Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells

Cancer Immunol Res. 2015 Feb;3(2):206-16. doi: 10.1158/2326-6066.CIR-14-0163. Epub 2014 Oct 29.


Genetic engineering of T cells for adoptive transfer by introducing a tumor-targeting chimeric antigen receptor (CAR) is a new approach to cancer immunotherapy. A challenge for the field is to define cell surface molecules that are both preferentially expressed on tumor cells and can be safely targeted with T cells. The orphan tyrosine kinase receptor ROR1 is a candidate target for T-cell therapy with CAR-modified T cells (CAR-T cells) because it is expressed on the surface of many lymphatic and epithelial malignancies and has a putative role in tumor cell survival. The cell surface isoform of ROR1 is expressed in embryogenesis but absent in adult tissues except for B-cell precursors and low levels of transcripts in adipocytes, pancreas, and lung. ROR1 is highly conserved between humans and macaques and has a similar pattern of tissue expression. To determine if low-level ROR1 expression on normal cells would result in toxicity or adversely affect CAR-T cell survival and/or function, we adoptively transferred autologous ROR1 CAR-T cells into nonhuman primates. ROR1 CAR-T cells did not cause overt toxicity to normal organs and accumulated in bone marrow and lymph node sites, where ROR1-positive B cells were present. The findings support the clinical evaluation of ROR1 CAR-T cells for ROR1(+) malignancies and demonstrate the utility of nonhuman primates for evaluating the safety of immunotherapy with engineered T cells specific for tumor-associated molecules that are homologous between humans and nonhuman primates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / immunology
  • Cell Survival / immunology
  • Cytokines / blood
  • Genetic Engineering / methods
  • Genetic Vectors
  • Humans
  • Immunotherapy, Adoptive / adverse effects*
  • Immunotherapy, Adoptive / methods
  • Macaca mulatta
  • Models, Animal
  • Receptor Tyrosine Kinase-like Orphan Receptors / metabolism*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Retroviridae / genetics
  • T-Lymphocytes / immunology*
  • Transduction, Genetic


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