Transgenic expression of CD40L and interleukin-2 induces an autologous antitumor immune response in patients with non-Hodgkin's lymphoma

Satoshi Takahashi, Patricia Yotnda, Raphael F. Rousseau, Zhuyong Mei, Susan Smith, Donna Rill, Anas Younes, Malcolm Brenner

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The malignant B cells of non-Hodgkin's lymphoma (B-NHL cells) express peptides derived from tumor-specific antigens such as immunoglobulin idiotypes, and also express major histocompatibility complex antigens. However, they do not express co-stimulatory molecules, which likely contributes to their protection from host antitumor immunity. To stimulate NHL-specific immune responses, we attempted to transfer the human CD40 ligand (hCD40L) gene to B-NHL cells and enhance their co-stimulatory potential. We found that an adenoviral vector encoding human CD40L (AdhCD40L) was ineffective at transducing B-NHL cells because these cells lack the coxsackievirus B-adenovirus receptor and αv integrins. However, preculture of the B-NHL cells with the human embryonic lung fibroblast line, MRC-5, significantly up-regulated expression of integrin αvβ3 and markedly increased their susceptibility to adenoviral vector transduction. After prestimulation, transduction with AdhCD40L increased CD40L expression on B-NHL cells from 1.3±0.2% to 40.8±11.9%. Transduction of control adenoviral vector had no effect. Expression of transgenic human CD40L on these CD40-positive cells was in turn associated with up-regulation of other co-stimulatory molecules including B7-1/-2. Transduced B-NHL cells were now able to stimulate DNA synthesis of autologous T cells. However, the stimulated T cells were unable to recognize unmodified lymphoma cells, a requirement for an effective tumor vaccine. Based on previous results in an animal model, we determined the effects of combined use of B-NHL cells transduced with AdhCD40L and AdhIL2 vectors. The combination enhanced initial T-cell activation and generated autologous T cells capable of specifically recognizing and killing parental (unmodified) B-NHL cells via major histocompatibility complex-restricted cytotoxic T lymphocytes. These findings suggest that the combination of CD40L and IL2 gene-modified B-NHL cells will induce a cytotoxic immune response in vivo directed against unmodified tumor cells.

Original languageEnglish (US)
Pages (from-to)378-387
Number of pages10
JournalCancer Gene Therapy
Volume8
Issue number5
DOIs
StatePublished - 2001

Keywords

  • Adenovirus
  • CD40 ligand
  • Cytotoxic T lymphocyte
  • Interleukin-2
  • Non-Hodgkin's lymphoma

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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