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NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma

2015; Nature Portfolio; Volume: 21; Issue: 8 Linguagem: Inglês

10.1038/nm.3910

1546-170X

Aaron P. Rapoport, Edward A. Stadtmauer, Gwendolyn Binder-Scholl, Olga Goloubeva, Dan T. Vogl, Simon F. Lacey, Ashraf Badros, Alfred L. Garfall, Brendan M. Weiss, Jeffrey Finklestein, Irina Kulikovskaya, Sanjoy K. Sinha, Shari S. Kronsberg, Minnal Gupta, Sarah Bond, Luca Melchiori, Joanna E. Brewer, Alan Bennett, Andrew B. Gerry, Nicholas J. Pumphrey, Daniel Williams, Helen K Tayton- Martin, Lilliam Ribeiro, Tom Holdich, Saul Yanovich, Nancy M. Hardy, Jean A. Yared, Naseem Kerr, Sunita Philip, Sandra Westphal, Don L. Siegel, Bruce L. Levine, Bent K. Jakobsen, Michael Kalos, Carl H. June,

Viral Infectious Diseases and Gene Expression in Insects

Carl June and colleagues report the results of a phase I/II trial of adoptively transferred engineered T cells in patients with advanced multiple myeloma. Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 109 engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1–LAGE-1 TCR–engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.