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

Authors: Pegram, H. J.; Purdon, T. J.; van Leeuwen, D. G.; Curran, K. J.; Giralt, S. A.; Barker, J. N.; Brentjens, R. J.
Article Title: IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia
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.
Keywords: controlled study; nonhuman; disease free survival; cd8+ t lymphocyte; t lymphocyte; animal cell; mouse; interleukin 2; cancer immunotherapy; interleukin 7; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; acute lymphoblastic leukemia; viral gene delivery system; granzyme b; gamma interferon; cd4+ t lymphocyte; chimeric antigen receptor; umbilical cord blood; adoptive transfer; effector cell; cytokine release; graft versus leukemia effect; interleukin 12; interleukin 15; cd19 antigen; cell transfer; b cell leukemia; memory t lymphocyte; stem cell expansion; cd4 cd8 ratio; priority journal; article; b cell acute lymphoblastic leukemia; umbilical cord blood derived t lymphocyte
Journal Title: Leukemia
Volume: 29
Issue: 2
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2015-02-01
Start Page: 415
End Page: 422
Language: English
DOI: 10.1038/leu.2014.215
PROVIDER: scopus
PUBMED: 25005243
PMCID: PMC5189717
Notes: Export Date: 2 March 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Renier J Brentjens
    274 Brentjens
  2. Sergio Andres Giralt
    792 Giralt
  3. Kevin Joseph Curran
    101 Curran
  4. Juliet N Barker
    302 Barker
  5. Hollie Jaine Pegram
    19 Pegram
  6. Terence John Purdon
    59 Purdon