Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma

• Published in: Cancer discovery 2018-08, Vol.8 (8), p.944-957
• Main Authors: 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.
• Format: Article
• Language: English
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-17-1417

We evaluated the 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/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T 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-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T 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-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR. See related commentary by Keung and Tawbi, p. 914. This article is highlighted in the In This Issue feature, p. 899