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

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 alpha(v) integrins. However, preculture of the B-NHL cells with the human embryonic lung fibroblast line, MRC-5, significantly up-regulated expression of integrin alpha(v)beta 3 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.

• Authors: S Takahashi, P Yotnda, R F Rousseau, Z Mei, S Smith, D Rill, A Younes, M K Brenner
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 8 Issue 5 Pg. 378-87 (May 2001) ISSN: 0929-1903 [Print] England
• PMID: 11477458 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Autoantigens
• Integrins
• Interleukin-2
• Receptors, Virus
• CD40 Ligand
• Interferon-gamma

Topics

• Adenoviridae (genetics)
• Antibodies, Monoclonal
• Autoantigens (immunology)
• CD40 Ligand (genetics, immunology)
• Coculture Techniques
• Enzyme-Linked Immunosorbent Assay
• Fibroblasts (cytology)
• Flow Cytometry
• Humans
• Integrins (metabolism)
• Interferon-gamma (metabolism)
• Interleukin-2 (genetics, immunology)
• Lymphocyte Depletion
• Lymphoma, B-Cell (immunology, pathology, therapy)
• Receptors, Virus (metabolism)
• T-Lymphocytes, Cytotoxic (immunology)
• Transgenes (genetics)
• Tumor Cells, Cultured