title: IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.
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.
authors.affiliation: Department of Pediatrics, Division of Hematology, Oncology and Stem Cell Transplantation, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Division of Hematology, Oncology and Stem Cell Transplantation, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Haein
authors.initials: H
authors.lastname: Park
authors.affiliation: University of Minnesota College of Biological Sciences, Minneapolis, MN, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Greene
authors.affiliation: New York Medical College School of Medicine, Valhalla, NY, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Pao
authors.affiliation: New York Medical College School of Medicine, Valhalla, NY, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Mulvey
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Sophia X
authors.initials: SX
authors.lastname: Zhou
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Albert
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Fred
authors.initials: F
authors.lastname: Moy
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Deepali
authors.initials: D
authors.lastname: Sachdev
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL, United States of America; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, United States of America.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Carl V
authors.initials: CV
authors.lastname: Hamby
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Loeb
authors.affiliation: Department of Pediatrics, Division of Hematology, Oncology and Stem Cell Transplantation, New York Medical College, Valhalla, NY, United States of America; Department of Pathology, New York Medical College, Valhalla, NY, United States of America; Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, United States of America; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States of America; Department of Medicine, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
authors.affiliation: Department of Pediatrics, Division of Hematology, Oncology and Stem Cell Transplantation, New York Medical College, Valhalla, NY, United States of America; Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, United States of America; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States of America.
authors.forename: Xianzheng
authors.initials: X
authors.lastname: Zhou
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D001859:Bone Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D004251:DNA Transposable Elements / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000276:immunology / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D012509:Sarcoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D004251:DNA Transposable Elements; C000597236:IGF1R protein, human; D016898:Interferon-alpha; D018793:Interleukin-13; D011948:Receptors, Antigen, T-Cell; D017451:Receptors, Somatomedin; D007371:Interferon-gamma; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D017526:Receptor, IGF Type 1