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 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.
Hudecek
Michael
M
Clinical Research Division, Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. mhudecek@fhcrc.org
Schmitt
Thomas M
TM
Baskar
Sivasubramanian
S
Lupo-Stanghellini
Maria Teresa
MT
Nishida
Tetsuya
T
Yamamoto
Tori N
TN
Bleakley
Marie
M
Turtle
Cameron J
CJ
Chang
Wen-Chung
WC
Greisman
Harvey A
HA
Wood
Brent
B
Maloney
David G
DG
Jensen
Michael C
MC
Rader
Christoph
C
Riddell
Stanley R
SR
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
D011948:Receptors, Antigen, T-Cell; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors