Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression Journal Article

Authors: Curran, K. J.; Seinstra, B. A.; Nikhamin, Y.; Yeh, R.; Usachenko, Y.; van Leeuwen, D. G.; Purdon, T.; Pegram, H. J.; Brentjens, R. J.
Article Title: Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression
Abstract: Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory T<inf>H</inf>1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40+ tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40+ tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19+ systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy. © 2015 The American Society of Gene & Cell Therapy.
Keywords: cancer survival; controlled study; human cell; nonhuman; antigen expression; lymphocyte proliferation; t lymphocyte; mouse; mus; cancer immunotherapy; cell maturation; dendritic cell; cd40 ligand; fas antigen; interleukin 12p70; animal experiment; animal model; in vivo study; in vitro study; dna modification; immunogenicity; hla dr antigen; hla antigen class 1; chimeric antigen receptor; cell therapy; clinical effectiveness; th1 cell; cytokine release; follicular lymphoma; intercellular adhesion molecule 1; lymphocyte function associated antigen 3; adoptive immunotherapy; b7 antigen; cd86 antigen; cell mediated cytotoxicity; cd40 antigen; human; article; cd70 antigen
Journal Title: Molecular Therapy
Volume: 23
Issue: 4
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2015-04-01
Start Page: 769
End Page: 778
Language: English
DOI: 10.1038/mt.2015.4
PROVIDER: scopus
PMCID: PMC4395796
PUBMED: 25582824
Notes: Export Date: 4 May 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Renier J Brentjens
    279 Brentjens
  2. Kevin Joseph Curran
    109 Curran
  3. Hollie Jaine Pegram
    19 Pegram
  4. Raymond Yeh
    18 Yeh
  5. Terence John Purdon
    60 Purdon