CD40 ligand(Amgen, Inc.)

X-linked hyper IgM syndrome (XHM) is a combined immune deficiency disorder caused by genetic alterations in CD40 ligand. The purpose of this study was to investigate the safety and efficacy of recombinant CD40 ligand (rCD40L) in the treatment of the disease. Three children were administered rCD40L subcutaneously 3 times per week at 0.03 mg/kg for 22 weeks, and after a 12-week drug-free interval, the dose was increased to 0.05 mg/kg for an additional 22 weeks of treatment. Although specific antibody responses to T cell–dependent antigens was lacking, administration of rCD40 resulted in acquisition of the capacity to mount cutaneous delayed type hypersensitivity reactions that disappeared during the drug-free interval as well as the postbiologic follow-up period. With rCD40L treatment, patient T cells developed a new capacity to respond to T-cell mitogens with synthesis of IFN-γ and TNF-α. Intracellular cytokine staining studies showed that both CD4+ and CD8+ T cells participated in this response. Finally, CD40L therapy was associated with changes in lymph node size and architecture based on comparison of biopsies taken before and after therapy. This clinical study showed that rCD40L is capable of improving T cell–immune function in patients with XHM.

Vaccination with idiotype (Id) protein‐pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id‐ and keyhole limpet haemocyanin (KLH)‐pulsed, CD40 ligand‐matured DCs administered intranodally. Nine patients with smouldering or stable myeloma without treatment were enrolled and DC vaccines were administered at weekly intervals for a total of four doses. Following vaccination, all patients mounted Id‐specific γ‐interferon T‐cell response. Interleukin‐4 response was elicited in two, and skin delayed‐type hypersensitivity reaction occurred in seven patients. More importantly, Id‐specific cytotoxic T‐cell responses were also detected in five patients. Most if not all patients mounted a positive T‐cell response to KLH following vaccination. At 1‐year follow‐up, six of the nine patients had stable disease, while three patients had slowly progressive disease even during the vaccination period. At 5‐year follow‐up, four of the six patients continued with stable disease. No major side effects were noted. In summary, intranodal administration of Id‐pulsed CD40 ligand‐matured DCs was able to induce Id‐specific T and B‐cell responses in patients. Current efforts are geared towards breaking tumour‐mediated immune suppression and improving clinical efficacy of this immunotherapy.