Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells.
Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells.
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通过化学自我组装的标记T细胞消除已建立的肿瘤。
DOI：
10.1021/acsnano.8b01308
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发表时间：
2018-07-24
期刊：
影响因子：
17.1
通讯作者：
Wagner CR
中科院分区：
文献类型：
--
作者：
Petersburg JR;Shen J;Csizmar CM;Murphy KA;Spanier J;Gabrielse K;Griffith TS;Fife B;Wagner CR
我们的实验室已经开发出化学自组装纳米环（CSAN）作为T细胞表面非遗传修饰的人工抗原受体（PAR）。PAR已在体外成功地用于激活T细胞以选择性杀死白血病细胞。然而，PAR的疗效尚未在体内或针对实体瘤进行评估。因此，我们开发了选择性靶向人CD 3受体和人上皮细胞粘附分子（EpCAM）的双特异性PAR，EpCAM在多种癌和癌症干细胞上过表达。发现αEpCAM/α CD 3 PAR稳定结合T细胞>4天，并且用αEpCAM/α CD 3 PAR功能化的T细胞处理EpCAM+ MCF-7乳腺癌细胞导致诱导IL-2、IFN-γ和MCF-7细胞毒性。此外，原位乳腺癌模型验证了αEpCAM/α CD 3 PAR治疗在体内将T细胞裂解活性导向EpCAM+乳腺癌细胞从而导致肿瘤根除的能力。体内生物分布研究表明，PAR-T细胞在体内形成，并持续超过48小时，在肿瘤组织中快速积累。PAR治疗后，通过输注临床相关浓度的FDA批准的抗生素甲氧苄啶，可显著降低IL-2、IFN-γ、IL-6和TNF-α的产生，从而发出药理学PAR失活信号。重要的是，CSAN不诱导幼稚T细胞活化，因此表现出有限的诱导幼稚T细胞无反应性的潜力。此外，鼠免疫原性研究表明，CSAN不会诱导显著的抗体应答，也不会激活脾细胞。总的来说，我们的结果表明，双特异性CSAN能够非遗传地产生可逆修饰的T细胞，这些细胞能够根除靶向实体瘤。
Our laboratory has developed chemically self-assembled nanorings (CSANs) as prosthetic antigen receptors (PARs) for the non-genetic modification of T-cell surfaces. PARs have been successfully employed in vitro to activate T cells for the selective killing of leukemia cells. However, PAR efficacy has yet to be evaluated in vivo or against solid tumors. Therefore, we developed bispecific PARs that selectively target the human CD3 receptor and human Epithelial Cell Adhesion Molecule (EpCAM), which is overexpressed on multiple carcinomas and cancer stem cells. The αEpCAM/αCD3 PARs were found to stably bind T cells for >4 days, and treating EpCAM+ MCF-7 breast cancer cells with αEpCAM/αCD3 PAR-functionalized T cells resulted in the induction of IL-2, IFN-γ and MCF-7 cytotoxicity. Furthermore, an orthotopic breast cancer model validated the ability of αEpCAM/αCD3 PAR therapy to direct T cell lytic activity towards EpCAM+ breast cancer cells in vivo leading to tumor eradication. In vivo biodistribution studies demonstrated that PAR-T cells were formed in vivo and persist for over 48 hours with rapid accumulation in tumor tissue. Following PAR treatment, the production of IL-2, IFN-γ, IL-6 and TNF-α could be significantly reduced by an infusion of clinically-relevant concentrations of the FDA-approved antibiotic, trimethoprim, signaling pharmacologic PAR deactivation. Importantly, CSANs did not induce naïve T cell activation and thus exhibit a limited potential to induce naïve T cell anergy. In addition, murine immunogenicity studies demonstrated that CSANs do not induce a significant antibody response, nor do they activate splenic cells. Collectively, our results demonstrate that bispecific CSANs are able to non-genetically generate reversibly modified T cells that are capable of eradicating targeted solid tumors.
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影响因子：
3.8
作者：
Gostner JM;Fong D;Wrulich OA;Lehne F;Zitt M;Hermann M;Krobitsch S;Martowicz A;Gastl G;Spizzo G
通讯作者：
Spizzo G
影响因子：
5.7
作者：
El-Sahwi K;Bellone S;Cocco E;Casagrande F;Bellone M;Abu-Khalaf M;Buza N;Tavassoli FA;Hui P;Rüttinger D;Silasi DA;Azodi M;Schwartz PE;Rutherford TJ;Pecorelli S;Santin AD
通讯作者：
Santin AD
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
3.6
作者：
Brischwein, K;Schlereth, B;Baeuerle, PA
通讯作者：
Baeuerle, PA
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M