IGF1R- and ROR1-Specific CAR T cells as a potential therapy for high risk sarcomas

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0133152
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 14 2015
Externally publishedYes

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sarcoma
T-Cell Antigen Receptor
Sarcoma
T-lymphocytes
antigens
therapeutics
receptors
Beauty
Therapeutics
Osteosarcoma
IGF Type 1 Receptor
osteosarcoma
Interleukin-13
Alveolar Rhabdomyosarcoma
Embryonal Rhabdomyosarcoma
insulin-like growth factor I receptor
Heterografts
Inbred NOD Mouse
Refractory materials
Ewing's Sarcoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Huang, X., Park, H., Greene, J., Pao, J., Mulvey, E., Zhou, S. X., ... Zhou, X. (2015). IGF1R- and ROR1-Specific CAR T cells as a potential therapy for high risk sarcomas. PLoS One, 10(7), [e0133152]. https://doi.org/10.1371/journal.pone.0133152

IGF1R- and ROR1-Specific CAR T cells as a potential therapy for high risk sarcomas. / Huang, Xin; Park, Haein; Greene, Joseph; Pao, James; Mulvey, Erin; Zhou, Sophia X.; Albert, Catherine M.; Moy, Fred; Sachdev, Deepali; Yee, Douglas; Rader, Christoph; Hamby, Carl V.; Loeb, David M.; Cairo, Mitchell S.; Zhou, Xianzheng.

In: PLoS One, Vol. 10, No. 7, e0133152, 14.07.2015.

Research output: Contribution to journalArticle

Huang, X, Park, H, Greene, J, Pao, J, Mulvey, E, Zhou, SX, Albert, CM, Moy, F, Sachdev, D, Yee, D, Rader, C, Hamby, CV, Loeb, DM, Cairo, MS & Zhou, X 2015, 'IGF1R- and ROR1-Specific CAR T cells as a potential therapy for high risk sarcomas', PLoS One, vol. 10, no. 7, e0133152. https://doi.org/10.1371/journal.pone.0133152
Huang X, Park H, Greene J, Pao J, Mulvey E, Zhou SX et al. IGF1R- and ROR1-Specific CAR T cells as a potential therapy for high risk sarcomas. PLoS One. 2015 Jul 14;10(7). e0133152. https://doi.org/10.1371/journal.pone.0133152
Huang, Xin ; Park, Haein ; Greene, Joseph ; Pao, James ; Mulvey, Erin ; Zhou, Sophia X. ; Albert, Catherine M. ; Moy, Fred ; Sachdev, Deepali ; Yee, Douglas ; Rader, Christoph ; Hamby, Carl V. ; Loeb, David M. ; Cairo, Mitchell S. ; Zhou, Xianzheng. / IGF1R- and ROR1-Specific CAR T cells as a potential therapy for high risk sarcomas. In: PLoS One. 2015 ; Vol. 10, No. 7.
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