title: Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas.
abstract: Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+sarcoma and neuroblastoma cell lines in vitro However, in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+sarcoma, despite effectively controlling GD2+neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSC) that inhibited human CAR T-cell responses in vitro Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. Cancer Immunol Res; 4(10); 869-80. ©2016 AACR.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Long
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Highfill
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Smith
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Walker
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Sneha
authors.initials: S
authors.lastname: Ramakrishna
authors.affiliation: Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
authors.forename: Rana
authors.initials: R
authors.lastname: El-Etriby
authors.affiliation: Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
authors.forename: Susana
authors.initials: S
authors.lastname: Galli
authors.affiliation: Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Tsokos
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Rimas J
authors.initials: RJ
authors.lastname: Orentas
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. Department of Pediatrics, Stanford University School of Medicine, Stanford, California. cmackall@stanford.edu.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002648:Child; D003131:Combined Modality Therapy; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016688:Mice, Inbred NOD; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012509:Sarcoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D016896:Treatment Outcome; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C000605956:CD19-specific chimeric antigen receptor; D005732:Gangliosides; D011948:Receptors, Antigen, T-Cell; D014212:Tretinoin; C019403:ganglioside, GD2