CD30-REDIRECTED CHIMERIC ANTIGEN RECEPTOR T CELLS TARGET EMBRYONAL CARCINOMA VIA ANTIGEN-DEPENDENT AND FAS/FASL INTERACTIONS

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  • March 20, 2019
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  • Hong, Lee
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Embryonal carcinomas (ECs) and mixed testicular germ cell tumors (TGCTs) containing EC express CD30 and are the most aggressive TGCT subtypes. Chimeric antigen receptor T cells (CAR-Ts) combine the cytotoxic properties of T cells with the antigen specificity of monoclonal antibodies to target antigen-expressing cells, such as infected or cancerous cells. CAR-Ts targeting CD30 (CD30.CAR-Ts) have shown robust anti-tumor activity against Hodgkin’s lymphoma, but have not been tested against solid tumors. We tested whether CD30.CAR-Ts could also target ECs using in vitro and in vivo models. CD30.CAR-Ts exhibited anti-tumor activity in vitro against the human EC cell lines Tera-1, Tera-2 and NCCIT, and putative EC stem cells identified by Hoechst dye staining. Cytolytic activity of CD30.CAR-Ts was complemented by sustained proliferation and pro-inflammatory cytokine production. CD30.CAR-Ts also demonstrated anti-tumor activity in an in vivo xenograft NSG mouse model of metastatic EC. Remarkably, we observed that CD30.CAR-Ts, while targeting CD30+ EC tumor cells through the CAR (i.e. antigen-dependent targeting), also eliminated surrounding CD30– EC cells in an antigen-independent manner via cell-cell contact-dependent Fas/FasL interaction. In addition, inducing Fas (CD95) expression in CD30+ but Fas– EC was sufficient to improve CD30.CAR-T anti-tumor activity. Overall, these data suggest that CD30.CAR-Ts can be used as a novel immunotherapy for ECs. Additionally, Fas/FasL interaction between tumor cells and CAR-Ts can be exploited to reduce tumor escape due to heterogeneous antigen expression or to improve CAR-T anti-tumor activity.
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Advisor
  • Tisch, Roland
  • Sheikh, Shehzad
  • Whitmire, Jason
  • Dotti, Gianpietro
  • Wan, Yisong
  • Savoldo, Barbara
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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