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

TY - JOUR

T1 - Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells

AU - Berger, Carolina

AU - Sommermeyer, Daniel

AU - Hudecek, Michael

AU - Berger, Michael

AU - Balakrishnan, Ashwini

AU - Paszkiewicz, Paulina J

AU - Kosasih, Paula L

AU - Rader, Christoph

AU - Riddell, Stanley R

N1 - ©2014 American Association for Cancer Research.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Movement/immunology

KW - Cell Survival/immunology

KW - Cytokines/blood

KW - Genetic Engineering/methods

KW - Genetic Vectors

KW - Humans

KW - Immunotherapy, Adoptive/adverse effects

KW - Macaca mulatta

KW - Models, Animal

KW - Receptor Tyrosine Kinase-like Orphan Receptors/metabolism

KW - Receptors, Antigen, T-Cell/genetics

KW - Retroviridae/genetics

KW - T-Lymphocytes/immunology

KW - Transduction, Genetic

U2 - 10.1158/2326-6066.CIR-14-0163

DO - 10.1158/2326-6066.CIR-14-0163

M3 - SCORING: Journal article

C2 - 25355068

VL - 3

SP - 206

EP - 216

JO - CANCER IMMUNOL RES

JF - CANCER IMMUNOL RES

SN - 2326-6066

IS - 2

ER -