IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas

Authors

• Xin Huang
• Haein Park
• Joseph Greene
• James Pao
• Erin Mulvey
• Sophia Zhou
• Catherine M. Albert
• Fred Moy, New York Medical CollegeFollow
• Deepali Sachdev
• Douglas Yee
• Christoph Rader
• Carl Hamby, New York Medical CollegeFollow
• David Loeb
• Mitchell Cairo, New York Medical CollegeFollow
• Xianzheng Zhou, New York Medical CollegeFollow

Author Type(s)

Faculty

DOI

10.1371/journal.pone.0133152

Journal Title

PLoS One

First Page

0133152

Last Page

0133152

Document Type

Article

Publication Date

1-1-2015

Department

Pediatrics

Keywords

Adoptive Transfer, Animals, Bone Neoplasms, Cell Line, Tumor, DNA Transposable Elements, Humans, Interferon-alpha, Interferon-gamma, Interleukin-13, K562 Cells, MCF-7 Cells, Mice, Mice, Inbred NOD, Mice, SCID, Receptor Tyrosine Kinase-like Orphan Receptors, Receptor, IGF Type 1, Receptors, Antigen, T-Cell, Receptors, Somatomedin, Sarcoma, T-Lymphocytes

Disciplines

Medicine and Health Sciences

Abstract

Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.

Recommended Citation

Huang, X., Park, H., Greene, J., Pao, J., Mulvey, E., Zhou, S., Albert, C. M., Moy, F., Sachdev, D., Yee, D., Rader, C., Hamby, C., Loeb, D., Cairo, M., & Zhou, X. (2015). IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas. PLoS One, 10 (7), 0133152-0133152. https://doi.org/10.1371/journal.pone.0133152