The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor

Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a high...

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Bibliographic Details
Published in:Blood 2010-11, Vol.116 (22), p.4532-4541
Main Authors: Hudecek, Michael, Schmitt, Thomas M., Baskar, Sivasubramanian, Lupo-Stanghellini, Maria Teresa, Nishida, Tetsuya, Yamamoto, Tori N., Bleakley, Marie, Turtle, Cameron J., Chang, Wen-Chung, Greisman, Harvey A., Wood, Brent, Maloney, David G., Jensen, Michael C., Rader, Christoph, Riddell, Stanley R.
Format: Article
Language:English
Subjects:
Adult
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
B-Lymphocytes - pathology
Biological and medical sciences
Bone Marrow - immunology
Bone Marrow - metabolism
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cell Line, Tumor
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Hematologic and hematopoietic diseases
Humans
Immunobiology
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - immunology
Lymphoma, Mantle-Cell - genetics
Lymphoma, Mantle-Cell - immunology
Medical sciences
Receptor Tyrosine Kinase-like Orphan Receptors - genetics
Receptor Tyrosine Kinase-like Orphan Receptors - immunology
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - immunology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Transduction, Genetic
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Summary:Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2010-05-283309