免疫系统
嵌合抗原受体
肿瘤微环境
胶质瘤
过继性细胞移植
癌症研究
流式细胞术
白细胞介素12
生物
体内
细胞毒性T细胞
免疫疗法
体外
细胞生物学
免疫学
T细胞
生物化学
生物技术
作者
Thomas Look,Serena De Fazio,Niklas Binder,Charles L. Sentman,Patrick Roth,César Nombela Arrieta,Roman Sankowski,Steve Pascolo,Michael Weller,Tobias Weiß
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2023-11-01
卷期号:25 (Supplement_5): v243-v243
标识
DOI:10.1093/neuonc/noad179.0933
摘要
Abstract Adoptive transfer of engineered immune cells expressing chimeric antigen receptors (CAR) is an emerging cancer immunotherapy that is also being investigated for glioblastoma. Many separate studies focus on either CAR T or CAR NK cells, and CAR macrophages are in early stages of development. However, a systemic cross-comparison of engineered immune effector cells against solid tumors, including glioblastoma, is lacking. Here, we generated second-generation NKG2D CAR mouse and human T cells, NK cells and macrophages and characterized them in vitro in co-culture assays with glioma cells and in vivo in orthotopic glioma mouse models. In vitro, mouse and human CAR T cells and CAR NK cells exhibited the highest tumor-killing activity. In contrast, in vivo, only CAR T cells exhibited anti-tumor activity in two immunocompetent orthotopic glioma-bearing mouse models, whereas CAR NK cells and CAR macrophages failed to prolong survival. More in-depth characterizations using flow cytometry, in vivo imaging and 3D microscopy, revealed that CAR T cells had the best tumor migration properties upon i.v. administration with distinct spatial distribution within the tumor compared to CAR NK cells and CAR macrophages. To profile the effects on bystander immune cells within the tumor microenvironment, we employed flow cytometry and single-cell RNA sequencing. This revealed effector cell-specific effects on the tumor microenvironment and provided insights into why the effective in vitro activity did not translate to in vivo. To unleash the anti-tumor potential of CAR immune effector cells, we engineered them to co-express the pro-inflammatory cytokines IL-12/IFNα2. This improved the in vivo anti-tumor activity of all effector cells and led to the highest fraction of long-term surviving mice with CAR NK cells. This study offers the first cross-comparison of different CAR immune effector cells against gliomas, providing valuable insights for the design of future adoptive cell therapies targeting malignant brain tumors.
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