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

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.

MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo

“…Adoptive transfer of transgenic (tg) cytotoxic CD8 + T cells targeting cancer/testis antigens, such as NY-ESO1, are currently evaluated in clinical trials with promising results [10,11]. Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a tumor-associated antigen due to its high expression in several cancers, including EwS.…”

Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

“…Clinical ACT trials with TCR transgenic T cells have so far evaluated the safety and anti-tumor function of T cells directed against differentiation antigens in melanoma (melanoma antigen recognized by T-cells 1, MART-1; tyrosinase/gp100) [ 81 , 82 , 83 ] and colorectal cancer (carcinoembryonic antigen, CEA) [ 84 ], CTAs (NY-ESO-1, MAGE) in a variety of solid tumors and multiple myeloma [ 4 , 5 , 6 , 7 , 77 , 79 , 85 , 86 , 87 , 88 , 89 ], the overexpressed self-antigen WT-1 in myeloid malignancies [ 9 , 90 ], and Human Papilloma Virus 16 (HPV-16)-associated antigen E6 in epithelial cancers [ 8 ]. All but one of these TCRs were HLA class I-restricted, and the only class II-restricted TCR was directed against MAGE-A3 [ 86 ].…”

“…TCR sequences used in these trials originated from healthy human donors, TILs of cancer patients or vaccinated HLA transgenic mice. Some of the TCRs were ex vivo engineered, high-affinity variants with improved anti-tumor function [ 4 , 5 , 6 , 73 , 77 , 78 , 79 , 84 , 87 , 88 , 91 , 92 ]. Of these affinity-engineered TCRs, unfortunately only the HLA-A*02:01-restricted NY-ESO-1 1G4-a95:LY or c259 TCR proved safe [ 4 , 5 ], while the other three TCRs produced significant, and in some cases lethal, toxicities [ 9 , 77 , 79 , 83 , 84 ].…”

Emerging Therapies in Thoracic Malignancies—Immunotherapy, Targeted Therapy, and T-Cell Therapy in Non–Small Cell Lung Cancer

“…Studies in sarcoma and melanoma have been promising. 91 , 92 , 93 In NSCLC, although experience has been limited so far, no additional safety concerns have been raised and assessment of safety and clinical efficacy is ongoing in several studies. 94 , 95 …”