Immunotherapy for Infectious Diseases

108 Kundu-Raychaudhuri and Engleman
proliferative responses. A recipient of autologous DC with a CD4� T-cell count of
723/mm 3 showed an increase in peptide-specific lymphocyte-proliferative responses
after three infusions. There was a good correlation between the presence of specific
virus sequences obtained by bulk plasma viral RNA sequencing and peptide-specific
endogenous CTL responses measured by both direct and indirect CTL assays. Thus,
these responses appeared to be recall responses. Three other allogeneic DC recipients
with CD4� T-cell counts �410/mm 3 did not show increases in their HIV-specific
immune responses.
No clinically significant adverse effects were noted in this study and CD4� T-cell numbers
and plasma HIV-1 RNA detected by reverse transcriptase polymerase chain reaction of
all seven patients were stable during the study period. Thus, both allogeneic and autologous
DC infusions were well tolerated, and in patients with normal or near normal CD4�
T-cell counts, administration of these antigen-pulsed cells enhanced the immune response
to HIV. Future studies of HIV antigen-pulsed DC infusion in HIV-infected patients will
be required to determine whether this approach is clinically beneficial.
Cancer Trials
In contrast to infectious disease, a number of groups are pursuing DC-based
immunotherapy trials for cancer. In the first reported DC trial, our group assessed the
effect of autologous DCs pulsed ex vivo with tumor-specific antigen in patients with
malignant B-cell lymphoma who had failed conventional chemotherapy. Like other Blymphocytes,
the neoplastic cells in these patients express surface immunoglobulin
receptors, and because B-cell lymphomas are monoclonal, all the cells of a given tumor
express identical surface immunoglobulin. Moreover, this immunoglobulin is potentially
immunogenic by virtue of its unique idiotypic determinants, which are formed
by the combination of the variable regions of immunoglobulin heavy and light chains
(127–129). To prepare idiotype proteins for this clinical study, patients underwent
tumor biopsies, and the immunoglobulin (idiotype) produced by each tumor was “rescued”
by somatic cell fusion techniques and purified from hybridoma supernatants
(130). This protein, together with keyhole limpet hemocyanin, which served as a control
antigen, was used to pulse autologous DCs obtained from the patients by leukapheresis,
and the antigen-pulsed cells were administered to the patients by intravenous
infusion. This procedure was repeated three times at monthly intervals with a booster
immunization given 4–6 months later. Throughout the trial the patients were followed
for the development of an immune response to the idiotype, and their tumor burden
was monitored.
A report of the results obtained in our initial four patients has been published (108).
All of these treated patients, as well as six not described in our published report, tolerated
their infusions well, and none experienced clinically significant toxicity at any
point during the study. In addition, most of the patients developed T-cell-mediated antiidiotype
responses that were not observed prior to treatment initiation. The antiidiotype
responses were specific for autologous tumor immunoglobulin compared with irrelevant,
isotype-matched immunoglobulins. In addition to these proliferative responses,
T-cells from one patient were expanded for several weeks in vitro in the presence
of idiotype protein and shown to lyse autologous tumor hybridoma cells but not an
isotype-matched, unrelated hybridoma. Most importantly, two of the patients experienced