title: Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells.
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.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington. cberger@fhcrc.org.
authors.forename: Carolina
authors.initials: C
authors.lastname: Berger
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sommermeyer
authors.affiliation: Department of Medicine II-Hematology and Medical Oncology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hudecek
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Germany. Institute for Advanced Study, Technical University of Munich, Germany.
authors.forename: Paulina J
authors.initials: PJ
authors.lastname: Paszkiewicz
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Kosasih
authors.affiliation: Department of Cancer Biology, Scripps Florida, The Scripps Research Institute, Jupiter, Florida. Department of Molecular Therapeutics, Scripps Florida, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington. Institute for Advanced Study, Technical University of Munich, Germany.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000097:blood; D005818:Genetic Engineering / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods; D008253:Macaca mulatta; D023421:Models, Animal; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors