Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers
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- Qiong J. Wang
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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- Zhiya Yu
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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- Ken-ichi Hanada
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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- Krishna Patel
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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- David Kleiner
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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- Nicholas P. Restifo
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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- James C. Yang
- Surgery Branch and Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
説明
<jats:title>Abstract</jats:title><jats:p>Purpose: CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate “on-target, off-tumor” toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70.</jats:p><jats:p>Experimental Design: Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different costimulatory domains from CD28 and/or 41BB were constructed. In vitro functionality of these receptors was compared and in vivo treatment efficacy was evaluated in a xenograft mouse model. A homologous, all murine anti-CD70 CAR model was also used to assess treatment-related toxicities.</jats:p><jats:p>Results: The CAR consisting of the extracellular binding portion of CD27 fused with 41BB and CD3-zeta (trCD27-41BB-zeta) conferred the highest IFNγ production against CD70-expressing tumors in vitro, and NSG mice bearing established CD70-expressing human tumors could be cured by human lymphocytes transduced with this CAR. In the murine CD27-CD3-zeta CAR model, significant reduction of established tumors and prolonged survival were achieved using CAR-transduced splenocytes in a dose-dependent manner. Host preirradiation enhanced treatment efficacy but increased treatment-related toxicities such as transient weight loss and hematopoetic suppression. The treatment did not appear to block adaptive host immune responses.</jats:p><jats:p>Conclusions: Preclinical testing supports the safety and efficacy of a CD27-containing CAR targeting CD70-expressing tumors. Clin Cancer Res; 23(9); 2267–76. ©2016 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 23 (9), 2267-2276, 2017-04-30
American Association for Cancer Research (AACR)