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

Abstract

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.

• Authors: Michael Hudecek, Thomas M Schmitt, Sivasubramanian Baskar, Maria Teresa Lupo-Stanghellini, Tetsuya Nishida, Tori N Yamamoto, Marie Bleakley, Cameron J Turtle, Wen-Chung Chang, Harvey A Greisman, Brent Wood, David G Maloney, Michael C Jensen, Christoph Rader, Stanley R Riddell
• Journal: Blood (Blood) Vol. 116 Issue 22 Pg. 4532-41 (Nov 25 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20702778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Antigen, T-Cell
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors

Topics

• Adult
• B-Lymphocytes (immunology, metabolism, pathology)
• Bone Marrow (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Gene Expression Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, immunology)
• Lymphoma, Mantle-Cell (genetics, immunology)
• Receptor Tyrosine Kinase-like Orphan Receptors (genetics, immunology)
• Receptors, Antigen, T-Cell (genetics, immunology)
• T-Lymphocytes (immunology, metabolism)
• Transduction, Genetic