Adoptive therapy of ROR1+ murine solid tumors with chimeric antigen receptor-modified T cells (VAC7P.1045)

Abstract

Abstract Adoptive therapy with T cells modified to express chimeric antigen receptors (CARs) holds promise for treating epithelial cancers if target molecules can be identified and strategies developed to overcome the immunosuppressive mechanisms of solid tumors. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in many blood and solid tumors but is absent from vital adult tissues, making it a potential tumor-specific target for therapy. We developed ROR1-specific CARs comprised of an extracellular single chain antibody linked to various intracellular signaling modules. T cells modified to express ROR1-CARs exerted potent anti-tumor effects against ROR1+ leukemia and lymphoma in vivo, but their effectiveness against solid tumors is not known. To test this, we used the orthotopic 4T1 mouse mammary tumor model that recapitulates the immunosuppressive microenvironment and metastatic pattern of human breast cancer. We transduced 4T1 cells with firefly luciferase (ffluc) to allow in vivo imaging of tumor growth, along with mouse or human ROR1. Murine CD8+ T cells modified to express ROR1-CARs lysed ROR1+ but not ROR1- 4T1 cells in vitro, while unmodified T cells were unable to lyse either ROR1+ or ROR1- 4T1 cells. We are currently evaluating the anti-tumor activity of ROR1-CAR T cells against 4T1-ffluc/ROR1 cells in vivo to define optimal CAR constructs and cell compositions and identify what immunosuppressive pathways to target to improve anti-tumor activity.