Innovative T Cell-Targeted Therapy for Ovarian Cancer.

摘要

Major advances have been made in two main areas. Firstly, Receptor tyrosine kinase-like orphan receptor-1 (ROR1) was identified as a tumor antigen expressed on ovarian cancer (OvCa), but not expressed on normal tissue(s). Second generation chimeric antigen receptors (CARs) were designed with CD3z and either CD28 or CD137 endodomains fused to the antigen-binding region of a ROR1-specific monoclonal antibody (clone 4A5). CARs were stably expressed in T cells following Sleeping Beauty SB11 transposition and propagation on ROR1+ artificial antigen presenting cells (aAPC). Re-directed cytolysis of ROR1+ OvCa cell lines by CAR+ T cells was demonstrated. Secondly, the anti-tumor activity of gd T cells was harnessed to kill OvCa. Our aAPC were used to massively expand for the first time a polyclonal population of gd T cells for immunotherapy. OvCa cell lines and xenografts were eliminated by these massively expanded polyclonal gd T cells. gd T cells are HLA-unrestricted and rapid expansion with our novel aAPCs may also have utility as off the shelf therapy for Ebola virus and other virus and bacteria mediated outbreaks. Based on this work, a ROR1 CAR clinical trial has been registered at ClinicalTrials.gov and opened in January 2015 (NCT02194374).