Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1(c259) T Cells in Synovial Sarcoma

作者：D'Angelo, Sandra P.^*; Melchiori, Luca; Merchant, Melinda S.; Bernstein, Donna; Glod, John; Kaplan, Rosandra; Grupp, Stephan; Tap, William D.; Chagin, Karen; Binder, Gwendolyn K.; Basu, Samik; Lowther, Daniel E.; Wang, Ruoxi; Bath, Natalie; Tipping, Alex; Betts, Gareth; Ramachandran, Indu; Navenot, Jean-Marc; Zhang, Hua; Wells, Daniel K.; Van Winkle, Erin; Kari, Gabor; Trivedi, Trupti; Holdich, Tom; Pandite, Lini; Amado, Rafael; Mackall, Crystal L.

来源：Cancer Discovery, 2018, 8(8): 944-957.

DOI：10.1158/2159-8290.CD-17-1417

• IMMUNE CHECKPOINT BLOCKADE
• CHIMERIC ANTIGEN RECEPTOR
• PD-1 BLOCKADE
• B-CELL
• CANCER-IMMUNOTHERAPY
• LUNG-CANCER
• EXPRESSION
• VACCINATION
• TUMORS
• COSTIMULATION

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1(c259), an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1(c259)T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1(c259)T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1(c259)T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8(+) NY-ESO-1(c259)T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1(c259)T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects. @@@ SIGNIFICANCE: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8(+) NY-ESO-1(c259)T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen.

• 出版日期2018-8