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

Cancer Gene Therapy volume 8, pages 378–387 (2001)Cite this article

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 cellsvia 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 responsein vivo directed against unmodified tumor cells. Cancer Gene Therapy (2001) 8, 378–387

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Acknowledgements

We thank Vien Holcombe for excellent technical assistance and Xiuwei Xu for vector preparation. We are grateful for the persistent and reliable support of Brian Newsom, Mike Cubbage, Tatiana Gotsolva, Nirmali Ponweera, and April Durett of the Flow Cytometry Core Facility for FACS analyses. We also thank Gloria Levin for help in preparing this manuscript. This study was supported by National Institutes of Health Grant nos. RO1 CA75014 and RO1 CA78792.

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Authors and Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas

    Satoshi Takahashi, Patricia Yotnda, Raphael F Rousseau, Zhuyong Mei, Susan Smith, Donna Rill & Malcolm K Brenner

  2. Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, Texas

    Anas Younes

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  1. Satoshi Takahashi
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Correspondence to Malcolm K Brenner.

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Takahashi, S., Yotnda, P., Rousseau, R. et al. Transgenic expression of CD40L and interleukin-2 induces an autologous antitumor immune response in patients with non-Hodgkin's lymphoma. Cancer Gene Ther 8, 378–387 (2001). https://doi.org/10.1038/sj.cgt.7700315

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