IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia

Leukemia. 2015 Feb;29(2):415-22. doi: 10.1038/leu.2014.215. Epub 2014 Jul 9.

Abstract

Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19(+) tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism*
  • B-Lymphocytes / cytology*
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Disease Progression
  • Disease-Free Survival
  • Fetal Blood / cytology*
  • Flow Cytometry
  • Humans
  • Immunologic Memory
  • Immunotherapy / methods*
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism*
  • Interleukin-15 / immunology
  • Mice
  • Mice, SCID
  • Phenotype
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Recurrence
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Transgenes

Substances

  • Antigens, CD19
  • Cytokines
  • Interleukin-15
  • Interleukin-12