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

• Published in: Cancer immunology research Vol. 3; no. 2; p. 206
• Main Authors: Berger, Carolina, Sommermeyer, Daniel, Hudecek, Michael, Berger, Michael, Balakrishnan, Ashwini, Paszkiewicz, Paulina J, Kosasih, Paula L, Rader, Christoph, Riddell, Stanley R
• Format: Journal Article
• Language: English
• Published: United States 01.02.2015
• Subjects: 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
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-14-0163

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.