In a phase 1/2 clinical trial, 12 patients with metastatic synovial sarcoma were treated with autologous T cells engineered to express an affinity-enhanced TCR recognizing a NY-ESO-1 derived peptide. Six of 12 patients responded (1 CR, 5 PR). The NY-ESO-1c259 T cells expanded significantly in responding patients, persisted long-term, remained polyfunctional, and were enriched in central memory and stem cell memory phenotypes. TCR sequencing revealed the presence of a broad initial and persisting TCR repertoire derived from multiple phenotypes, and raised questions regarding a T cell model based on hierarchical, linear differentiation.
We evaluated safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE-1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259 T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259 T cells were present post-infusion in all patients and persisted for at least 6 months in all responders. Most infused NY-ESO-1c259 T cells exhibited an effector memory phenotype following the ex vivo expansion, but the persisting pools comprised largely central memory and stem cell memory subsets, which remained polyfunctional and showed no evidence for T cell exhaustion despite persistent tumor burdens. Next generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259 T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259 T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.
Author Info: (1) Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College dangelos@mskcc.org. (2) Adaptimmune (United Kingdom). (3) NIH. (4)
Author Info: (1) Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College dangelos@mskcc.org. (2) Adaptimmune (United Kingdom). (3) NIH. (4) Pediatric Oncology Branch, National Cancer Institute. (5) Pediatric Oncology Branch, National Institutes of Health. (6) Tumor Microenvironment and Metastasis Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute. (7) Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania. (8) Department of Medicine, Memorial Sloan Kettering Cancer Center. (9) Adaptimmune (United Kingdom). (10) Adaptimmune (United Kingdom). (11) Adaptimmune (United Kingdom). (12) Translational Sciences, Adaptimmune (United Kingdom). (13) Adaptimmune. (14) Adaptimmune (United Kingdom). (15) Adaptimmune. (16) Immunology, Adaptimmune (United Kingdom). (17) Adaptimmune (United Kingdom). (18) Biomarkers and Companion Diagnostic, Adaptimmune (United Kingdom). (19) NIH. (20) Parker Institute for Cancer Immunotherapy. (21) Clinical Development, Adaptimmune (United Kingdom). (22) Adaptimmune (United Kingdom). (23) Adaptimmune (United Kingdom). (24) Clinical, Adaptimmune (United Kingdom). (25) Clinical Development, Adaptimmune (United Kingdom). (26) Clinical Development, Adaptimmune (United Kingdom). (27) Stanford Cancer Institute and Department of Pediatrics, Stanford University.
