Serial Multi-omics Uncovers Anti-Glioblastoma Responses Not Evident by Routine Clinical Analyses (Immunopeptidomics)

Recurrent glioblastoma (rGBM) is incurable. Serial “multi-omic” assays from longitudinal rGBM biopsies may unravel tumor responses to a treatment. Despite traditional imaging indicating tumor progression, 86 serial rGBM biopsies cores obtained over 4 months from the first two patients on a clinical trial of repeated intratumoral doses of the immunotherapeutic agent, CAN-3110, revealed therapeutic effects by multi-omic analyses, including: a-longitudinal and spatial reshaping of the rGBM’s microenvironment, b- expansion of new T cell tissue-resident effector memory clonotypes against newly characterized CAN-3110 epitopes and other undetermined antigens, and c-novel expression of HLA-immunopeptides including cancer testes antigens. The two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand GBM’s evolution during an investigational therapy.

复发性胶质母细胞瘤（rGBM）目前仍无法治愈。对复发性胶质母细胞瘤活检标本开展的纵向多组学（multi-omic）检测，或可阐明肿瘤对治疗的应答机制。尽管传统影像学检查提示肿瘤进展，但针对两项临床试验中前两位患者、历时4个月获取的86份连续rGBM活检芯样，经多组学分析却揭示了免疫治疗药物CAN-3110瘤内重复给药方案的治疗效果，具体包括：a. rGBM微环境的纵向与空间重塑；b. 针对新鉴定的CAN-3110表位及其他未明确抗原的新型组织驻留效应记忆T细胞克隆型的扩增；c. 包含癌症睾丸抗原在内的HLA免疫肽的全新表达。两位接受治疗的患者分别获得了病理学应答与临床病情稳定。上述结果证实，纵向组织采样在阐明试验性治疗过程中胶质母细胞瘤演化机制方面具有重要价值。