期研究，以测试多聚肌苷酸-多聚胞苷酸稳定的多聚赖氨酸和羧甲基纤维素佐剂的 IMA950 多种肽疫苗在人类白细胞抗原 A2+神经胶质瘤患者中的安全性和免疫原性。
方法
新诊断为胶质母细胞瘤（n=16）和 3 级星形细胞瘤（n=3）的成年患者接受放化疗后接受 IMA950/多聚肌苷酸-多聚胞苷酸疫苗接种。前 6 名患者接受 IMA950（9 个主要组织相容性复合体[MHC]I 类和 2 个 MHC II 类肽）皮内和多聚肌苷酸-多聚胞苷酸肌内（i.m.）注射。在方案修订后，将 IMA950 和多聚肌苷酸-多聚胞苷酸混合并皮下（n=7）或肌内（n=6）注射。主要终点是安全性和免疫原性。次要终点是总生存期、6 个月和 9 个月时的无进展生存期，以及疫苗特异性外周分化簇（CD）4 和 CD8 T 细胞反应。
结果
IMA950/多聚肌苷酸-多聚胞苷酸疫苗安全且耐受良好。4 例患者出现脑水肿，迅速恢复。对于前 6 名患者，疫苗诱导的 CD8 T 细胞反应仅限于单一肽，CD4 反应缺失。在优化疫苗配方后，我们观察到多肽 CD8 和持续的 T 辅助 1 CD4 T 细胞反应。对于整个队列，分别有 63.2%和 36.8%的患者观察到对单个或多个肽的 CD8 T 细胞反应。胶质母细胞瘤患者的中位总生存期为 19 个月。
结论
我们在一项临床试验中提供了使用细胞表面呈递抗原的信息，以优化产生效应 T 细胞的疫苗，用于神经胶质瘤患者。
试验注册
Clinicaltrials.gov NCT01920191。
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