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Immunology |
Baylor Institute for Immunology Research, Dallas, Texas 75204 [J. B., A. K. P., S. B., N. T., A. R., S. T., S. C., L. P., J. F.]; Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021-6399 [M. D., N. B., R. S.]; and General Clinical Research Center, The Rockefeller University Hospital, New York, New York 10021-6399 [K. M. W.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DCs4 are antigen-presenting cells specialized to initiate and regulate immune responses (10 , 11) . Their clinical use as adjuvants has been aided by the development of methodologies to generate large numbers of these cells in culture from blood monocytes (12 , 13) or CD34+ progenitors (14) . In contrast to Mo-DCs, DCs derived from CD34+ cells consist of two phenotypically and functionally distinct populations (15) . One subset is similar to the epidermal LCs, and the other termed "interstitial/dermal DCs" is similar to those derived from blood monocytes (15) . Immune responses to these unique LCcontaining preparations need to be evaluated in humans. Here we describe the safety and immunogenicity of antigen-bearing CD34-DCs in patients with stage IV melanoma.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Table 1
). Four patients (patients 1, 9, 12, and 13)
had CNS involvement treated by surgery and radiation before entry into the
trial,
four patients (2
, 4
, 5 , and 16)
had received prior chemotherapy, and
five patients (2
, 4
, 6
, 9
, and 15)
had received prior biological
therapy without a clinical or immune response (Table 1)
. Three patients
(3
, 13 , and 20)
progressed before completing the trial. Inclusion
criteria were: biopsy-proven American Joint Committee on Cancer
stage IV metastatic melanoma; age, 
18 years; Karnofsky performance
status, >80%; HLA-A*0201 phenotype; intradermal skin test
positivity to mumps, histoplasmosis, or streptokinase antigen; normal
blood CD4 and CD8 T-cell numbers by flow cytometry; and normal
quantitative immunoglobulin levels. Exclusion criteria were: prior
chemotherapy or biologicals <4 weeks before trial entry; untreated CNS
lesions; bulky hepatic metastatic lesions; pregnancy; or concurrent
corticosteroid/immunosuppressive therapy. Patients with history of
asthma, venous thrombosis, congestive heart failure, autoimmune
disease, or active infections, including viral hepatitis, were also
excluded. All of the patients were presented with several treatment
alternatives, including surgery, high-dose cytokines, chemotherapy, or
alternative immunotherapy. Patients were unlikely to be cured with
surgery because of the presence of visceral metastases in most
patients, including CNS involvement. Patient 10 had recurrent disease
close to a prior biopsy site and refused further surgery. All of the
patients gave a written informed consent, and the study was approved by
the Food and Drug Administration, the NCI, and the Institutional Review
Board. Patients received a 6-week outpatient vaccination course with
antigen-loaded CD34-DCs given s.c. every 14 days for a total of four
vaccinations. DCs were administered in a dose-escalation design at the
dose level per cohort of 0.1, 0.25, 0.5, and 1 x 106 DCs/kg/injection. The calculated DC dose was
the actual number of CD1a+ and CD14+ cells in the cell preparation (see
below).
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Preparation of DC Vaccine.
All procedures were performed according to Good Laboratory Practice
standards. CD34-DCs were generated from CD34+ HPC
by culture at a concentration of 0.5 x 106/ml culture medium (X-VIVO-15; BioWhittaker)
supplemented with autologous serum, 10-5
M 2-ß-mercaptoethanol and 1% L-glutamine.
The following human recombinant cytokines, approved for clinical use,
were used: GM-CSF (50 ng/ml; Immunex Corp.), FLT3-L (100 ng/ml; Immunex
Corp.), and TNF (10 ng/ml; CellPro, Inc.). Cultures were conducted in a
humidified incubator at 37°C and 5% CO2 with a
separate incubator being assigned to each patient. On day 8 of culture,
all of the cells were pulsed overnight with KLH (2 µg/ml; Intracell),
20% of the cells were pulsed separately with HLA-A*0201 restricted
Flu-MP GILGFVFTL58–66 (2.5 µg/ml), and 80% of
the cells were pulsed overnight with a mix of four HLA-A201 restricted
peptides (2.5 µg/ml) derived from MelAgs
(MelanA/MART-127–35: AAGIGILTV;
gp100g209–2 M: IMDQVPFSV;
tyrosinase368–376: YMDGTMSQV; and
MAGE-3271–279: FLWGPRALV). After overnight
loading, all of the DCs were washed three times with sterile saline and
were counted and resuspended in 10 ml of sterile saline containing
melanoma peptides (1 µg/ml). After 2-h incubation at 22°C, the
cells were centrifuged and resuspended in 9 ml of sterile saline for
injection. All of the peptides were Good Manufacturing Practice (GMP)
quality and were either obtained from the NCI (MelanA/MART-1, gp100,
and tyrosinase) or purchased (Flu-MP and MAGE-3; MultiPeptide Systems,
San Diego, CA). Vaccine release criteria included: (a)
negative bacterial culture 48 h prior to DC injection;
(b) negative Gram’s staining after antigen pulsing;
(c) DC morphology on Giemsa-stained cytospins performed
2 h before DC administration, (d) cell viability
>80%; and (e) a minimum of 20% DCs (CD1a+ and CD14+) in
cell preparation as determined by phenotypic analysis. The remaining
cells contained DC precursors as well as cells with the ability to
induce mixed lymphocyte reaction (not shown). Further quality
testing of each DC batch included: (a) reactivity with a
panel of monoclonal antibodies; and (b) determination of
their stimulatory capacity in mixed lymphocyte reactions.
Administration of Vaccine.
Vaccination was administered s.c. in three injection sites (both thighs
and the upper arm). Limbs from which draining lymph nodes had been
surgically removed and/or irradiated were not injected. DCs were
injected using a long spinal-cord needle and were spread over a 6- to
8-cm distance.
Clinical Monitoring
Adverse events were graded according to the NCI Common Toxicity
Criteria. All of the patients underwent assessment of tumor status at
baseline and 4 weeks after the fourth DC vaccination (10 weeks from
trial entry). Disease progression was defined as >25% increase in
target lesions and/or the appearance of new lesions.
Immunological Monitoring
PBMCs samples from at least two time points before
vaccination, as well as 5 and/or 14 days after each vaccination and 14
or 28 days after the fourth vaccination, were harvested and frozen.
Pre- and postimmunization PBMCs were frozen in aliquots, coded, thawed
and assayed together in a blinded fashion.
Antigen-specific Proliferation
PBMCs (105 cells/well) were cultured in
triplicate wells in the absence or presence of graded doses of KLH at
1–10 µg/ml, and as a positive control, in the presence of
SEA. Assays were pulsed overnight with
[3H]thymidine on day 3 (SEA) or day 5 (KLH) of
culture and harvested 16 h later.
ELISPOT Assay for IFN-
Release from Single Antigen-specific T
Cells
ELISPOT assay for the detection of antigen-specific
IFN--producing T cells was performed as described previously
(16
, 17)
. Briefly, PBMCs (2 x 105 cells/well) were added to plates precoated
with 10 µg/ml of a primary anti-IFN- monoclonal antibody
(Mabtech, Stockholm, Sweden) in the presence or absence of 10 µg/ml
peptide antigens. The antigens were the same HLA A*0201-restricted
peptides (four melanoma peptides and Flu-MP) used in the DC vaccine.
HLA A*0201-restricted gag peptide was used as a negative
control, and SEA as a positive control for T-cell function. For some
experiments, depending on the cell yield, influenza virus-infected
PBMCs (MOI 2) were used as APCs. Antigen-specific SFCs were calculated
after subtracting the background obtained with control peptide. Immune
responses were scored as positive if the postimmunization measurements
for antigen-specific SFCs were >2-fold higher than the baseline and
>10 SFC/2 x 105 cells
(16)
.
Antigen-specific Recall T-cell Responses
To evaluate the ability of antigen-specific T cells to
proliferate and differentiate in culture, pre- and postimmunization
PBMCs were thawed together and cocultured (2 x 105 cells/well) for 7 days with autologous mature
DCs (PBMC:DC ratio, 30:1) pulsed with 1 µg/ml peptides. After 7 days,
cells were transferred to an ELISPOT plate and cultured overnight with
(T-cell:APC ratio, 20:1) irradiated (3000 rads) T2 cells with or
without specific antigen. Antigen-specific SFCs were calculated after
subtracting the background obtained with unpulsed T2 cells.
DTH Reactions
CD34-DCs (105), pulsed separately with
each antigen, were injected intradermally on the patient’s back and
induration at the injection site was measured at 48 h.
Statistical Analysis
The sign test for discretized data were used to
demonstrate the presence of specific immune response to KLH and Flu-MP
(18)
. Because the role of different MelAgs with regard to
protective immunity is not known, we integrated postvaccination
responses to all four MelAgs, as measured by both direct and recall
assays, into an immunity score using a nonparametric method based on
the marginal likelihood approach (19
, 20)
. To score
n individuals according to their immune response profiles,
one computes all rankings (permutations of numbers 1...
n) that are compatible with all pairwise orderings. An
immune response is considered higher if it is at least as high for each
of the eight variables and higher for at least one variable. A
patient’s immunity score is the average of the corresponding ranks
among the compatible rankings minus the expected score. All of the
immunized patients were included in the analysis in an "intent to
treat" approach.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, and FLT3-L yielded MHC class I+,
HLA-DR+, CD80+,
CD86low, and CD83low DCs
(not shown). Although CD83low, these DCs are not
considered immature because they are generated in the presence of
TNF- (a well-established DC maturation factor) and routinely induce
proliferation of allogeneic CD8 T cells (not shown). The DCs included
CD1a+CD14- LCs as well as
CD1a±CD14+ interstitial DC
precursors (intDC). The LC phenotype was confirmed by confocal
microscopy revealing Langerin staining in
CD1a+ DCs (not shown; 21
). The mean
proportion of CD1a+CD14-
cells was 9 ± 3% (range, 4–17%; median, 9%) and
that of CD1a±CD14+ cells
was 32 ± 9% (range, 19–52%; median, 30%). The
composition of DC vaccine for each patient is given in Table 3
.
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). There is no indication that higher DC doses induced
greater KLH-specific proliferation. Fifteen patients (all except
patients 3, 13, and 20) were evaluated for DTH after they completed the
vaccination protocol (four DC vaccines). Thirteen of these patients
(all except patients 1 and 19) developed DTH to KLH (median, 10 mm;
range, 6–47 mm). Of the 17 patients injected with Flu-MP-pulsed DCs
(all except patient 18 with a history of allergy to flu vaccine),
enhancement of Flu-MP-specific memory T-cell responses by at least one
assay was observed in 15 patients (all except patients 3 and 13; Table 2
; Fig. 2B
). The elicited T cells also recognized the
naturally processed antigen from flu-infected PBMCs (not shown). The
finding that all except two patients responded to both KLH and
Flu-MP-pulsed DCs indicates that patients with metastatic melanoma
enrolled in our study were immunocompetent.
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-producing cells
were detected in baseline blood samples (Table 2
; Fig. 3
). The response was considered as enhanced if there was a >2-fold
increase and a minimum of 10 MelAg-specific ELISPOTs (after subtracting
the values obtained from control wells) in postimmunization samples.
After DC vaccination, enhanced responses to 1 MelAgs were detectable
in uncultured T cells in 8 of 18 patients (Table 2)
. Five patients
showed increased responses to MAGE-3, four to MelanA/MART-1, five to
gp100, and seven to tyrosinase peptide (Table 2
; Fig. 3A
).
There is no indication that higher DC doses induce greater
melanoma-specific immunity. We conclude that MelAg-pulsed CD34-DCs lead
to enhancement of MelAg-specific circulating effectors in melanoma
patients.
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; Fig. 3B
), and 5 of these patients
(patients 1, 5, 9, 16, and 17) responded to all four melanoma peptides.
Overall Response to MelAgs
Overall, enhanced immunity to 1 MelAgs by at least one assay was
observed in 16 of 18 patients after DC vaccination. Of these, enhanced
immunity to two, three, or all four MelAgs was seen by at least one
assay in patients 3, 4, and 6, respectively. Thus, vaccination with
melanoma-peptide-pulsed CD34-DCs leads to enhanced immunity to several
MelAg peptides in melanoma patients.
DTH
Ten of 14 evaluated patients developed DTH to at least one peptide
after repeated DC vaccination. Thus, DTH to DCs pulsed with:
(a) MART-1 was observed in all 10 patients (median
induration, 7.5 mm); (b) MAGE-3 in 8 of 10 patients (median
induration, 9.5 mm); (c) tyrosinase in 8 of 10 patients
(median induration, 8 mm); and (d) gp100 in 9 of 10 patients
(median induration, 8 mm). In three patients, there was reactivity to
unpulsed DCs (erythema without induration (8 mm). There was no
correlation between the responses in blood and DTH.
Toxicity of DC Injection
Safety and tolerability were assessed with each DC vaccination and
1 month after the fourth vaccination. No patients developed injection
site erythema/irritation or systemic toxicity. Two patients (patients 4
and 8) with mild preexisting vitiligo developed progressive vitiligo
during the course of DC therapy (Table 1)
. Rheumatoid factor and
antithyroid antibodies were negative throughout the trial. The
antinuclear antibody titer of patient 8 was negative before the
first DC injection but increased to 1:80 after the fourth injection. No
clinical manifestations of autoimmune disease developed in this
patient.
Clinical Outcome.
Seven of 17 evaluable patients experienced tumor progression (PD, Table 1
). The remaining 10 patients did not progress at this time point (10
weeks from study entry). Among these, three patients (4
, 17
, and 21)
had neither new lesions nor progression of measurable disease; four
patients (5
, 8
, 12
, and 18)
with multiple lesions on entry experienced
regression at one or more disease sites; and three patients (1
, 9
, and 10)
, who had only limited disease on entry, cleared any evidence of
disease. Nonprogressing patients have received additional DC
vaccinations on a subsequent study; therefore, we cannot assess the
durability of these responses. Patient 5 has received additional
immunotherapy at another institution.
Correlation of Immunological Responses and Clinical Outcome
We first used >2-fold increase and 10 antigen-specific IFN-
ELISPOTS in the postvaccination assays as an indicator of immune
response (16)
. Two patients (3 and 13) who failed to
respond to either the control or MelAgs by any assay, experienced rapid
tumor progression and could not complete the planned therapy. Of 17
patients with evaluable disease, 6 of 7 patients who responded to zero,
one, or two MelAgs had PD on restaging 10 weeks after study entry
(Table 3)
. In contrast, tumor progression was seen in only 1 of the 10 patients
who responded to three or all four MelAgs (P = 0.002, Fisher exact test). Regression of >1 tumor metastases
were observed in seven of these patients.
To obtain an overall assessment of antitumor immunity after the DC
vaccination, we integrated data for absolute immune responses to all
four antigens by direct and recall assays into a tumor immunity score
(from -8.5 to +8.5), as described earlier (19
, 20) . By
this comprehensive analysis, tumor immunity is associated with clinical
outcome (P = 0.015). Six of the eight
patients with a negative score, but only 1 of the 9 patients with a
positive score, progressed (Fig. 4)
. Omitting data from the MAGE-3 epitope, which is thought to require an
immunoproteasome for presentation, yields similar results
(P = 0.009).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Injection of peptide-pulsed DCs correlates with enhanced immunity to multiple defined tumor antigens. The MelAg-specific T cells that were elicited after DC vaccine are functional and are detectable in effector T-cell assays without the need for prior ex vivo expansion. They are also capable of proliferation and effector function after short-term (1 week) coculture with antigen-bearing DCs, without the need for exogenous cytokines or multiple restimulations with antigen. The feasibility of eliciting immune response to multiple MelAgs suggests that tolerance to these self antigens, if present, may only be partial (23 , 24) .
The ability of DCs to elicit immune response to multiple tumor antigens in vivo may be clinically important. The development of T-cell response to multiple tumor antigens on peptide-pulsed DCs in this study was associated with a favorable early clinical outcome. Prior studies using chemical adjuvants have failed to reliably elicit immunity to MelAgs (25) . Improved results were obtained more recently with the use of modified peptides combined with IL-2 (26) . However, in most studies, limited clinical responses are observed, which may be attributable to targeting a limited number of epitopes.
We chose to test CD34-DCs because they are composed of two distinct DC subsets, LCs and interstitial DCs (15) . This contrasts with Mo-DCs, which are devoid of LCs (27) . Mo-DCs have been shown to act as immune adjuvants in healthy volunteers and in stage IV melanoma (16 , 17 , 22 , 28) . Injection of MAGE-3-pulsed Mo-DCs were recently shown to enhance circulating MAGE-3-specific active effectors in melanoma patients (29) . However, no clinical responses were observed, which may be attributable to the choice of the immunizing epitope or targeting of a single epitope. Others have reported that CD34-DCs can be more efficient than Mo-DCs in activating CTLs in vitro (30 , 31) . In the circumstances like the induction of tumor-specific CTLs, CD34-DCs could thus be advantageous. Another recent study evaluated CD34-DCs in advanced melanoma and found little clinical or immunological efficacy (32) . However, the DCs were cultured in the presence of IL-4 (which inhibits LC development; Ref. 27 ) and administered i.v. Controlled studies are needed to compare the immunogenicity of this new form of DCs (and their subsets) to those derived from blood monocyte precursors.
Although these data provide encouragement for targeting MelAgs using DCs in the clinic, additional studies are needed to establish and optimize their clinical efficacy. The patients who experienced favorable clinical outcome had relatively limited disease and no history of chemotherapy, which supports the concept of testing DC vaccines earlier, e.g., in a surgical adjuvant setting. Optimizing variables such as peptide loading, vaccine schedule, and DC maturation may further improve the immunogenicity of these DCs.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from Baylor Health Care
Systems Foundation, Falk Foundation, Cancer Research Institute (to
J. F.; Investigator award to M. D.), NIH [CA78846 (to
J. B.), CA 81138 to (M. D.), PO-1 CA84512 (to R. S.), and
MO-1-RR00102 (to Rockefeller General Clinical Research
Center)], and the American Cancer Society (to R. S.). 
2 J. B., A. K. P., and M. D.
contributed equally to the work.
3 To whom requests for reprints should addressed,
at Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, TX
75204. Phone: (214) 820-7450; Fax: (214) 820-4813; E-mail: j.banchereau{at}baylordallas.edu
4 The abbreviations used are: DC, dendritic cell;
LC, Langerhans cell; HPC, hematopoietic progenitor cell; GM-CSF,
granulocyte-macrophage colony-stimulating factor; FLT3-L, Flt3 ligand;
TNF, tumor necrosis factor; KLH, keyhole limpet hemocyanin; SEA,
staphylococcal enterotoxin A; SFC, spot-forming cell; DTH, delayed-type
hypersensitivity; CD34+-DC, CD34+-derived DC;
CNS, central nervous system; NCI, National Cancer Institute; PBMC,
peripheral blood mononuclear cell; ELISPOT, enzyme-linked immunospot;
MelAg, melanoma antigen; PD, progression of measurable disease and/or
new lesions; Mo-DC, monocyte-derived DC; IL, interleukin.
Received 3/ 2/01. Accepted 7/16/01.
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A. Grover, G. J. Kim, G. Lizee, M. Tschoi, G. Wang, J. R. Wunderlich, S. A. Rosenberg, S. T. Hwang, and P. Hwu Intralymphatic dendritic cell vaccination induces tumor antigen-specific, skin-homing T lymphocytes. Clin. Cancer Res., October 1, 2006; 12(19): 5801 - 5808. [Abstract] [Full Text] [PDF]
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R. J.C.L.M. Vuylsteke, B. G. Molenkamp, P. A.M. van Leeuwen, S. Meijer, P. G.J.T.B. Wijnands, J. B.A.G. Haanen, R. J. Scheper, and T. D. de Gruijl Tumor-Specific CD8+ T Cell Reactivity in the Sentinel Lymph Node of GM-CSF-Treated Stage I Melanoma Patients is Associated with High Myeloid Dendritic Cell Content. Clin. Cancer Res., May 1, 2006; 12(9): 2826 - 2833. [Abstract] [Full Text] [PDF]
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D. H. Schuurhuis, N. van Montfoort, A. Ioan-Facsinay, R. Jiawan, M. Camps, J. Nouta, C. J. M. Melief, J. S. Verbeek, and F. Ossendorp Immune complex-loaded dendritic cells are superior to soluble immune complexes as antitumor vaccine. J. Immunol., April 15, 2006; 176(8): 4573 - 4580. [Abstract] [Full Text] [PDF]
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I. I. Slukvin, M. A. Vodyanik, J. A. Thomson, M. E. Gumenyuk, and K.-D. Choi Directed Differentiation of Human Embryonic Stem Cells into Functional Dendritic Cells through the Myeloid Pathway. J. Immunol., March 1, 2006; 176(5): 2924 - 2932. [Abstract] [Full Text] [PDF]
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V. Lennerz, M. Fatho, C. Gentilini, R. A. Frye, A. Lifke, D. Ferel, C. Wolfel, C. Huber, and T. Wolfel The response of autologous T cells to a human melanoma is dominated by mutated neoantigens PNAS, November 1, 2005; 102(44): 16013 - 16018. [Abstract] [Full Text] [PDF]
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T. P. Moran, M. Collier, K. P. McKinnon, N. L. Davis, R. E. Johnston, and J. S. Serody A Novel Viral System for Generating Antigen-Specific T Cells J. Immunol., September 1, 2005; 175(5): 3431 - 3438. [Abstract] [Full Text] [PDF]
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N. Bertho, H. Adamski, L. Toujas, M. Debove, J. Davoust, and V. Quillien Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction Blood, September 1, 2005; 106(5): 1734 - 1741. [Abstract] [Full Text] [PDF]
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K. Mahnke, Y. Qian, S. Fondel, J. Brueck, C. Becker, and A. H. Enk Targeting of Antigens to Activated Dendritic Cells In vivo Cures Metastatic Melanoma in Mice Cancer Res., August 1, 2005; 65(15): 7007 - 7012. [Abstract] [Full Text] [PDF]
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M. Rossi and J. W. Young Human Dendritic Cells: Potent Antigen-Presenting Cells at the Crossroads of Innate and Adaptive Immunity J. Immunol., August 1, 2005; 175(3): 1373 - 1381. [Abstract] [Full Text] [PDF]
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L. M. Liau, R. M. Prins, S. M. Kiertscher, S. K. Odesa, T. J. Kremen, A. J. Giovannone, J.-W. Lin, D. J. Chute, P. S. Mischel, T. F. Cloughesy, et al. Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment Clin. Cancer Res., August 1, 2005; 11(15): 5515 - 5525. [Abstract] [Full Text] [PDF]
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A. A. Jungbluth, S. Ely, M. DiLiberto, R. Niesvizky, B. Williamson, D. Frosina, Y.-T. Chen, N. Bhardwaj, S. Chen-Kiang, L. J. Old, et al. The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation Blood, July 1, 2005; 106(1): 167 - 174. [Abstract] [Full Text] [PDF]
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A. H. Tien, L. Xu, and C. D. Helgason Altered Immunity Accompanies Disease Progression in a Mouse Model of Prostate Dysplasia Cancer Res., April 1, 2005; 65(7): 2947 - 2955. [Abstract] [Full Text] [PDF]
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S. J. Prasad, K. J. Farrand, S. A. Matthews, J. H. Chang, R. S. McHugh, and F. Ronchese Dendritic Cells Loaded with Stressed Tumor Cells Elicit Long-Lasting Protective Tumor Immunity in Mice Depleted of CD4+CD25+ Regulatory T Cells J. Immunol., January 1, 2005; 174(1): 90 - 98. [Abstract] [Full Text] [PDF]
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G. Parmiani, A. Testori, M. Maio, C. Castelli, L. Rivoltini, L. Pilla, F. Belli, V. Mazzaferro, J. Coppa, R. Patuzzo, et al. Heat Shock Proteins and Their Use as Anticancer Vaccines Clin. Cancer Res., December 15, 2004; 10(24): 8142 - 8146. [Full Text] [PDF]
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F. Ito, Q. Li, A. B. Shreiner, R. Okuyama, M. N. Jure-Kunkel, S. Teitz-Tennenbaum, and A. E. Chang Anti-CD137 Monoclonal Antibody Administration Augments the Antitumor Efficacy of Dendritic Cell-Based Vaccines Cancer Res., November 15, 2004; 64(22): 8411 - 8419. [Abstract] [Full Text] [PDF]
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R. J. C. L. M. Vuylsteke, B. G. Molenkamp, H. A. Gietema, P. A. M. van Leeuwen, P. G. J. T. B. Wijnands, W. Vos, P. J. van Diest, R. J. Scheper, S. Meijer, and T. D. de Gruijl Local Administration of Granulocyte/Macrophage Colony-stimulating Factor Increases the Number and Activation State of Dendritic Cells in the Sentinel Lymph Node of Early-Stage Melanoma Cancer Res., November 15, 2004; 64(22): 8456 - 8460. [Abstract] [Full Text] [PDF]
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Y. Sakai, B. J. Morrison, J. D. Burke, J.-M. Park, M. Terabe, J. E. Janik, G. Forni, J. A. Berzofsky, and J. C. Morris Vaccination by Genetically Modified Dendritic Cells Expressing a Truncated neu Oncogene Prevents Development of Breast Cancer in Transgenic Mice Cancer Res., November 1, 2004; 64(21): 8022 - 8028. [Abstract] [Full Text] [PDF]
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S. Cloosen, M. Thio, A. Vanclee, E. B. M. van Leeuwen, B. L. M. G. Senden-Gijsbers, E. B. H. Oving, W. T. V. Germeraad, and G. M. J. Bos Mucin-1 is expressed on dendritic cells, both in vitro and in vivo Int. Immunol., November 1, 2004; 16(11): 1561 - 1571. [Abstract] [Full Text] [PDF]
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D. W. O'Neill, S. Adams, and N. Bhardwaj Manipulating dendritic cell biology for the active immunotherapy of cancer Blood, October 15, 2004; 104(8): 2235 - 2246. [Abstract] [Full Text] [PDF]
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D. Avigan Dendritic Cell-Tumor Fusion Vaccines for Renal Cell Carcinoma Clin. Cancer Res., September 15, 2004; 10(18): 6347S - 6352S. [Abstract] [Full Text] [PDF]
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G. Ratzinger, J. Baggers, M. A. de Cos, J. Yuan, T. Dao, J. L. Reagan, C. Munz, G. Heller, and J. W. Young Mature Human Langerhans Cells Derived from CD34+ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells J. Immunol., August 15, 2004; 173(4): 2780 - 2791. [Abstract] [Full Text] [PDF]
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M. Di Nicola, C. Carlo-Stella, R. Mortarini, P. Baldassari, A. Guidetti, G. F. Gallino, M. Del Vecchio, F. Ravagnani, M. Magni, P. Chaplin, et al. Boosting T Cell-Mediated Immunity to Tyrosinase by Vaccinia Virus-Transduced, CD34+-Derived Dendritic Cell Vaccination: A Phase I Trial in Metastatic Melanoma Clin. Cancer Res., August 15, 2004; 10(16): 5381 - 5390. [Abstract] [Full Text] [PDF]
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M. Viguier, F. Lemaitre, O. Verola, M.-S. Cho, G. Gorochov, L. Dubertret, H. Bachelez, P. Kourilsky, and L. Ferradini Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells J. Immunol., July 15, 2004; 173(2): 1444 - 1453. [Abstract] [Full Text] [PDF]
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S. Mocellin, E. Wang, M. Panelli, P. Pilati, and F. M. Marincola DNA Array-Based Gene Profiling in Tumor Immunology Clin. Cancer Res., July 15, 2004; 10(14): 4597 - 4606. [Abstract] [Full Text] [PDF]
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D. Avigan, B. Vasir, J. Gong, V. Borges, Z. Wu, L. Uhl, M. Atkins, J. Mier, D. McDermott, T. Smith, et al. Fusion Cell Vaccination of Patients with Metastatic Breast and Renal Cancer Induces Immunological and Clinical Responses Clin. Cancer Res., July 15, 2004; 10(14): 4699 - 4708. [Abstract] [Full Text] [PDF]
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D. Schrama, R. Xiang, A. O. Eggert, M. H. Andersen, L. O. Pedersen, E. Kampgen, T. N. Schumacher, R. R. Reisfeld, and J. C. Becker Shift from Systemic to Site-Specific Memory by Tumor-Targeted IL-2 J. Immunol., May 15, 2004; 172(10): 5843 - 5850. [Abstract] [Full Text] [PDF]
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G. J. Ullenhag, J.-E. Frodin, M. Jeddi-Tehrani, K. Strigard, E. Eriksson, A. Samanci, A. Choudhury, B. Nilsson, E. D. Rossmann, S. Mosolits, et al. Durable Carcinoembryonic Antigen (CEA)-Specific Humoral and Cellular Immune Responses in Colorectal Carcinoma Patients Vaccinated with Recombinant CEA and Granulocyte/Macrophage Colony-Stimulating Factor Clin. Cancer Res., May 15, 2004; 10(10): 3273 - 3281. [Abstract] [Full Text] [PDF]
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R. Rouas, P. Lewalle, F. El Ouriaghli, B. Nowak, H. Duvillier, and P. Martiat Poly(I:C) used for human dendritic cell maturation preserves their ability to secondarily secrete bioactive IL-12 Int. Immunol., May 1, 2004; 16(5): 767 - 773. [Abstract] [Full Text] [PDF]
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K.-J. Liu, C.-C. Wang, L.-T. Chen, A.-L. Cheng, D.-T. Lin, Y.-C. Wu, W.-L. Yu, Y.-M. Hung, H.-Y. Yang, S.-H. Juang, et al. Generation of Carcinoembryonic Antigen (CEA)-Specific T-Cell Responses in HLA-A*0201 and HLA-A*2402 Late-Stage Colorectal Cancer Patients after Vaccination with Dendritic Cells Loaded with CEA Peptides Clin. Cancer Res., April 15, 2004; 10(8): 2645 - 2651. [Abstract] [Full Text] [PDF]
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S.-C. Yang, S. Hillinger, K. Riedl, L. Zhang, L. Zhu, M. Huang, K. Atianzar, B. Y. Kuo, B. Gardner, R. K. Batra, et al. Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity Clin. Cancer Res., April 15, 2004; 10(8): 2891 - 2901. [Abstract] [Full Text] [PDF]
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S. Yang and F. G. Haluska Treatment of Melanoma with 5-Fluorouracil or Dacarbazine In Vitro Sensitizes Cells to Antigen-Specific CTL Lysis through Perforin/Granzyme- and Fas-Mediated Pathways J. Immunol., April 1, 2004; 172(7): 4599 - 4608. [Abstract] [Full Text] [PDF]
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W. Chen, S. Antonenko, J. M. Sederstrom, X. Liang, A. S. H. Chan, H. Kanzler, B. Blom, B. R. Blazar, and Y.-J. Liu Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors Blood, April 1, 2004; 103(7): 2547 - 2553. [Abstract] [Full Text] [PDF]
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S. Vertuani, A. Sette, J. Sidney, S. Southwood, J. Fikes, E. Keogh, J. A. Lindencrona, G. Ishioka, J. Levitskaya, and R. Kiessling Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues J. Immunol., March 15, 2004; 172(6): 3501 - 3508. [Abstract] [Full Text] [PDF]
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C. M. Coughlin, B. A. Vance, S. A. Grupp, and R. H. Vonderheide RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy Blood, March 15, 2004; 103(6): 2046 - 2054. [Abstract] [Full Text] [PDF]
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D. Atanackovic, N. K. Altorki, E. Stockert, B. Williamson, A. A. Jungbluth, E. Ritter, D. Santiago, C. A. Ferrara, M. Matsuo, A. Selvakumar, et al. Vaccine-Induced CD4+ T Cell Responses to MAGE-3 Protein in Lung Cancer Patients J. Immunol., March 1, 2004; 172(5): 3289 - 3296. [Abstract] [Full Text] [PDF]
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M. Kuang, B. G. Peng, M. D. Lu, L. J. Liang, J. F. Huang, Q. He, Y. P. Hua, S. Totsuka, S. Q. Liu, K. W. Leong, et al. Phase II Randomized Trial of Autologous Formalin-Fixed Tumor Vaccine for Postsurgical Recurrence of Hepatocellular Carcinoma Clin. Cancer Res., March 1, 2004; 10(5): 1574 - 1579. [Abstract] [Full Text] [PDF]
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J. Taieb, K. Maruyama, C. Borg, M. Terme, L. Zitvogel, S. Appel, and P. Brossart Imatinib mesylate impairs Flt3L-mediated dendritic cell expansion and antitumor effects in vivo Blood, March 1, 2004; 103(5): 1966 - 1967. [Full Text] [PDF]
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R. H. Vonderheide, S. M. Domchek, J. L. Schultze, D. J. George, K. M. Hoar, D.-Y. Chen, K. F. Stephans, K. Masutomi, M. Loda, Z. Xia, et al. Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes Clin. Cancer Res., February 1, 2004; 10(3): 828 - 839. [Abstract] [Full Text] [PDF]
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M. J. Palmowski, L. Lopes, Y. Ikeda, M. Salio, V. Cerundolo, and M. K. Collins Intravenous Injection of a Lentiviral Vector Encoding NY-ESO-1 Induces an Effective CTL Response J. Immunol., February 1, 2004; 172(3): 1582 - 1587. [Abstract] [Full Text] [PDF]
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D. Blaise, J. O. Bay, C. Faucher, M. Michallet, J.-M. Boiron, B. Choufi, J.-Y. Cahn, N. Gratecos, J.-J. Sotto, S. Francois, et al. Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors Blood, January 15, 2004; 103(2): 435 - 441. [Abstract] [Full Text] [PDF]
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L. A. O'Mara and P. M. Allen Pulmonary Tumors Inefficiently Prime Tumor-Specific T Cells J. Immunol., January 1, 2004; 172(1): 310 - 317. [Abstract] [Full Text] [PDF]
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S. Teitz-Tennenbaum, Q. Li, S. Rynkiewicz, F. Ito, M. A. Davis, C. J. Mcginn, and A. E. Chang Radiotherapy Potentiates the Therapeutic Efficacy of Intratumoral Dendritic Cell Administration Cancer Res., December 1, 2003; 63(23): 8466 - 8475. [Abstract] [Full Text] [PDF]
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R. S. Goldszmid, J. Idoyaga, A. I. Bravo, R. Steinman, J. Mordoh, and R. Wainstok Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma J. Immunol., December 1, 2003; 171(11): 5940 - 5947. [Abstract] [Full Text] [PDF]
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I. Bedrosian, R. Mick, S. Xu, H. Nisenbaum, M. Faries, P. Zhang, P. A. Cohen, G. Koski, and B. J. Czerniecki Intranodal Administration of Peptide-Pulsed Mature Dendritic Cell Vaccines Results in Superior CD8+ T-Cell Function in Melanoma Patients J. Clin. Oncol., October 15, 2003; 21(20): 3826 - 3835. [Abstract] [Full Text] [PDF]
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B. de Rijke, H. Fredrix, A. Zoetbrood, F. Scherpen, H. Witteveen, T. de Witte, E. van de Wiel-van Kemenade, and H. Dolstra Generation of autologous cytotoxic and helper T-cell responses against the B-cell leukemia-associated antigen HB-1: relevance for precursor B-ALL-specific immunotherapy Blood, October 15, 2003; 102(8): 2885 - 2891. [Abstract] [Full Text] [PDF]
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N. Haicheur, F. Benchetrit, M. Amessou, C. Leclerc, T. Falguieres, C. Fayolle, E. Bismuth, W. H. Fridman, L. Johannes, and E. Tartour The B subunit of Shiga toxin coupled to full-size antigenic protein elicits humoral and cell-mediated immune responses associated with a Th1-dominant polarization Int. Immunol., October 1, 2003; 15(10): 1161 - 1171. [Abstract] [Full Text] [PDF]
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D. Nagorsen, C. Scheibenbogen, F. M. Marincola, A. Letsch, and U. Keilholz Natural T Cell Immunity against Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4296 - 4303. [Abstract] [Full Text] [PDF]
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M. Girardi, E. Glusac, R. B. Filler, S. J. Roberts, I. Propperova, J. Lewis, R. E. Tigelaar, and A. C. Hayday The Distinct Contributions of Murine T Cell Receptor (TCR){gamma}{delta}+ and TCR{alpha}{beta}+ T Cells to Different Stages of Chemically Induced Skin Cancer J. Exp. Med., September 2, 2003; 198(5): 747 - 755. [Abstract] [Full Text] [PDF]
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R. Soiffer, F. S. Hodi, F. Haluska, K. Jung, S. Gillessen, S. Singer, K. Tanabe, R. Duda, S. Mentzer, M. Jaklitsch, et al. Vaccination With Irradiated, Autologous Melanoma Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor by Adenoviral-Mediated Gene Transfer Augments Antitumor Immunity in Patients With Metastatic Melanoma J. Clin. Oncol., September 1, 2003; 21(17): 3343 - 3350. [Abstract] [Full Text] [PDF]
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I. Lindner, M. A. Kharfan-Dabaja, E. Ayala, D. Kolonias, L. M. Carlson, Y. Beazer-Barclay, U. Scherf, J. H. Hnatyszyn, and K. P. Lee Induced Dendritic Cell Differentiation of Chronic Myeloid Leukemia Blasts Is Associated with Down-Regulation of BCR-ABL J. Immunol., August 15, 2003; 171(4): 1780 - 1791. [Abstract] [Full Text] [PDF]
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E. Orsini, A. Guarini, S. Chiaretti, F. R. Mauro, and R. Foa The Circulating Dendritic Cell Compartment in Patients with Chronic Lymphocytic Leukemia Is Severely Defective and Unable to Stimulate an Effective T-Cell Response Cancer Res., August 1, 2003; 63(15): 4497 - 4506. [Abstract] [Full Text] [PDF]
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A. Camporeale, A. Boni, G. Iezzi, E. Degl'Innocenti, M. Grioni, A. Mondino, and M. Bellone Critical Impact of the Kinetics of Dendritic Cells Activation on the in Vivo Induction of Tumor-specific T Lymphocytes Cancer Res., July 1, 2003; 63(13): 3688 - 3694. [Abstract] [Full Text] [PDF]
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M. Gilliet, M. Kleinhans, E. Lantelme, D. Schadendorf, G. Burg, and F. O. Nestle Intranodal injection of semimature monocyte-derived dendritic cells induces T helper type 1 responses to protein neoantigen Blood, July 1, 2003; 102(1): 36 - 42. [Abstract] [Full Text] [PDF]
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E. Davila, R. Kennedy, and E. Celis Generation of Antitumor Immunity by Cytotoxic T Lymphocyte Epitope Peptide Vaccination, CpG-oligodeoxynucleotide Adjuvant, and CTLA-4 Blockade Cancer Res., June 15, 2003; 63(12): 3281 - 3288. [Abstract] [Full Text] [PDF]
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A. C. Peterson, H. Harlin, and T. F. Gajewski Immunization With Melan-A Peptide-Pulsed Peripheral Blood Mononuclear Cells Plus Recombinant Human Interleukin-12 Induces Clinical Activity and T-Cell Responses in Advanced Melanoma J. Clin. Oncol., June 15, 2003; 21(12): 2342 - 2348. [Abstract] [Full Text] [PDF]
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Z. Su, J. Dannull, A. Heiser, D. Yancey, S. Pruitt, J. Madden, D. Coleman, D. Niedzwiecki, E. Gilboa, and J. Vieweg Immunological and Clinical Responses in Metastatic Renal Cancer Patients Vaccinated with Tumor RNA-transfected Dendritic Cells Cancer Res., May 1, 2003; 63(9): 2127 - 2133. [Abstract] [Full Text] [PDF]
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F. S. Hodi, M. C. Mihm, R. J. Soiffer, F. G. Haluska, M. Butler, M. V. Seiden, T. Davis, R. Henry-Spires, S. MacRae, A. Willman, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients PNAS, April 15, 2003; 100(8): 4712 - 4717. [Abstract] [Full Text] [PDF]
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K. Schlienger, C. S. Chu, E. Y. Woo, P. M. Rivers, A. J. Toll, B. Hudson, M. V. Maus, J. L. Riley, Y. Choi, G. Coukos, et al. TRANCE- and CD40 Ligand-matured Dendritic Cells Reveal MHC Class I-restricted T Cells Specific for Autologous Tumor in Late-Stage Ovarian Cancer Patients Clin. Cancer Res., April 1, 2003; 9(4): 1517 - 1527. [Abstract] [Full Text] [PDF]
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L. H. Butterfield, A. Ribas, V. B. Dissette, S. N. Amarnani, H. T. Vu, D. Oseguera, H.-J. Wang, R. M. Elashoff, W. H. McBride, B. Mukherji, et al. Determinant Spreading Associated with Clinical Response in Dendritic Cell-based Immunotherapy for Malignant Melanoma Clin. Cancer Res., March 1, 2003; 9(3): 998 - 1008. [Abstract] [Full Text] [PDF]
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K. Akiyama, S. Ebihara, A. Yada, K. Matsumura, S. Aiba, T. Nukiwa, and T. Takai Targeting Apoptotic Tumor Cells to Fc{gamma}R Provides Efficient and Versatile Vaccination Against Tumors by Dendritic Cells J. Immunol., February 15, 2003; 170(4): 1641 - 1648. [Abstract] [Full Text] [PDF]
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T. L. Whiteside, Y. Zhao, T. Tsukishiro, E. M. Elder, W. Gooding, and J. Baar Enzyme-linked Immunospot, Cytokine Flow Cytometry, and Tetramers in the Detection of T-Cell Responses to a Dendritic Cell-based Multipeptide Vaccine in Patients with Melanoma Clin. Cancer Res., February 1, 2003; 9(2): 641 - 649. [Abstract] [Full Text] [PDF]
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S. R. Reynolds, A. Zeleniuch-Jacquotte, R. L. Shapiro, D. F. Roses, M. N. Harris, D. Johnston, and J.-C. Bystryn Vaccine-induced CD8+ T-cell Responses to MAGE-3 Correlate with Clinical Outcome in Patients with Melanoma Clin. Cancer Res., February 1, 2003; 9(2): 657 - 662. [Abstract] [Full Text] [PDF]
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G. Consogno, S. Manici, V. Facchinetti, A. Bachi, J. Hammer, B. M. Conti-Fine, C. Rugarli, C. Traversari, and M. P. Protti Identification of immunodominant regions among promiscuous HLA-DR-restricted CD4+ T-cell epitopes on the tumor antigen MAGE-3 Blood, February 1, 2003; 101(3): 1038 - 1044. [Abstract] [Full Text] [PDF]
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I. D. Davis, M. Jefford, P. Parente, and J. Cebon Rational approaches to human cancer immunotherapy J. Leukoc. Biol., January 1, 2003; 73(1): 3 - 29. [Abstract] [Full Text] [PDF]
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C. La Rosa, Z. Wang, J. C. Brewer, S. F. Lacey, M. C. Villacres, R. Sharan, R. Krishnan, M. Crooks, S. Markel, R. Maas, et al. Preclinical development of an adjuvant-free peptide vaccine with activity against CMV pp65 in HLA transgenic mice Blood, November 15, 2002; 100(10): 3681 - 3689. [Abstract] [Full Text] [PDF]
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P. Luhrs, W. Schmidt, R. Kutil, M. Buschle, S. N. Wagner, G. Stingl, and A. Schneeberger Induction of Specific Immune Responses by Polycation-Based Vaccines J. Immunol., November 1, 2002; 169(9): 5217 - 5226. [Abstract] [Full Text] [PDF]
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 G. Parmiani, C. Castelli, P. Dalerba, R. Mortarini, L. Rivoltini, F. M. Marincola, and A. Anichini Cancer Immunotherapy With Peptide-Based Vaccines: What Have We Achieved? Where Are We Going? J Natl Cancer Inst, June 5, 2002; 94(11): 805 - 818. [Abstract] [Full Text] [PDF]
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B. Schuler-Thurner, E. S. Schultz, T. G. Berger, G. Weinlich, S. Ebner, P. Woerl, A. Bender, B. Feuerstein, P. O. Fritsch, N. Romani, et al. Rapid Induction of Tumor-specific Type 1 T Helper Cells in Metastatic Melanoma Patients by Vaccination with Mature, Cryopreserved, Peptide-loaded Monocyte-derived Dendritic Cells J. Exp. Med., May 20, 2002; 195(10): 1279 - 1288. [Abstract] [Full Text] [PDF]
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M. Schnurr, C. Scholz, S. Rothenfusser, P. Galambos, M. Dauer, J. Robe, S. Endres, and A. Eigler Apoptotic Pancreatic Tumor Cells Are Superior to Cell Lysates in Promoting Cross-Priming of Cytotoxic T Cells and Activate NK and {gamma}{delta} T Cells Cancer Res., April 1, 2002; 62(8): 2347 - 2352. [Abstract] [Full Text] [PDF]
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 C. Buteau, S. N. Markovic, and E. Celis Challenges in the Development of Effective Peptide Vaccines for Cancer Mayo Clin. Proc., April 1, 2002; 77(4): 339 - 349. [Abstract] [PDF]
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P. Kufer, A. Zippelius, R. Lutterbuse, I. Mecklenburg, T. Enzmann, A. Montag, D. Weckermann, B. Passlick, N. Prang, P. Reichardt, et al. Heterogeneous Expression of MAGE-A Genes in Occult Disseminated Tumor Cells: A Novel Multimarker Reverse Transcription-Polymerase Chain Reaction for Diagnosis of Micrometastatic Disease Cancer Res., January 1, 2002; 62(1): 251 - 261. [Abstract] [Full Text] [PDF]
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