Format

Send to

Choose Destination
J Immunother Cancer. 2019 Oct 24;7(1):276. doi: 10.1186/s40425-019-0762-2.

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

Author information

1
Adaptimmune, Oxford, UK.
2
Adaptimmune, Philadelphia, PA, USA.
3
National Cancer Institute, Bethesda, MD, USA.
4
Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
City of Hope, Duarte, CA, USA.
8
Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
9
Moffitt Cancer Center, Tampa, FL, USA.
10
Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
11
Pediatric Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
12
Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada.
13
Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
14
Adaptimmune, Oxford, UK. Samik.basu@adaptimmune.com.
15
Adaptimmune, Philadelphia, PA, USA. Samik.basu@adaptimmune.com.

Abstract

BACKGROUND:

Gene-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.

METHODS:

Four 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.

RESULTS:

Responses 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.

CONCLUSIONS:

Our 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 REGISTRATION:

ClinicalTrials.gov, NCT01343043 , Registered 27 April 2011.

KEYWORDS:

Adoptive immunotherapy; Antigen loss; Checkpoint therapy; Cyclophosphamide; Cytokine; Engineered cell therapy; Fludarabine; IL-15; NY-ESO-1; Synovial sarcoma; T cell; TCR

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center