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Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

Authors
  • Ramachandran, Indu1, 2
  • Lowther, Daniel E.1, 2
  • Dryer-Minnerly, Rebecca1, 2
  • Wang, Ruoxi1, 2
  • Fayngerts, Svetlana1, 2
  • Nunez, Daniel1, 2
  • Betts, Gareth1, 2
  • Bath, Natalie1, 2
  • Tipping, Alex J.1, 2
  • Melchiori, Luca1, 2
  • Navenot, Jean-Marc1, 2
  • Glod, John3
  • Mackall, Crystal L.4
  • D’Angelo, Sandra P.5
  • Araujo, Dejka M.6
  • Chow, Warren A.7
  • Demetri, George D.8
  • Druta, Mihaela9
  • Van Tine, Brian A.10
  • Grupp, Stephan A.11
  • And 9 more
  • 1 Adaptimmune, Oxford, UK , Oxford (United Kingdom)
  • 2 Adaptimmune, Philadelphia, PA, USA , Philadelphia (United States)
  • 3 National Cancer Institute, Bethesda, MD, USA , Bethesda (United States)
  • 4 Stanford University School of Medicine, Stanford, CA, USA , Stanford (United States)
  • 5 Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY, USA , New York (United States)
  • 6 The University of Texas MD Anderson Cancer Center, Department of Sarcoma Medical Oncology, Houston, TX, USA , Houston (United States)
  • 7 City of Hope, Duarte, CA, USA , Duarte (United States)
  • 8 Dana-Farber/Harvard Cancer Center, Boston, MA, USA , Boston (United States)
  • 9 Moffitt Cancer Center, Tampa, FL, USA , Tampa (United States)
  • 10 Washington University in St. Louis School of Medicine, St. Louis, MO, USA , St. Louis (United States)
  • 11 The Children’s Hospital of Philadelphia, Pediatric Oncology, Philadelphia, PA, USA , Philadelphia (United States)
  • 12 Princess Margaret Cancer Centre, Cancer Clinical Research Unit, Toronto, ON, Canada , Toronto (Canada)
  • 13 University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA , Miami (United States)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Oct 24, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0762-2
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundGene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.MethodsFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.ResultsResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.ConclusionsOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.Trial registrationClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

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