期刊
CLINICAL CANCER RESEARCH
卷 25, 期 19, 页码 5890-5900出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-3927
关键词
-
类别
资金
- international doctoral program i-Target - Elite Network of Bavaria
- Melanoma Research Alliance [N269626, 409510]
- Else Kroner-Fresenius-Stiftung
- German Cancer Aid
- Ernst-Jung-Stiftung
- Bundesministerium fur Bildung und Forschung VIP+ grant ONKATTRACT
- European Research Council [756017]
- Marie-Sklodowska-Curie Training Network for the Immunotherapy of Cancer (IMMUTRAIN) - H2020 program of the European Union
Purpose: Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing. Experimental Design: BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo. Results: Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3 zeta signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII x anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo. Conclusions: We describe a novel ACT platform with antitumor activity inmurine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据