B7.1 and Cytokines
- PDF / 244,123 Bytes
- 10 Pages / 468 x 720 pts Page_size
- 80 Downloads / 217 Views
B7.1 AND CYTOKINES Synergy in Cancer Gene Therapy
Marcel Kuiper1, Raquel Sanches1, Yves-Jean Bignon1, and Farzin Farzaneh2 1
Laboratoire de Thérapie Génique Humaine et Expérimentale INSERM CRI 9502 & EA 2145 Centre Jean Perrin, BP 392 63011 Clermont-Ferrand Cedex 1 France and 2 Immune Gene Therapy of Cancer Programme Department of Molecular Medicine King’s College School of Medicine and Dentistry Rayne Institute, 123 Coldharbour Lane London SE5 9NU, UK
1. INTRODUCTION Despite the existence of tumour-specific ‘cytotoxic’ T lymphocytes (CTL) in cancer patients, an effective immune response against neoplastic cells is rarely detectable. To avoid immune attack, tumour cells often secrete immunosuppressive cytokines like transforming growth factor vascular endothelial growth factor (VEGF) and interleukin-(IL-)10, or induce apoptosis in Fas-expressing effector cells by expressing the Fas ligand (FasL) (Chouaib, Asselin-Paturel, Mami-Chouaib, Caignard, and Blay, 1997). However, environmental factors, including, paradoxically, often block the elimination, via apoptosis, of these tumour-reactive CTL (Akbar and Salmon, 1997). The challenge of cancer immunotherapy and immune gene therapy is therefore to overcome this immunosuppression and reactivate suppressed tumourspecific CTL. Tumour cells genetically modified to express immunomodulatory factors are able to stimulate tumour-reactive CTL in a number of animal tumour models (Musiani, Modesti, Giovarelli, Cavallo, Colombo, Lollini, and Forni, 1997; Mackensen, Lindemann, and Mertelsmann, 1997). However, the efficacy of the introduction of such a gene, for example encoding the membrane-bound costimulator B7.1 (see below), may depend on the inherent immunogenicity of the tumour (Chen, McGowan, Ashe, Johnston, Li, Hellström, and Hellström, 1994). One approach to circumvent this problem, is Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/ Plenum Publishers, New York, 2000.
381
382
M. Kuiper et al.
the introduction of combinations of genes encoding immunomodulators, thereby providing a stronger immunostimulatory signal. This Chapter describes pre-clinical cancer gene therapy studies combining the genes encoding two types of immunomodulatory molecules, namely for membrane-bound B7.1 (CD80) and for secreted cytokines such as IL-2 and IL-12. The encouraging results in such animal tumour models have prompted the initiation of a number of clinical trials.
2. SINGLE-GENE CANCER IMMUNE GENE THERAPY
2.1. B7.1 (CD80) B7.1 is a highly glycosylated, membrane-bound ligand which is expressed by antigen-presenting cells (APC) including B lymphocytes, macrophages and dendritic cells. The receptors for this molecule, CD28 and CTLA4 (CD 152) are mainly found on T lymphocytes (Galea-Lauri, Farzaneh, and Gäken, 1996), although it is noteworthy that
CD28 is also expressed by murine and human natural killer (NK) cells, and involved in the activation of these cells (Azuma, Cayabyab, Buck, Phillips, and Lanier, 1992; GaleaLauri, Darling, Kuiper, Gä
Data Loading...
