Antitumor responses induced by transgenic expression of CD40 ligand.
Hum Gene Ther. 1997 Nov 1;8(16):1935-43. Unique Identifier : AIDSLINE MED/98043307 Grossmann ME; Brown MP; Brenner MK; Division of Bone Marrow Transplantation and Cell and Gene Therapy; Program, St. Jude Children's Research Hospital, Memphis, TN 38105,; USA.
Abstract:
Because CD40 ligand (CD40L) is a co-stimulator molecule for multiple components of the immune response, we wanted to determine whether transgenic expression of the molecule would increase immune responses against a weakly immunogenic murine tumor, neuro-2a. Tumor cells were transduced with a retroviral construct containing the CD40L gene and co-injected with variable numbers of non-CD40L transduced cells into syngeneic mice. Mice injected with cells that expressed CD40L had a significant reduction in average tumor size as compared to controls (p < 0.0001). In addition, survival of the neuro-2a/CD40L mice was 48 days versus 34 days for the neuro-2a/neo controls (p < 0.02). Expression of CD40L by less than 1.5% of neuro-2a cells was sufficient for significant antitumor effects (p < 0.001). These antitumor effects protected mice from subsequent challenge with parental neuro-2a cells. The protective effects of CD40L were associated with systemic immunomodulation. In vivo depletion of CD8+ cells abrogated the CD40L-mediated antitumor effects. Analysis of spleens from CD40L-protected animals showed increased numbers of CD4+ and CD8+ cells, the majority of which co-expressed the activation marker CD25. In addition, an increased number of antigen-presenting cells (APCs) expressed the co-stimulatory molecule CD86. These experiments illustrate that transducing even a small percentage of tumor cells with CD40 ligand can create a long-lasting systemic immune response capable of impeding growth of unmodified neuroblastoma cells.
Keywords: *Gene Transfer *Membrane Glycoproteins/GENETICS *Neuroblastoma/IMMUNOLOGY *Neuroblastoma/THERAPY *Transgenes 980430
M9841855
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