title: 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: Clinical Research Division, Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. mhudecek@fhcrc.org
authors: Michael
authors: M
authors: Hudecek
authors: Thomas M
authors: TM
authors: Schmitt
authors: Sivasubramanian
authors: S
authors: Baskar
authors: Maria Teresa
authors: MT
authors: Lupo-Stanghellini
authors: Tetsuya
authors: T
authors: Nishida
authors: Tori N
authors: TN
authors: Yamamoto
authors: Marie
authors: M
authors: Bleakley
authors: Cameron J
authors: CJ
authors: Turtle
authors: Wen-Chung
authors: WC
authors: Chang
authors: Harvey A
authors: HA
authors: Greisman
authors: Brent
authors: B
authors: Wood
authors: David G
authors: DG
authors: Maloney
authors: Michael C
authors: MC
authors: Jensen
authors: Christoph
authors: C
authors: Rader
authors: Stanley R
authors: SR
authors: Riddell
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000276:immunology*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D011948:Receptors, Antigen, T-Cell; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors