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) since 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.

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

“…For future clinical trials, there is a pre-clinical development pipeline with CARs specific for target antigens in other hematologic and solid tumors, including a SLAMF7-specific CAR in multiple myeloma, and a ROR1specific CAR in lymphoma, breast and lung cancer (Berger et al, 2015;Hudecek et al, 2013). Importantly, the MC-encoded SB transposon can accommodate additional genetic cargo without compromising transposition efficacy.…”

Gene Therapy with the Sleeping Beauty Transposon System

“…For example, clinical trials using viral-based gene transfer will test CARs specific for target antigens in other hematologic and solid tumors, including a SLAMF7-specific CAR for multiple myeloma and a ROR1-specific CAR for lymphoma, breast, and lung cancer [117,118]. The gene transfer technology enabled by SB to redirect T cell specificity can be extended beyond CAR.…”

Cellular Immunotherapy in B-Cell Malignancy

“…Zah et al [59] recently reported on the development of a bispecific CD19/CD20 CAR construct with increased anti-tumor effect and prevention of CD19-negative ALL outgrowth. CAR constructs against alternative targets like CD22 [60] or ROR1 [61] are currently in development.…”