Cytokine gene transfer into tumor cells has been shown subsequent first clinical phase I study six patients with to mediate tumor regression and antimetastatic effects in metastatic melanoma were vaccinated with autologous, several animal models via immunomodulation. Therefore, interleukin-12 gene-modified tumor cells. Melanoma cells clinical protocols have been developed to treat cancer were expanded in vitro from surgically removed metastpatients with cytokine gene-modified tumor cells. We ases, transduced by ballistic gene transfer, irradiated and inserted the genes coding for the p35 and p40 chain of were then injected subcutaneously (s.c.) at weekly interinterleukin-12 (IL-12) in two independent eukaryotic vals. Clinically, there was no major toxicity except for mild expression vectors and transduced melanoma cells of 15 fever. All patients completed more than four s.c. vaccidifferent primary tumor cultures with both plasmids by a nations over 6 weeks and were eligible for immunological ballistic gene transfer approach. Secreted IL-12 demonevaluation. Post-vaccination, peripheral mononuclear cells strated strong bioactivity by inducing interferon-␥ release were found to contain an increased number of tumorfrom peripheral blood lymphocytes upon coculture with cell reactive proliferative as well as cytolytic cells as determculture supernatants after IL-12 gene transfer which could ined by a limiting dilution analysis in two patients. Two at least partly be blocked by IL-12-specific antisera. Further patients developed DTH reactivity against autologous enrichment of transduced tumor cells by magnetic separmelanoma cells and one had a minor clinical response. ation directly after gene transfer increased cytokine Biopsies taken from that patient's metastases revealed a secretion from a mean of 119 pg in the unsorted to 507 heavy infiltration of CD4 + and CD8 + T lymphocytes. In conpg IL-12 (24 h/10 6 cells) in the magnetically enriched cell clusion, vaccination induced immunological changes even fraction. Irradiation of these cells led to a further elevation in a group of advanced, terminally ill patients. These of secreted IL-12 (mean 987 pg). Elevated IL-12 levels changes can be interpreted as an increased antitumor were detected over 7 days after irradiation in vitro. In a immune response.

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Graft-versus-hose disease (GVHD) and infections are the major complications of allogeneic peripheral blood progenitor cell (PBPC) transplantation. Isolated acute hepatic GVHD is an uncommon complication that is difficult to distinguish from hepatic failure owing to therapy-related toxicity, infections, or veno-occlusive disease. 1 Liver biopsy is diagnostic, characterized by a lymphocytic infiltrate localized mainly in the portal tract. 2 The clinical severity of it is monitored by measuring serum bilirubin, aminotransferases, and alkaline phosphatase. If standard immunosuppressive medications (corticosteroids, cyclosporine, antithymocyte globulin, micofenolate, and tacrolimus) fail to control acute hepatic GVHD, the disease may progress to fatal hepatic failure. Extracorporeal photochemotherapy (ECP) is a therapeutic alternative for patients who do not respond to immunosuppressive medications. 3,4 We report our experience using ECP for acute hepatic GVHD in a 2-year-old girl after two consecutive PBPC transplants for hemophagocytic lymphohistiocytosis (HLH or Griscelli syndrome), a rare autosomal recessive disorder characterized by lymphocytic and macrophage activation, skin and hair pigment dilution, and dysregulation of the immune system. The only curative treatment for HLH is progenitor cell transplantation. 5 Both transplants were PBPCs from her HLA-haploidentical mother.The patient came to our center 76 days after the second transplant with jaundice, moderate hepatomegaly, and weakness. Her treatment consisted of tacrolimus (2.5 mg/daily) plus methylprednisolone (40 mg/daily). Laboratory findings included a total bilirubin level of 8.2 mg per dL (conjugated bilirubin, 7 mg/dL); aspartate aminotransferase (AST), 447 mU per mL; alanine aminotransferase (ALT), 567 mU per mL; g -glutamyltransferase ( g GT), 1074 mU per mL; and alkaline phosphatase, 878 mU per mL. Hematologic analysis included a hemoglobin (Hb) level of 8 g per dL; hematocrit (Hct), 27 percent; white blood cell count, 4.6 ¥ 10 3 per m L (lymphocytes, 1.3 ¥ 10 3 / m L; monocytes, 0.12 ¥ 103/ m L); and PLT count, 184 ¥ 10 3 / m L. Full donor chimerism was documented. Liver biopsy revealed cholestasis, diffuse hydropic hepatocyte degeneration, lymphocytic infiltrate of portal tract with cholangitis, and reactive atypia of biliary epithelium.We began ECP immediately (3 procedures per week), following our standard (Pavia) protocol for children 6 with the following changes. Because of the patient's fragile clinical status, together with her low body weight, we primed the cell separator with irradiated RBCs diluted with 0.9 percent sodium chloride to a Hct level of 32 percent (taking care to maintain the patient's Hb level > 9 g/dL). Additional precautions included a blood warmer on the return blood line and a continuous infusion of calcium gluconate. After 7 ECP procedures, there were decreased bilirubin (total, 7.3 mg/dL; conjugated, 5.6 mg/dL), AST (170 mU/mL), and ALT (492 mU/mL) levels. Methylprednisolone was tapered to 30 mg daily; tacrolimus wa...