Journal Article

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

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

2015

Overview

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 × 10 9 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059/2325 / 631/67/70 / Aged / Antigens / Antigens, Neoplasm - genetics / Antigens, Neoplasm - immunology / Antigens, Surface - genetics / Antigens, Surface - immunology / Biomedical research / Biomedicine / Blood / Cancer Research / Care and treatment / Cytokines / Female / Genetic Engineering / Health aspects / Humans / Infectious Diseases / Lymphocytes / Male / Membrane Proteins - genetics / Membrane Proteins - immunology / Metabolic Diseases / Middle Aged / Molecular Medicine / Multiple myeloma / Multiple Myeloma - immunology / Multiple Myeloma - mortality / Multiple Myeloma - therapy / Neurosciences / Receptors, Antigen, T-Cell - physiology / Stem cells / Syndecan-1 - analysis / T cells / T-Lymphocytes - immunology