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IMMUNOBIOLOGY
From the University of Tübingen, Department of
Hematology, Oncology and Immunology, Tübingen, Germany.
Vaccination of patients with cancer using dendritic cells (DCs) was
shown to be effective for B-cell lymphoma and malignant melanoma. Here
we provide evidence that patients with advanced breast and ovarian
cancer can be efficiently vaccinated with autologous DCs pulsed with
HER-2/neu- or MUC1-derived peptides. Ten patients were included in
this pilot study. The DC vaccinations were well tolerated with no side
effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes
(CTLs) could be detected in the peripheral blood using both
intracellular IFN- The identification of tumor-associated antigens
(TAAs) opened new opportunities for the treatment of patients with
malignant diseases.1,2 For the treatment of breast and
ovarian cancer, however, only few T-cell epitopes have been identified,
including those derived from the HER-2/neu protooncogene and the
epithelial mucin MUC1. HER-2/neu is overexpressed in 20% to 30% of
patients with breast and ovarian cancer and correlates with a poor
prognosis.3-5 Two HLA-A2 binding peptides (E75 and GP2)
derived from the HER-2/neu protein were identified6,7 and
in vitro studies in our laboratory using these peptides for cytotoxic
T-lymphocyte (CTL) induction demonstrated that these epitopes
efficiently elicit antigen-specific T-cell responses against a variety
of solid tumors, including renal cell and colon carcinoma when loaded
on DCs.8 In contrast to the restricted expression of
HER-2/neu, the MUC1 protein is overexpressed on more than 90% of
breast and ovarian cancers and is therefore a suitable candidate for
broadly applicable vaccine therapies.9-13 Mucins are
transmembrane type I glycoproteins with a unique extracellular domain
consisting mostly of 20 to 60 tandem repeats (VNTRs).9 We
recently identified 2 novel 9-mer peptides, M1.1 and M1.2, with a
high-binding probability to HLA-A2; the M1.1 peptide is derived from
the VNTR domain of the MUC1 protein, whereas the M1.2 peptide is
located in the leader sequence.14 CTL induced with these
peptides efficiently lysed target cells pulsed with the cognate peptide
or tumor cells naturally expressing MUC1 in major histocompatibility
complex (MHC)-restricted and antigen-specific
manner.14
Dendritic cells (DCs) are the most potent antigen-presenting cells with
the unique ability to initiate and maintain primary immune responses
when pulsed with antigens.15-20 They originate from the
bone marrow and their precursors migrate via the blood stream to almost
all the organs, where they can be found in an immature state
characterized by a high rate of antigen uptake.21 On
stimulation with bacterial products, cytokines, or CD40 ligation, DCs
undergo characteristic modulations of their phenotype,
antigen-presenting function and the ability to migrate to the secondary
lymphoid organs. These mature DCs express high levels of costimulatory and MHC molecules and are regarded as the initiators of primary immune
responses. In vitro, DCs can develop from peripheral blood CD14+ monocytes when grown in the presence of
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
interleukin 4 (IL-4). These cells have the characteristics of immature
DCs and can be further induced to mature by inflammatory stimuli such
as tumor necrosis factor Vaccinations using DCs pulsed with TAAs were shown to be effective for
patients with B-cell lymphoma and malignant melanoma,25-29 for which spontaneous remissions30,31 due to
immunologic reactions as well as responses to immunotherapy based
treatments were reported. In this phase I/II study, we analyzed the
feasibility and efficacy of HER-2/neu or MUC1 peptide-pulsed
"mature" DC vaccinations in heavily pretreated patients with
metastatic breast and ovarian cancer. We show that this approach is
feasible and induces specific cytotoxic T-cell responses without any
side effects. In addition, we demonstrate that vaccinations with a
single tumor antigen can induce responses against different epitopes
derived from other tumor antigens not used for vaccination, suggesting
that epitope spreading might occur in vivo after the vaccination with a
single tumor antigen.
Patient characteristics and clinical protocol
Peptide-pulsed DCs generated from peripheral blood monocytes were
injected subcutaneously into the upper limb close to the inguinal lymph
nodes on days 1, 14, and 28, respectively. On day 35, an evaluation of
clinical responses was performed. The vaccine treatment was continued
in case of stable disease or tumor regression every 28 days until tumor
progression. Patients with progressive disease after 3 vaccinations
went off study. The World Health Organization (WHO) definitions of
clinical responses and adverse effects were applied.
Cell isolation and cultures
IL-4 (1000 IU/mL) and TNF- The peptides derived from HER-2/neu (E75: KIFGSLAFL, GP2: IISAVVGIL) and MUC1 (M1.1 STPPVHNV, M1.2: LLLLTVLTV) were synthesized using standard Fmoc chemistry on a peptide synthesizer (432A, Applied Biosystems, Weiterstadt, Germany) and analyzed by reverse phase high-performance liquid chromatography (HPLC) and mass spectrometry. The patients received either HER-2/neu or MUC1 peptides, corresponding to the histologic analysis. If the tumor samples expressed both antigens, patients received HER-2/neu peptides only. DCs were separately pulsed for 2 hours with 50 µg/mL of each peptide and washed 3 times with phosphate-buffered saline (PBS) before application. Immunostaining Cell staining was performed using fluorescein isothiocyanate (FITC)- or phycoerythrin (PE)-conjugated mouse mAbs against CD86, CD40 (all purchased from Pharmingen, Hamburg, Germany); CD3, CD19, CD20, CD80, HLA DR, CD54, CD14 (Becton Dickinson, Heidelberg, Germany), CD83 (Coulter-Immunotech Diagnostics, Hamburg, Germany), CD1a (OKT6, Ortho Diagnostic Systems; and T6-RD1, Coulter Immunology, Hialeah, FL), and mouse IgG isotype controls. Samples were analyzed on a FACScan Calibur (Becton Dickinson, Seattle, WA).Intracellular IFN-  production was performed
as recently described.30 The 2.5 × 105
PBMNCs obtained before and after the vaccinations were stimulated with
the MUC1- or HER-2/neu-derived peptides (50 µg/mL) for 6 hours. The
10 mmol Brefeldin A (Sigma Chemical Co, St Louis, MO) were added during
the last 3 hours. An HLA-A2 binding HIV peptide (pol HIV-1 reverse
transcriptase peptide, amino acids 476-484, ILKEPVHGV) was used as a
negative control. In addition, HLA-A2 binding peptides derived from CEA
(CAP-1, amino acids 571-579, YLSGANLNL) and MAGE-3 (M3-271, amino acids
271-279, FLWGPRALV) were used in the assay. Positive controls were
performed by stimulating the cells with PMA (50 ng/mL, Sigma)
and ionomycin (500 ng/mL, Sigma). Cells were stained with a
FITC-conjugated anti-CD8 (Becton Dickinson, Heidelberg, Germany). After
washing, cells were fixed with 2% formaldehyde/PBS for 15 minutes at
room temperature, permeabilized in 0.5% saponin, 2% bovine serum
albumin in PBS, and stained with a PE-labeled antibody reactive with
human IFN- (Pharmingen, Hamburg, Germany).
To confirm that the results obtained with this method are not a
reflection of random fluctuations, blood samples from patients were
split into several portions and analyzed 2 to 3 times at different time
points. These repeated analyses of samples drawn from the same patient
at the same time gave identical results. Furthermore, blood samples of
5 healthy donors and 9 patients with metastatic malignant diseases,
including pancreatic cancer (n = 3), cancer of unknown primary
(n = 1), and renal cell carcinoma (n = 5), were analyzed. The level
of IFN- Analysis of antigen-specific cytotoxic T-lymphocyte responses after in vitro restimulation The 5 × 105 DCs were pulsed with 50 µg/mL of the synthetic peptides for 2 hours, washed, and incubated with 2.5 × 106 autologous PBMNCs in RP10 medium. Cells were restimulated after 7 days of culture and 1 ng/mL human recombinant IL-2 (Genzyme) was added every other day.8 The cytolytic activity of the CTLs was analyzed on day 5 after the restimulation in a standard 51Cr-release assay.Cytotoxic T-lymphocyte assay The standard 51Cr-release assay was performed with some modifications as described.8 MCF-7 (breast cancer cell line, HLA-A2+, MUC1+), A498 (renal cell carcinoma, HLA-A2+, HER-2/neu+), SK-OV-3 cells (ovarian cancer, HLA-A2 , MUC1+,
HER-2/neu+), Croft cell line (immortalized B-cell line,
HLA-A2+, HER-2/neu, MUC1,
kindly provided by O. J. Finn, University of Pittsburgh, PA), K562
(no MHC expression, MUC1+, sensitive to natural killer
[NK]-cell-mediated lysis), and T2 cells (174 × CEM.T2 hybridoma,
HLA-A2+, and TAP1 and TAP2 deficient) were used as target
cells in the assay. T2 cells were pulsed with 25 µg/mL peptide for 2 hours and labeled with [51Cr]-sodium chromate in RP10 for
1 hour at 37°C. The 104 cells were transferred to a well
of a round-bottomed 96-well plate. Varying numbers of CTLs were added
to give a final volume of 200 µL and incubated for 4 hours at 37°C.
At the end of the assay, supernatants (50 µL per well) were harvested
and counted in a microbeta counter (Wallac). The percentage specific
lysis was calculated as: 100 × (experimental release  spontaneous release/maximal release spontaneous release).
Spontaneous and maximal release were determined in the presence of
either medium or 1% Triton X-100, respectively.
Clinical results of vaccinations using HER-2/neu or MUC1 peptide-pulsed dendritic cells DCs were generated under serum-free conditions from peripheral blood monocytes using GM-CSF and IL-4 and activated by the addition of TNF- to the culture medium, as previous in vitro studies
demonstrated that TNF- may increase the antigen-specific stimulatory
capacity of T cells by DCs.8
DCs obtained after 7 days of culture expressed high levels of CD83,
HLA-DR, and costimulatory molecules, corresponding to the mature
phenotype, as a result of TNF- DCs were injected subcutaneously close to the inguinal lymph nodes of the patients. The patients received a median of 6.5 × 106 DCs (range 2-17 × 106 DCs) per vaccine. The administration of DCs was performed every 14 days 3 times and repeated afterward every 28 days until tumor progression was observed. A total of 53 vaccinations were performed. The DC injections were well tolerated with no side effects. One patient (no. 8) with metastatic breast cancer who was treated with
MUC1 peptide-pulsed DCs developed a regression of her multiple
subcutaneous lesions. In parallel with the disappearance of the
soft-tissue metastases, the serum levels of CA125 and CA15.3 continuously decreased after the third vaccination but started to
increase again 5 months later (Figure 1).
Extensive staging procedures 6 months after starting DC therapy
revealed multiple central nervous system (CNS) metastases but
no signs of visceral disease, with the exception of a small soft-tissue
nodule in her left axilla that was detected by the patient and that was
not clinically evident before. This residual nodule was removed and analyzed histologically for the presence of infiltrating T lymphocytes. As shown in Figure 2, both
tumor-infiltrating CD8 and CD4 positive T cells were detected. HLA-DR
staining of the tumor sample revealed the presence of large MHC class
II-positive cells in the lesion that might represent
antigen-presenting cells such as DCs or macrophages.
Before entering the DC vaccination trial, this patient was on palliative gosereline and tamoxifen treatment since July 1997, when she developed multiple progressive soft-tissue nodules, ovarian enlargement, and a continuous increase in her tumor marker levels until October 1998 when we started the DC vaccinations. Between the second and third DC vaccination, her tumor-infiltrated ovaries were removed by a gynecologist working outside the clinical trial by laparoscopy. Although we cannot exclude that ovariectomy contributed to the decline in the CA125 levels, it seems unlikely that the soft-tissue metastases disappeared as a result of ovariectomy, because the patient was already functionally ovariectomized since 1997 on the gosereline and tamoxifen treatment, and the soft-tissue nodules developed during this antihormonal therapy. However, the clinical response observed in this individual cannot be considered as proof that the vaccination works, particularly because the vaccination and ovariectomy were performed concurrently. Another patient with ovarian cancer (no. 6) had stable disease (8+ months) after having had progressive disease before the vaccination and a debulking surgery. She is currently continuing the DC vaccinations. One additional patient (no. 7) had a short period of disease stabilization (approximately 8 weeks) after the third vaccination with MUC-1 peptide-pulsed DCs. Peptide-specific T-cell responses in patients after dendritic cell immunizations The antigen-specific response in the 10 patients receiving peptide-pulsed DC immunizations was determined by analysis of IFN- production by T lymphocytes on stimulation with the cognate peptide in
vitro. IFN- production in CD8+ lymphocytes was assessed
by flow cytometry after intracellular staining with IFN--specific
antibody. No reactivity against the used peptide antigens was observed
in any tested patient before vaccination or after the first 2 DC
vaccinations (Figure 3 and data not
shown). After 3 vaccinations, however, in 5 of 10 patients (3 immunized
with the MUC1 and 2 with HER-2/neu peptides), antigen-specific T-cell
responses could be detected in peripheral blood using intracellular IFN- staining (Table 2 and Figure 3).
In HER-2/neu-immunized patients, the major CTL response in vivo was
induced with the E75 peptide. Patients receiving MUC1 peptides had a
stronger response to the M1.2 peptide derived from the leader sequence,
suggesting that the E75 and M1.2 peptides might be immunodominant.
After 3 vaccinations, approximately 0.5% to 2% of all
CD8+ lymphocytes (Table 2 and Figure 3) produced IFN- on
stimulation with the cognate peptide. The HIV peptide was used as a
negative control and considered as a background reactivity.
Interestingly, as analyzed in 2 patients (no. 6 and no. 8), E75
and M1.2 peptide-specific T-cell responses could be detected even at 6 and 9 months after initiation of DC vaccinations, as analyzed by
intracellular IFN-
Immunization with a single tumor antigen can induce T-cell responses against epitopes not used for vaccination To analyze whether immunizations with a single TAA can lead to induction of CTL specific for antigens not used for vaccination (antigen spreading) as a result of cross priming, we used a set of several HLA-A2 binding peptides, including the CAP-1 (CEA) and M3-271 (MAGE-3) peptides derived from antigens known to be expressed in breast and ovarian cancers. This analysis has been performed by intracellular IFN- staining in 4 patients who showed peptide-specific reactivity
against antigens used for vaccination. In patient no. 8 who was
vaccinated with the MUC1 peptides and responded to the treatment, CEA-
and MAGE-3 peptide-specific T cells were observed after 6 and 9 vaccinations, suggesting that epitope spreading might occur in vivo
after successful vaccination (Figure 4, Table 3). No such reactivity
could be detected in this patient before the therapy or after the first
5 vaccinations (Table 3). Interestingly, whereas the T-cell response to
the M1.2 peptide was still present after 9 vaccinations, no reactivity against the second M1.1 peptide could be detected in the peripheral blood of this patient.
In a second patient (no. 6) who was immunized with HER-2/neu peptides, antigen-specific reactivity against the M1.2 and M1.1 peptides was detected in peripheral blood after 7 vaccinations. This MUC1-specific T-cell response was not present after the first 5 immunizations (Table 4). These findings were supported by the histologic analysis of tumor samples that confirmed MUC1 expression by tumor cells (data not shown). In vivo-induced T cells can lyse tumor cells expressing the antigen In addition to the analysis of IFN- production by
peripheral blood T lymphocytes, analyses of peptide-specific CTL
responses before and after 3 vaccinations were performed. From all 5 patients who had evidence of peptide-specific T cells by intracellular IFN- staining, peptide-specific CTLs were generated in vitro using
peptide-pulsed DCs as antigen-presenting cells (APCs) (Table 2). Results from experiments obtained with CTL derived from patient no.
8 and patient no. 2 are presented in Figures
5 and 6,
respectively. The CTL obtained after one in vitro restimulation
efficiently lysed T2 target cells pulsed with the antigenic peptide, as
well as the allogeneic HLA-A2+ tumor cell lines naturally
expressing the TAA (MCF7 cells expressing MUC1 and A498 cells
expressing HER2/neu). No lysis was detected when K562 or tumors missing
either HLA-A2 (SK-OV-3 cells, MUC+, HER-2/neu+,
HLA-A2) or TAA (Croft cells, HER-2/neu,
MUC1, HLA-A2+) expression were used as target
cells in the assay. Consistent with the results from previous IFN-
staining experiments, a stronger response was observed against the M1.2
(Figure 5) and E75 (Figure 6) peptides. In contrast, no in vitro CTL
activity was detected in the peripheral blood obtained before the
therapy in any of these patients (Figure 5C,D; Figure 6C,D).
DCs are critical in the function of the immune system because they
are the primary antigen-presenting cells for the initiation of
T-lymphocyte responses. Several murine studies reported a successful elimination of established tumors using DCs pulsed with
TAAs.17-20 In humans, vaccination therapies using DCs were
shown to be effective for B-cell lymphoma and malignant
melanoma.25-29 Melanoma, however, is a highly immunogenic
tumor and spontaneous remissions due to immune reactions as well as
remissions after IL-2- and IFN- In this study, we show for the first time that a vaccination approach using HLA-A2-restricted HER-2/neu or MUC1 peptide-pulsed DCs can safely be applied in patients with advanced metastatic breast and ovarian cancers and induce immunologic responses directed against these less immunogenic tumors. No side effects were observed in these patients, particularly no clinically relevant anemia, though we have shown recently that normal erythroid bone marrow progenitor and precursor cells coexpress MUC1 molecules.33 However, most of the more mature erythroid progenitor cells are MHC class I negative and therefore are not targets for MUC-1 peptide-specific CTL. In addition, no autoimmune phenomena were observed in our study patients on the vaccination with these self-peptides. Interestingly, in 5 of 10 vaccinated patients, peptide-specific CD8+ cytolytic T cells were detected in the peripheral blood after 3 vaccinations, suggesting that peptide-pulsed DCs can induce antigen-specific T cells in vivo in heavily pretreated patients with cancer, even after high-dose chemotherapy. Moreover, we provide evidence that epitope spreading might occur in vivo on vaccination with a single tumor antigen (Figure 4, Table 3, and Table 4). We observed MAGE-3- and CEA-peptide-specific CD8+ T cells in one patient (no. 8) treated with MUC-1 peptide-pulsed DCs, and moreover, MUC1 peptide-specific T cells were observed in another patient (no. 6) after vaccinations with HER-2/neu-derived peptides. One possible explanation for this phenomenon might be that the destruction of the tumor cells by the in vivo-induced peptide-specific T cells leads to the induction of other tumor antigen-specific CTLs as a result of tumor cell uptake and processing by APCs, such as DCs or macrophages that were demonstrated to be involved in the cross-priming phenomenon.35-38 The main immunologic responses in our study were directed against the M1.2 and E75 peptides, suggesting that these 2 peptides might be immunodominant and could be preferentially used in future vaccination trials, particularly in the setting of minimal residual disease as demontrated recently for low-grade lymphomas.29 In summary, in this report we show for the first time that vaccination therapy using DCs pulsed with HER-2/neu- or MUC1-derived peptides can be effective in patients with advanced metastatic breast and ovarian cancers. Immunologic responses were induced in patients with advanced diseases that were pretreated by multiple cycles of chemotherapy, including high-dose chemotherapy and autologous stem cell transplantation, indicating that peptide-pulsed DC vaccinations could also be successfully applied after intensive or even high-dose chemotherapy to eliminate residual disease. Furthermore, this report might be helpful to design future studies for the treatment of a variety of other tumors expressing HER-2/neu or MUC1, including renal cell carcinoma, non-small cell lung cancer, and colon and pancreatic carcinoma.
We gratefully acknowledge the excellent technical assistance of Stefanie Kurtz and Yvonne Hoffmann. We thank Prof Bültmann and Prof Kaiserling, Institute of Pathology, University of Tübingen, for performing immunohistologic analyses of the tumor specimens. Finally, we thank Prof Rammensee and Dr Stefan Stevanovic, Institute for Cell Biology, Department of Immunology, University of Tübingen, for providing the peptides.
Submitted February 8, 2000; accepted June 26, 2000.
Supported in part by grants from Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft (SFB 510).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Wolfram Brugger, University of Tübingen, Department of Hematology, Oncology and Immunology, Otfried-Müller-Strasse-10, D-72076 Tübingen, Germany; e-mail: wolfram.brugger{at}med.uni-tuebingen.de.
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© 2000 by The American Society of Hematology.
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C. L-L. Chiang, J. A. Ledermann, E. Aitkens, E. Benjamin, D. R. Katz, and B. M. Chain Oxidation of Ovarian Epithelial Cancer Cells by Hypochlorous Acid Enhances Immunogenicity and Stimulates T Cells that Recognize Autologous Primary Tumor Clin. Cancer Res., August 1, 2008; 14(15): 4898 - 4907. [Abstract] [Full Text] [PDF]
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H. Conrad, K. Gebhard, H. Kronig, J. Neudorfer, D. H. Busch, C. Peschel, and H. Bernhard CTLs Directed against HER2 Specifically Cross-React with HER3 and HER4 J. Immunol., June 15, 2008; 180(12): 8135 - 8145. [Abstract] [Full Text] [PDF]
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R. Sartorius, P. Pisu, L. D'Apice, L. Pizzella, C. Romano, G. Cortese, A. Giorgini, A. Santoni, F. Velotti, and P. De Berardinis The Use of Filamentous Bacteriophage fd to Deliver MAGE-A10 or MAGE-A3 HLA-A2-Restricted Peptides and to Induce Strong Antitumor CTL Responses J. Immunol., March 15, 2008; 180(6): 3719 - 3728. [Abstract] [Full Text] [PDF]
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G. E. Peoples, J. P. Holmes, M. T. Hueman, E. A. Mittendorf, A. Amin, S. Khoo, Z. A. Dehqanzada, J. M. Gurney, M. M. Woll, G. B. Ryan, et al. Combined Clinical Trial Results of a HER2/neu (E75) Vaccine for the Prevention of Recurrence in High-Risk Breast Cancer Patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02 Clin. Cancer Res., February 1, 2008; 14(3): 797 - 803. [Abstract] [Full Text] [PDF]
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L. Luketic, J. Delanghe, P. T. Sobol, P. Yang, E. Frotten, K. L. Mossman, J. Gauldie, J. Bramson, and Y. Wan Antigen Presentation by Exosomes Released from Peptide-Pulsed Dendritic Cells Is not Suppressed by the Presence of Active CTL J. Immunol., October 15, 2007; 179(8): 5024 - 5032. [Abstract] [Full Text] [PDF]
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A. D. Gritzapis, L. G. Mahaira, S. A. Perez, N. T. Cacoullos, M. Papamichail, and C. N. Baxevanis Vaccination with Human HER-2/neu (435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor Cells In vivo. Cancer Res., May 15, 2006; 66(10): 5452 - 5460. [Abstract] [Full Text] [PDF]
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T. A. Rohn, A. Reitz, A. Paschen, X. D. Nguyen, D. Schadendorf, A. B. Vogt, and H. Kropshofer A Novel Strategy for the Discovery of MHC Class II-Restricted Tumor Antigens: Identification of a Melanotransferrin Helper T-Cell Epitope Cancer Res., November 1, 2005; 65(21): 10068 - 10078. [Abstract] [Full Text] [PDF]
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S. S. Neelapu, S. Baskar, B. L. Gause, C. B. Kobrin, T. M. Watson, A. R. Frye, R. Pennington, L. Harvey, E. S. Jaffe, R. J. Robb, et al. Human Autologous Tumor-Specific T-Cell Responses Induced by Liposomal Delivery of a Lymphoma Antigen Clin. Cancer Res., December 15, 2004; 10(24): 8309 - 8317. [Abstract] [Full Text] [PDF]
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K. Kono, E. Sato, H. Naganuma, A. Takahashi, K. Mimura, H. Nukui, and H. Fujii Trastuzumab (Herceptin) Enhances Class I-Restricted Antigen Presentation Recognized by HER-2/neu-Specific T Cytotoxic Lymphocytes Clin. Cancer Res., April 1, 2004; 10(7): 2538 - 2544. [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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A. J. Reefer, R. M. Carneiro, N. J. Custis, T. A. E. Platts-Mills, S.-S. J. Sung, J. Hammer, and J. A. Woodfolk A Role for IL-10-Mediated HLA-DR7-Restricted T Cell-Dependent Events in Development of the Modified Th2 Response to Cat Allergen J. Immunol., March 1, 2004; 172(5): 2763 - 2772. [Abstract] [Full Text] [PDF]
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M. R. Muller, G. Tsakou, F. Grunebach, S. M. Schmidt, and P. Brossart Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells Blood, March 1, 2004; 103(5): 1763 - 1769. [Abstract] [Full Text] [PDF]
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I. J. M. de Vries, W. J. Lesterhuis, N. M. Scharenborg, L. P. H. Engelen, D. J. Ruiter, M.-J. P. Gerritsen, S. Croockewit, C. M. Britten, R. Torensma, G. J. Adema, et al. Maturation of Dendritic Cells Is a Prerequisite for Inducing Immune Responses in Advanced Melanoma Patients Clin. Cancer Res., November 1, 2003; 9(14): 5091 - 5100. [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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C. Rentzsch, S. Kayser, S. Stumm, I. Watermann, S. Walter, S. Stevanovic, D. Wallwiener, and B. Guckel Evaluation of Pre-existent Immunity in Patients with Primary Breast Cancer: Molecular and Cellular Assays to Quantify Antigen-Specific T Lymphocytes in Peripheral Blood Mononuclear Cells Clin. Cancer Res., October 1, 2003; 9(12): 4376 - 4386. [Abstract] [Full Text] [PDF]
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M. R. Muller, F. Grunebach, K. Kayser, W. Vogel, A. Nencioni, W. Brugger, L. Kanz, and P. Brossart Expression of Her-2/neu on Acute Lymphoblastic Leukemias: Implications for the Development of Immunotherapeutic Approaches Clin. Cancer Res., August 1, 2003; 9(9): 3448 - 3453. [Abstract] [Full Text] [PDF]
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V. Renard, L. Sonderbye, K. Ebbehoj, P. B. Rasmussen, K. Gregorius, T. Gottschalk, S. Mouritsen, A. Gautam, and D. R. Leach HER-2 DNA and Protein Vaccines Containing Potent Th Cell Epitopes Induce Distinct Protective and Therapeutic Antitumor Responses in HER-2 Transgenic Mice J. Immunol., August 1, 2003; 171(3): 1588 - 1595. [Abstract] [Full Text] [PDF]
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S. M. Schmidt, K. Schag, M. R. Muller, M. M. Weck, S. Appel, L. Kanz, F. Grunebach, and P. Brossart Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells Blood, July 15, 2003; 102(2): 571 - 576. [Abstract] [Full Text] [PDF]
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M. R. Muller, F. Grunebach, A. Nencioni, and P. Brossart Transfection of Dendritic Cells with RNA Induces CD4- and CD8-Mediated T Cell Immunity Against Breast Carcinomas and Reveals the Immunodominance of Presented T Cell Epitopes J. Immunol., June 15, 2003; 170(12): 5892 - 5896. [Abstract] [Full Text] [PDF]
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N. K. Dakappagari, J. Pyles, R. Parihar, W. E. Carson, D. C. Young, and P. T. P. Kaumaya A Chimeric Multi-Human Epidermal Growth Factor Receptor-2 B Cell Epitope Peptide Vaccine Mediates Superior Antitumor Responses J. Immunol., April 15, 2003; 170(8): 4242 - 4253. [Abstract] [Full Text] [PDF]
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K. Kono, A. Takahashi, H. Sugai, H. Fujii, A. R. Choudhury, R. Kiessling, and Y. Matsumoto Dendritic Cells Pulsed with HER-2/neu-derived Peptides Can Induce Specific T-Cell Responses in Patients with Gastric Cancer Clin. Cancer Res., November 1, 2002; 8(11): 3394 - 3400. [Abstract] [Full Text] [PDF]
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J. L. Murray, M. E. Gillogly, D. Przepiorka, H. Brewer, N. K. Ibrahim, D. J. Booser, G. N. Hortobagyi, A. P. Kudelka, K. H. Grabstein, M. A. Cheever, et al. Toxicity, Immunogenicity, and Induction of E75-specific Tumor-lytic CTLs by HER-2 Peptide E75 (369-377) Combined with Granulocyte Macrophage Colony-stimulating Factor in HLA-A2+ Patients with Metastatic Breast and Ovarian Cancer Clin. Cancer Res., November 1, 2002; 8(11): 3407 - 3418. [Abstract] [Full Text] [PDF]
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T. Weinschenk, C. Gouttefangeas, M. Schirle, F. Obermayr, S. Walter, O. Schoor, R. Kurek, W. Loeser, K.-H. Bichler, D. Wernet, et al. Integrated Functional Genomics Approach for the Design of Patient-individual Antitumor Vaccines Cancer Res., October 15, 2002; 62(20): 5818 - 5827. [Abstract] [Full Text] [PDF]
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M. Wykes, K. P. A. MacDonald, M. Tran, R. J. Quin, P. X. Xing, S. J. Gendler, D. N. J. Hart, and M. A. McGuckin MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells J. Leukoc. Biol., October 1, 2002; 72(4): 692 - 701. [Abstract] [Full Text] [PDF]
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F. Okano, W. J. Storkus, W. H. Chambers, I. F. Pollack, and H. Okada Identification of a Novel HLA-A*0201-restricted, Cytotoxic T Lymphocyte Epitope in a Human Glioma-associated Antigen, Interleukin 13 Receptor {alpha}2 Chain Clin. Cancer Res., September 1, 2002; 8(9): 2851 - 2855. [Abstract] [Full Text] [PDF]
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A. M. Krackhardt, M. Witzens, S. Harig, F. S. Hodi, A. J. Zauls, M. Chessia, P. Barrett, and J. G. Gribben Identification of tumor-associated antigens in chronic lymphocytic leukemia by SEREX Blood, August 28, 2002; 100(6): 2123 - 2131. [Abstract] [Full Text] [PDF]
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H. J. Bontkes, T. D. de Gruijl, G. J. Schuurhuis, R. J. Scheper, C. J. L. M. Meijer, and E. Hooijberg Expansion of dendritic cell precursors from human CD34+ progenitor cells isolated from healthy donor blood; growth factor combination determines proliferation rate and functional outcome J. Leukoc. Biol., August 1, 2002; 72(2): 321 - 329. [Abstract] [Full Text] [PDF]
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R. Spisek, P. Chevallier, N. Morineau, N. Milpied, H. Avet-Loiseau, J.-L. Harousseau, K. Meflah, and M. Gregoire Induction of Leukemia-specific Cytotoxic Response by Cross-Presentation of Late-Apoptotic Leukemic Blasts by Autologous Dendritic Cells of Nonleukemic Origin Cancer Res., May 1, 2002; 62(10): 2861 - 2868. [Abstract] [Full Text] [PDF]
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T. D. Schell and S. S. Tevethia Control of Advanced Choroid Plexus Tumors in SV40 T Antigen Transgenic Mice Following Priming of Donor CD8+ T Lymphocytes by the Endogenous Tumor Antigen J. Immunol., December 15, 2001; 167(12): 6947 - 6956. [Abstract] [Full Text] [PDF]
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K. Kato, Y. Takaue, and H. Wakasugi T-cell-conditioned medium efficiently induces the maturation and function of human dendritic cells J. Leukoc. Biol., December 1, 2001; 70(6): 941 - 949. [Abstract] [Full Text] [PDF]
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P. Brossart, A. Schneider, P. Dill, T. Schammann, F. Grunebach, S. Wirths, L. Kanz, H.-J. Buhring, and W. Brugger The Epithelial Tumor Antigen MUC1 Is Expressed in Hematological Malignancies and Is Recognized by MUC1-specific Cytotoxic T-Lymphocytes Cancer Res., September 1, 2001; 61(18): 6846 - 6850. [Abstract] [Full Text] [PDF]
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C. Meyer zum Buschenfelde, J. Metzger, C. Hermann, N. Nicklisch, C. Peschel, and H. Bernhard The Generation of Both T Killer and Th Cell Clones Specific for the Tumor-Associated Antigen HER2 Using Retrovirally Transduced Dendritic Cells J. Immunol., August 1, 2001; 167(3): 1712 - 1719. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
) to
assess a MHC class I-restricted CTL response in vitro. Cytotoxic
activity of induced CTLs was determined after one restimulation in a
standard 51Cr-release assay using MCF-7
(HLA-A2+/MUC1+, 
) and T-2
(HLA-A2+) cells as targets pulsed for 2 hours with 25 µg
of the cognate peptide (
). Control
targets included K562 cells (
), Croft cells (
), and SK-OV-3
cells (
).
