CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response

Cancer Cell. 2019 Mar 18;35(3):473-488.e6. doi: 10.1016/j.ccell.2019.02.006.

Abstract

Chimeric antigen receptor (CAR) T cells provide great efficacy in B cell malignancies. However, improved CAR T cell therapies are still needed. Here, we engineered tumor-targeted CAR T cells to constitutively express the immune-stimulatory molecule CD40 ligand (CD40L) and explored efficacy in different mouse leukemia/lymphoma models. We observed that CD40L+ CAR T cells circumvent tumor immune escape via antigen loss through CD40/CD40L-mediated cytotoxicity and induction of a sustained, endogenous immune response. After adoptive cell transfer, the CD40L+ CAR T cells displayed superior antitumor efficacy, licensed antigen-presenting cells, enhanced recruitment of immune effectors, and mobilized endogenous tumor-recognizing T cells. These effects were absent in Cd40-/- mice and provide a rationale for the use of CD40L+ CAR T cells in cancer treatment.

Keywords: CAR T cells; CD40; CD40 ligand; antigen-presenting cells; chimeric antigen receptor; endogenous T cells; immunotherapy; leukemia; lymphoma.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • CD40 Ligand / genetics
  • CD40 Ligand / immunology*
  • Cell Line, Tumor
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology*
  • Tumor Escape
  • Xenograft Model Antitumor Assays

Substances

  • Receptors, Chimeric Antigen
  • CD40 Ligand