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      Neutralization of murine myeloid-derived suppressor cells enhances the efficacy of a chimeric antigen receptor T-cells directed against pediatric solid tumors

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      1 , , 1 , 1 , 1
      Journal for Immunotherapy of Cancer
      BioMed Central
      Society for Immunotherapy of Cancer 28th Annual Meeting
      8-10 November 2013

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          Abstract

          Genetically engineered T-cells that express chimeric antigen receptors (CARs) to directly target tumor-expressed antigens have shown remarkable activity in clinical trials for hematologic malignancies, but remain unproven for the treatment of solid tumors. We find that in addition to its well known high expression in neuroblastoma, the disialoganglioside GD2 is also highly expressed on pediatric sarcomas. Some human sarcoma cell lines have GD2 expression levels equivalent to that of the prototypical neuroblastoma cell line LAN5, and immunohistochemical staining of primary human tumor tissue samples taken from essentially all patients with metastatic osteosarcoma and a subset of patients with alveolar rhabdomyosarcoma demonstrate robust expression of GD2 on the cell surface. Based on these results, we have developed models to test the ability of GD2-CAR T-cells to target and lyse human sarcomas in vitro and in vivo. We find that GD2-CAR modified T-cells induce specific lysis of GD2-expressing solid tumors in vitro even at effector:target ratios as low as 1:1, but fail to induce a significant response in vivo using the same human cell lines. Interestingly, we discovered that the pediatric sarcoma xenografts induce a large expansion of murine CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) that inhibit human T-cell responses in vitro. These results lead us to adopt a combinatorial therapeutic strategy in which we first neutralized the suppressive potential of MDSC by administration of all-trans retinoic acid (ATRA) followed by GD2-CAR therapy. This combinatorial approach results in significant improvements in both overall survival and tumor growth. Given that retinoids are already available in the clinic, these results suggest that the effectiveness of CAR T-cell therapy for solid tumors could be enhanced by coadministration of retinoids to modulate the myeloid derived suppressor cells.

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          Author and article information

          Conference
          J Immunother Cancer
          J Immunother Cancer
          Journal for Immunotherapy of Cancer
          BioMed Central
          2051-1426
          2013
          7 November 2013
          : 1
          : Suppl 1
          : P265
          Affiliations
          [1 ]Pediatric Oncology Branch, NCI, Bethesda, MD, USA
          Article
          2051-1426-1-S1-P265
          10.1186/2051-1426-1-S1-P265
          3990346
          799ccb4e-066d-45a9-8463-1b066d00b15b
          Copyright © 2013 Highfill et al; licensee BioMed Central Ltd.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

          Society for Immunotherapy of Cancer 28th Annual Meeting
          National Harbor, MD, USA
          8-10 November 2013
          History
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          Poster Presentation

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