Safety of targeting ROR1 for cancer immunotherapy with chimeric antigen receptor-modified T cells in a primate model

Background Immunotherapy with T cells expressing chimeric antigen receptors (CARs) specific for a tumor cell-surface molecule is effective for CD19 B cell malignancies. There is interest in extending CAR-T cell therapy to epithelial tumors, which requires identifying molecules that can be targeted safely. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed at the cell-surface in chronic lymphocytic leukemia, mantle cell lymphoma, and many epithelial malignancies where it contributes to tumor survival. ROR1 is also abundantly expressed in embryogenesis but the cell surface isoform is absent from vital adult tissues by Western blot. However, ROR1 is expressed on pre-B cells and adipocytes, and low levels of transcripts are detected in lung and pancreas, raising concern that targeting ROR1 may cause serious toxicity, as seen in clinical trials of gene-modified T cells for other targets that are not completely tumor-restricted in expression. We developed a CAR (R12) that recognizes a region of ROR1 conserved in macaques and humans but not mice. Here, we transduced autologous T cells from macaca mulatta with the R12-CAR and a control vector, and studied their safety, migration, and persistence after adoptive transfer.