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Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells.


ABSTRACT: Our laboratory has developed chemically self-assembled nanorings (CSANs) as prosthetic antigen receptors (PARs) for the nongenetic 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 ?EpCAM/?CD3 PARs were found to stably bind T cells for >4 days, and treating EpCAM+ MCF-7 breast cancer cells with ?EpCAM/?CD3 PAR-functionalized T cells resulted in the induction of IL-2, IFN-?, and MCF-7 cytotoxicity. Furthermore, an orthotopic breast cancer model validated the ability of ?EpCAM/?CD3 PAR therapy to direct T cell lytic activity toward 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 h with rapid accumulation in tumor tissue. Following PAR treatment, the production of IL-2, IFN-?, IL-6, and TNF-? 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 nongenetically generate reversibly modified T cells that are capable of eradicating targeted solid tumors.

SUBMITTER: Petersburg JR 

PROVIDER: S-EPMC6506352 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells.

Petersburg Jacob R JR   Shen Jingjing J   Csizmar Clifford M CM   Murphy Katherine A KA   Spanier Justin J   Gabrielse Kari K   Griffith Thomas S TS   Fife Brian B   Wagner Carston R CR  

ACS nano 20180604 7


Our laboratory has developed chemically self-assembled nanorings (CSANs) as prosthetic antigen receptors (PARs) for the nongenetic 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  ...[more]

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