Microarray studies comparing gene expression in B-cell chronic lymphocytic leukemia (B-CLL) and normal mature B cells first identified Ror1 as a signature gene in B-CLL ( 14, 15). Ror1 expression has mainly been evaluated by transcriptional analysis of normal tissue and tumor biopsy specimens. Clinical testing of ROR1-targeted therapies in patients with solid tumors will require careful monitoring of normal tissue toxicities or additional strategies, such as combinatorial circuits to improve tumor-specific targeting. Contrary to previous reports, we also found that ROR1 is highly expressed in the parathyroid, pancreatic islets, and several regions in the gut, raising concerns for potential off-tumor toxicity. We show that ROR1 is frequently expressed homogenously in multiple types of ovarian cancer, triple-negative breast cancer, and lung adenocarcinomas. We developed a sensitive ROR1-specific monoclonal antibody and characterized cell surface ROR1 expression in tumors and normal tissues. Multiple groups are investigating the cell surface receptor tyrosine kinase ROR1 as a target in solid tumors for monoclonal antibodies or chimeric antigen receptor–modified T cells because of its reported high expression in tumors and low expression in normal tissues. Clinical translation of ROR1-targeted therapies warrants careful monitoring of toxicities to normal organs and may require strategies to ensure patient safety. The 6D4 mAb recognizes rhesus ROR1, and ROR1 expression was similar in human and macaque tissues, suggesting that the macaque is a suitable model to evaluate safety of ROR1-targeted therapies.Ĭonclusions: ROR1 is a promising immunotherapeutic target in many epithelial tumors however, high cell surface ROR1 expression in multiple normal tissues raises concerns for on-target off-tumor toxicities. Contrary to previous findings, we found ROR1 is expressed on several normal tissues, including parathyroid pancreatic islets and regions of the esophagus, stomach, and duodenum. The data show that ROR1 is homogenously expressed on a subset of ovarian cancer, triple-negative breast cancer, and lung adenocarcinomas. Results: The 6D4 mAb is a sensitive and specific reagent to detect cell surface ROR1 by IHC. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1 and evaluated its specificity and sensitivity in IHC. On-target, off-tumor toxicity is a challenge for most nonmutated tumor antigens however, prior studies suggest that ROR1 is absent on most normal tissues.Įxperimental Design: Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell surface ROR1 by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression, and multiple groups are developing antibodies and/or chimeric antigen receptor–modified T cells to target ROR1. Purpose: This study examines cell surface ROR1 expression in human tumors and normal tissues.
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