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

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

Author information

1
Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington. cberger@fhcrc.org.
2
Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Department of Medicine II-Hematology and Medical Oncology, University of Wuerzburg, Wuerzburg, Germany.
4
Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Germany. Institute for Advanced Study, Technical University of Munich, Germany.
5
Department of Cancer Biology, Scripps Florida, The Scripps Research Institute, Jupiter, Florida. Department of Molecular Therapeutics, Scripps Florida, The Scripps Research Institute, Jupiter, Florida.
6
Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington. Institute for Advanced Study, Technical University of Munich, Germany.

Abstract

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.

PMID:
25355068
PMCID:
PMC4324006
DOI:
10.1158/2326-6066.CIR-14-0163
[Indexed for MEDLINE]
Free PMC Article

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