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

PLoS One. 2015 Jul 14;10(7):e0133152. doi: 10.1371/journal.pone.0133152. eCollection 2015.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • DNA Transposable Elements
  • IGF1R protein, human
  • Interferon-alpha
  • Interleukin-13
  • Receptors, Antigen, T-Cell
  • Receptors, Somatomedin
  • Interferon-gamma
  • ROR1 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Receptor, IGF Type 1