The CD40CD40L Pathway

The Revised Authoritative Guide To Vaccine Legal Exemptions

Vaccines Have Serious Side Effects

Get Instant Access

CD40 is a member of the tumor necrosis factor receptor (TNFR) family (62-65) broadly expressed on antigen-presenting cells (APCs), B cells, epithelial cells, and endothelial cells (66). Engagement of CD40 on APCs by its ligand CD40L (CD154) on responding T cells augments the resulting immune response (66). Exogenous activation of the CD40 pathway by agonist antibodies is capable of substituting for T-cell help (67), and augments both humoral and CTL responses (68). Manipulation of the CD40 pathway by engineering chronic lymphocytic leukemia (CLL) cells to overexpress CD40L by adenoviral gene transfer induces the expression of multiple costimulatory molecules. This augments the antigen-presenting capacity of both CD40L-modified CLL cells and unmodified bystander CLL cells in vitro, enabling both of them to prime CTL specific for autologous CLL (69). CD40L modification also augments the antigen-presenting capacity of human multiple myeloma cells in vitro (70,71). The ability of CD40L-modified cells to induce immune-mediated tumor regression in vivo has been demonstrated in animal models of B-cell lymphoma (72), melanoma (73), colon carcinoma (73), and bladder carcinoma (74). One clinical trial tested the infusion of autologous CLL modified with a replication-defective adenoviral vector delivering CD40L in 11 patients with progressive intermediate- or high-risk CLL (75). This therapy increased the expression of CD80, CD86, ICAM-1, and CD95 on uninfected CLL in vivo. Treated patients developed high plasma levels of the T helper type 1 cytokines IL-12 and IFN-y, increases in absolute T-cell counts over 240%, and increased numbers of CLL-specific, IFN-y-producing T cells by ELISPOT. These immune responses correlated with clinical responses as measured by reduced lymphocyte counts and lymph node size. Together, these data support the further investigation of CD40L-modified tumor cell vaccines for the treatment of both hematologic and solid-tumor malignancies.

Table 3

Cytokine Genes Transferred to Tumor Cells for Vaccine Development

Table 3

Cytokine Genes Transferred to Tumor Cells for Vaccine Development

Was this article helpful?

0 0

Post a comment