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

Jacob Petersburg, Jingjing Shen, Clifford M. Csizmar, Katherine A Murphy, Justin A Spanier, Kari Gabrielse, Thomas S Griffith, Brian T Fife, Carston R Wagner

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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 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-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 nongenetically generate reversibly modified T cells that are capable of eradicating targeted solid tumors.

Original languageEnglish (US)
Pages (from-to)6563-6576
Number of pages14
JournalACS nano
Volume12
Issue number7
DOIs
StatePublished - Jul 24 2018

Fingerprint

Nanorings
T-cells
Antigen Receptors
Antigens
Prosthetics
antigens
Tumors
tumors
Cell adhesion
Cell Adhesion Molecules
CD3 Antigens
adhesion
Molecules
cancer
breast
molecules
Interleukin-2
Cells
Trimethoprim
Antibiotics

Keywords

  • EpCAM
  • T cell
  • anticancer
  • bispecific
  • immunotherapy
  • nanotechnology

Cite this

Petersburg, J., Shen, J., Csizmar, C. M., Murphy, K. A., Spanier, J. A., Gabrielse, K., ... Wagner, C. R. (2018). Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells. ACS nano, 12(7), 6563-6576. https://doi.org/10.1021/acsnano.8b01308

Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells. / Petersburg, Jacob; Shen, Jingjing; Csizmar, Clifford M.; Murphy, Katherine A; Spanier, Justin A; Gabrielse, Kari; Griffith, Thomas S; Fife, Brian T; Wagner, Carston R.

In: ACS nano, Vol. 12, No. 7, 24.07.2018, p. 6563-6576.

Research output: Contribution to journalArticle

Petersburg, J, Shen, J, Csizmar, CM, Murphy, KA, Spanier, JA, Gabrielse, K, Griffith, TS, Fife, BT & Wagner, CR 2018, 'Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells', ACS nano, vol. 12, no. 7, pp. 6563-6576. https://doi.org/10.1021/acsnano.8b01308
Petersburg J, Shen J, Csizmar CM, Murphy KA, Spanier JA, Gabrielse K et al. Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells. ACS nano. 2018 Jul 24;12(7):6563-6576. https://doi.org/10.1021/acsnano.8b01308
Petersburg, Jacob ; Shen, Jingjing ; Csizmar, Clifford M. ; Murphy, Katherine A ; Spanier, Justin A ; Gabrielse, Kari ; Griffith, Thomas S ; Fife, Brian T ; Wagner, Carston R. / Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells. In: ACS nano. 2018 ; Vol. 12, No. 7. pp. 6563-6576.
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