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Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas.
Long, Adrienne H; Highfill, Steven L; Cui, Yongzhi; Smith, Jillian P; Walker, Alec J; Ramakrishna, Sneha; El-Etriby, Rana; Galli, Susana; Tsokos, Maria G; Orentas, Rimas J; Mackall, Crystal L.
Afiliação
  • Long AH; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Highfill SL; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Cui Y; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Smith JP; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Walker AJ; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Ramakrishna S; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • El-Etriby R; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
  • Galli S; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
  • Tsokos MG; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
  • Orentas RJ; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
  • Mackall CL; Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. Department of Pediatrics, Stanford University School of Medicine, Stanford, California. cmackall@stanford.edu.
Cancer Immunol Res ; 4(10): 869-880, 2016 10.
Article em En | MEDLINE | ID: mdl-27549124
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma / Tretinoína / Receptores de Antígenos de Linfócitos T / Imunoterapia Adotiva / Células Supressoras Mieloides Limite: Animals / Child / Humans Idioma: En Revista: Cancer Immunol Res Ano de publicação: 2016 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma / Tretinoína / Receptores de Antígenos de Linfócitos T / Imunoterapia Adotiva / Células Supressoras Mieloides Limite: Animals / Child / Humans Idioma: En Revista: Cancer Immunol Res Ano de publicação: 2016 Tipo de documento: Article País de publicação: Estados Unidos