Dendritic Cell Based Vaccines

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Dendritic cells (DC) are the most potent cells known in humans that prime and stimulate T-cell responses, and they are highly specialized cells which process and present antigens to immune cells. DCs have been grown from a variety of precursors, including peripheral blood monocytes, as well as selected CD34+ progenitors, and a number of cytokines and maturing stimuli have been used to generate human DC ex vivo for clinical trials of adoptive transfer after pulsing with antigen. Nestle and colleagues intravenously administered mature monocyte-derived DC cultured in vitro with IL-4 and GM-CSF and pulsed with tumor antigen peptides and/or tumor lysate to patients with stage IV melanoma.117 Five CR or PR were observed in 16 patients,118 and the trial has been extended to a larger multicenter Phase II trial.

Seven patients with metastatic melanoma received gp100 and MART-1 peptide-pulsed monocyte-derived DC.119 DC were administered intravenously four times at 3-week intervals in escalating doses. Only one of seven patients evaluated demonstrated an objective PR. Enhancement of CTL reactivity was seen in one of five patients who completed all four vaccines.

Eleven stage IV melanoma patients received mature monocyte-derived DC loaded with a MAGE-3A1 peptide.120 The patients received five vaccinations at 2-week intervals. The first three vaccinations were administered subcuta-neously and the last two were administered intradermally. Six of 11 patients had regression of their disease. ELISPOT assays indicated that peptide-specific CTL precursors were expanded in 8 of 11 patients. Intriguingly, immune responses declined after the regimen of injections.

Fourteen patients with malignant melanoma were given four intravenous injections of DC derived from CD34+ stem cells and matured with tumor necrosis factor (TNF)-a then pulsed with HLA-A1+ MAGE-1 and MAGE-3 peptides or with HLA-A2+ Melan-A, gp100, and tyrosinase peptides.121 Antitumor responses were observed in 2 patients and peptide-specific DTH reactions were found in 4.

Banchereau et al. immunized 11 patients with CD34+ progenitor-derived mature DC and achieved 3 CR. They showed that clinical response correlated with immune responses detected in the peripheral blood,122 and they have continued to treat patients with mature CD34-derived DC with excellent clinical results.

The CEA CAP1-6D-substituted peptide was pulsed onto DC in the presence of Flt3 ligand, a DC growth factor, in 12 patients with lung or colorectal cancer who were HLA A*0201+. Patients received subcutaneous cytokine for 10 days before immunization with escalating doses of intravenous peptide-pulsed DC. Lytic activity against target cells bearing CAP1-6D, as well as native CEA peptide, was observed in 7 of 12 patients. Five patients showed evidence of tumor regression, with 1 CR, 1 PR, 1 MR, and 2 with SD.

Evidence of clinical response correlated with the expansion of antigen-specific CTL by tetramer analysis. Dendritic cells that have been pulsed with autologous tumor lysates have been shown to mediate regression of pediatric tumors, including neuroblastoma and Ewing's sarcoma.123,124

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