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

Academic Article
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Overview

authors

  • Hudecek, M.
  • Schmitt, T. M.
  • Baskar, S.
  • Lupo-Stanghellini, M. T.
  • Nishida, T.
  • Yamamoto, T. N.
  • Bleakley, M.
  • Turtle, C. J.
  • Chang, W. C.
  • Greisman, H. A.
  • Wood, B.
  • Maloney, D. G.
  • Jensen, M. C.
  • Rader, Christoph
  • Riddell, S. R.

publication date

  • November 2010

journal

  • Blood  Journal

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.

subject areas

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

PubMed Central ID

  • PMC2996114

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2010-05-283309

PubMed ID

  • 20702778
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Additional Document Info

start page

  • 4532

end page

  • 4541

volume

  • 116

issue

  • 22

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