Immunotherapy for Infectious Diseases

Dendritic Cells 109
complete tumor regression, including one who entered the trial with bulky disease and
remained in complete remission for more than 3 years. A third patient experienced a partial
response, whereas three have had stable disease and three have experienced disease
progression. Recently, a new cohort of patients has been vaccinated while in remission,
and their follow-up is ongoing.
Two vaccine trials for melanoma have also been reported in which the immunogenicity
of DCs pulsed with a panel of melanoma-derived HLA-restricted peptides was
investigated. Both trials utilized DC derived from monocytes by culture in GM-CSF
and IL-4. Nestle et al. limited their clinical trial to patients expressing the HLA*A1
or A2 alleles and reported that 5 of 15 patients developed clinical responses including
2 who developed complete remissions (115). Induction of delayed-type hypersensitivity
(as measured by skin testing) to the antigen was seen with this vaccination approach.
Lotze et al. also reported the results of their clinical trial in melanoma with one complete
response in their cohort of six patients (116).
Recently, we treated a cohort of advanced colorectal cancer patients with recombinant
Flt3 ligand, a hematopoietic growth factor, and observed a 20-fold increase in circulating
DC (119). Subsequently, these cells were isolated and loaded with a synthetic
peptide derived from carcinoembryonic antigen (CEA) and mutated at a single amino
acid position to make it a more potent T cell antigen. Following vaccination with these
cells, more than half of the patients developed CD8 cytotoxic T cells that recognized
tumor cells expressing endogenous CEA. Moreover, two of 12 patients experienced
dramatic tumor regression and several other patients had stable disease. Finally, clinical
response correlated with the expansion of CEA specific CD8 T cells, confirming
the role of such cells in this treatment strategy. Based on these encouraging results, a
number of investigators are now pursuing DC-based clinical trials in patients with a
variety of malignancies.
FUTURE DIRECTIONS
Although DC-based vaccination trials have yielded promising results, particularly in
cancer, the procedures used to date to isolate, load, and activate DCs are cumbersome. As
discussed in this review, newer methods for DC mobilization or expression appear to
address problems related to cell yield. The potential benefits of coadministration of
immunomodulatory cytokines with DCs is another new area being explored. Preliminary
results of animal studies in which IL-12 and DC are coadministered have been encouraging.
Similarly, synergistic effects of IL-2 with DC vaccination have been demonstrated in
an animal model (131). Efforts to genetically engineer DCs to augment their secretion of
cytokines and/or chemokines (immune-enhanced DCs) are also advancing. For example,
DC precursors transfected with retroviral vectors containing IL-12 and IFN-� and pulsed
with H. capsulatum, Leishmania donovani, and Mycobacterium kansasii antigens have
been used to generate antigen-specific CD8� T-cell responses in an in vitro system (132).
The antiinfective efficacy of Th1 cytokines delivered by genetically modified and microbial
antigen-pulsed DCs in animal models of tuberculosis and leishmaniasis is also under
investigation (132). Eventually, however, simpler forms of therapy that utilize DCs must
be developed before the properties of this cell type can be exploited widely in clinical
practice. Identification of agents that induce DC maturation, in vivo, combined with methods
of delivering antigens of interest to DC in vivo, would provide an elegant solution.