Autologous antileukemic immune response induced by chronic lymphocytic leukemia B cells expressing the CD40 ligand and interleukin 2 transgenes

S. Takahashi, R. F. Rousseau, P. Yotnda, Z. Mei, G. Dotti, D. Rill, R. Hurwitz, F. Marini, M. Andreeff, M. K. Brenner

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Although the B cells of chronic lymphocytic leukemia (B-CLL cells) express both tumor-specific peptides and major histocompatibility complex (MHC) class I antigens, they lack the capacity for costimulatory signaling, contributing to their protection against host antitumor immunity. To stimulate CLL-specific immune responses, we sought to transfer the human CD40 ligand (hCD40L) gene to B-CLL cells, using an adenoviral vector, in order to upregulate costimulating factors on these cells. Because efficient gene transduction with adenoviral vectors requires the expression of virus receptors on target cells, including the coxsackievirus B-adenovirus receptors (CAR) and αv integrins, we cocultured B-CLL cells with human embryonic lung fibroblasts (MRC-5 line). This exposure led to increased expression of integrin αvβ3 on B-CLL cells, which correlated with higher transduction rates. Using this novel prestimulation system, we transduced B-CLL cells with the hCD40L gene. The Ad-hCD40L-infected cells had higher expression of B7 molecules and induced activation of autologous T cells in vitro, but these T cells could not recognize parental leukemic cells. By contrast, an admixture of Ad-hCD40L-positive cells and leukemic cells transduced with the human interleukin 2 (IL-2) gene produced greater T cell activation than did either immunostimulator population alone. Importantly, this combination generated autologous T cells capable of specifically recognizing parental B-CLL cells. These findings suggest that the combined use of genetically modified CD40L-expressing B-CLL cells in combination with IL-2-expressing B-CLL cells may induce therapeutically significant leukemia-specific immune responses.

Original languageEnglish (US)
Pages (from-to)659-670
Number of pages12
JournalHuman Gene Therapy
Volume12
Issue number6
DOIs
StatePublished - Apr 9 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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