NY-ESO-1-specific TCR-engineered T Cells Mediate Sustained Antigen-Specific Antitumor Effects in Myeloma

Nat Med. 2015 Aug;21(8):914-921. doi: 10.1038/nm.3910. Epub 2015 Jul 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Antigens, Surface / genetics
  • Antigens, Surface / immunology
  • Female
  • Genetic Engineering
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Middle Aged
  • Multiple Myeloma / immunology
  • Multiple Myeloma / mortality
  • Multiple Myeloma / therapy*
  • Receptors, Antigen, T-Cell / physiology*
  • Syndecan-1 / analysis
  • T-Lymphocytes / immunology*

Substances

  • Antigens, Neoplasm
  • Antigens, Surface
  • CTAG1B protein, human
  • CTAG2 protein, human
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • SDC1 protein, human
  • Syndecan-1