Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues

TY - JOUR

T1 - Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues

AU - Balakrishnan, Ashwini

AU - Goodpaster, Tracy

AU - Randolph-Habecker, Julie

AU - Hoffstrom, Benjamin G

AU - Jalikis, Florencia G

AU - Koch, Lisa K

AU - Berger, Carolina

AU - Kosasih, Paula L

AU - Rajan, Anusha

AU - Sommermeyer, Daniel

AU - Porter, Peggy L

AU - Riddell, Stanley R

N1 - ©2016 American Association for Cancer Research.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Purpose: This study examines cell surface ROR1 expression in human tumors and normal 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. 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.Experimental 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. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1 and evaluated its specificity and sensitivity in IHC.Results: The 6D4 mAb is a sensitive and specific reagent to detect cell surface ROR1 by IHC. The data show that ROR1 is homogenously expressed on a subset of ovarian cancer, triple-negative breast cancer, and lung adenocarcinomas. 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 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.Conclusions: 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. Clinical translation of ROR1-targeted therapies warrants careful monitoring of toxicities to normal organs and may require strategies to ensure patient safety. Clin Cancer Res; 23(12); 3061-71. ©2016 AACR.

AB - Purpose: This study examines cell surface ROR1 expression in human tumors and normal 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. 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.Experimental 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. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1 and evaluated its specificity and sensitivity in IHC.Results: The 6D4 mAb is a sensitive and specific reagent to detect cell surface ROR1 by IHC. The data show that ROR1 is homogenously expressed on a subset of ovarian cancer, triple-negative breast cancer, and lung adenocarcinomas. 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 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.Conclusions: 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. Clinical translation of ROR1-targeted therapies warrants careful monitoring of toxicities to normal organs and may require strategies to ensure patient safety. Clin Cancer Res; 23(12); 3061-71. ©2016 AACR.

KW - Antibodies, Monoclonal/immunology

KW - Carcinoma/drug therapy

KW - Cell Line, Tumor

KW - Female

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Humans

KW - Immunotherapy

KW - Male

KW - Molecular Targeted Therapy

KW - Receptor Tyrosine Kinase-like Orphan Receptors/genetics

KW - Receptors, Antigen, T-Cell/genetics

U2 - 10.1158/1078-0432.CCR-16-2083

DO - 10.1158/1078-0432.CCR-16-2083

M3 - SCORING: Journal article

C2 - 27852699

VL - 23

SP - 3061

EP - 3071

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 12

ER -