共查询到20条相似文献,搜索用时 15 毫秒
1.
Dendritic cell-based cancer immunotherapy targeting MUC-1 总被引:3,自引:0,他引:3
Vaccination therapy using dendritic cells (DC) as antigen presenting cells (APC) has shown significant promise in laboratory
and animal studies as a potential treatment for malignant diseases. Pulsing of autologous DCs with tumor-associated antigens
(TAA) is a method often used for antigen delivery and choice of suitable antigens plays an important role in designing an
effective vaccine. We identified two HLA-A2 binding novel 9-mer peptides of the TAA MUC1, which is overexpressed on various
hematological and epithelial malignancies. Cytotoxic T cells generated after pulsing DC with these peptides were able to induce
lysis of tumor cells expressing MUC1 in an antigen-specific and HLA-restricted fashion. Within two clinical studies, we demonstrated
that vaccination of patients with advanced cancer using DCs pulsed with MUC1 derived peptides is well tolerated without serious
side effects and can induce immunological responses. Of 20 patients with metastatic renal cell carcinoma, 6 patients showed
regression of metastases with 3 objective responses (1 CR, 2 PR). Furthermore, we found that in patients responding to treatment
T cell responses for antigens not used for treatment occurred suggesting that antigen spreading in vivo might be a possible
mechanism of mediating antitumor effects. These results demonstrate that immunotherapy in patients with advanced malignancies
using autologous DCs pulsed with MUC1 derived peptides can induce immunological and clinical responses. However, further clinical
studies are needed to identify the most potent treatment regimen that can consistently mediate an antitumor immune response
in vivo.
This article is a symposium paper from the conference “Progress in Vaccination against Cancer 2004 (PIVAC 4)”, held in Freudenstadt-Lauterbad,
Black Forest, Germany, on 22–25 September 2004. 相似文献
2.
Jun Zhou Desheng Weng Fangjian Zhou Ke Pan Haifeng Song Qijing Wang Huan Wang Hui Wang Yongqiang Li Lixi Huang Huakun Zhang Wei Huang Jianchuan Xia 《Cancer immunology, immunotherapy : CII》2009,58(10):1587-1597
Renal cell carcinoma (RCC) has been shown to be susceptible to immunotherapeutic treatment strategies. In the present study,
patient-derived tumor cells were fused with allogeneic dendritic cells (DC) to elicit anti-tumor activity against RCC. DC
from HLA-A2+ healthy donors were fused with primary RCC cells from ten patients. Phenotype of fusion cells were characterized
by flow cytometer and confocal microscopy. In vitro, T cell proliferation, IFN-γ secretion and cytotocic T lymphocytes (CTL)
activity elicited by allogeneic DC/RCC fusion cells were assessed. Clinically, ten patients were vaccinated with allogeneic
DC/RCC fusion vaccine. The adverse effects and toxicity were observed. The clinical response was evaluated by CT scans. After
fusion, the created hybrids expressed both tumor associated antigen and DC-derived molecules and could stimulate the proliferation
and IFN-γ secretion of T cells as well as elicit strong CTL activity against RCC cells in vitro. In vivo, no serious adverse
effects, toxicity, or signs of autoimmune disease were observed after vaccination therapy. Percentage of T lymphocyte subsets
in peripheral blood of patients was increased significantly. One of ten patients exhibited a partial response with regression
of lung metastases. Six patients showed stable disease with stabilization of previously progressive disease (follow up 1.5 years).
The PR and SD responses, exhibited by 7/10 patients who received the allogeneic DC/RCC fusion vaccine treatment, suggest that
this approach is safe and can elicit immunological responses in a significant portion of patients with RCC.
J. Zhou and D. Weng contributed equally. 相似文献
3.
Sandy Pelletier Simon Tanguay Stephen Lee Lakshman Gunaratnam Nathalie Arbour Réjean Lapointe 《Cancer immunology, immunotherapy : CII》2009,58(8):1207-1218
Objectives Patients with renal cell carcinomas (RCC) have few treatment options, underscoring the importance of developing new approaches
such as immunotherapy. However, few tumor associated antigens (TAA), which can be targeted by immunotherapy, have been identified
for this type of cancer. von Hippel-Lindau clear cell RCC (VHL−/−RCC) are characterized by mutations in the VHL tumor suppressor gene. Loss of VHL function causes the overexpression of transforming
growth factor (TGF)-α, leading us to hypothesize that TGF-α could be a potential TAA for immunotherapy of kidney cancer, which
was evaluated in this study.
Methods and results We first confirmed the absent or weak expression of TGF-α in important normal tissues as well as its overexpression in 61%
of renal tumors in comparison to autologous normal kidney tissues. In addition, we demonstrated the immunogenicity of TGF-α,
by expanding many T cell lines specific for certain TGF-α peptides or the mature TGF-α protein, when presented by major histocompatibility
complex (MHC) molecules on the surface of antigen-presenting cells. Interestingly, some of these TGF-α-specific T cells were
polyfunctionals and secreted IFN-γ, TNF-α and IL-2.
Conclusion We have shown that TGF-α is a valid candidate TAA, which should allow the development of a targeted immunotherapy. 相似文献
4.
Abhishek K. Srivastava Rajesh K. Sharma Esma S. Yolcu Vahap Ulker Kathryn MacLeod Gunes Dinc Haval Shirwan 《PloS one》2012,7(11)
Subunit vaccines containing universal tumor associated antigens (TAAs) present an attractive treatment modality for cancer primarily due to their safety and potential to generate long-term immunological responses that can safeguard against recurrences. However, TAA-based subunit vaccines require potent adjuvants for therapeutic efficacy. Using a novel form of the 4-1BBL costimulatory molecule, SA-4-1BBL, as the adjuvant of choice, we previously demonstrated that a single vaccination with survivin (SVN) as a bona fide self TAA was effective in eradicating weakly immunogenic 3LL tumors in >70% of C57BL/6 mice. The present study was designed to i) assess the therapeutic efficacy of a prime-boost vaccination and ii) investigate the mechanistic basis of vaccine efficacy. Our data shows that a prime-boost vaccination strategy was effective in eradicating 3LL lung carcinoma in 100% of mice. The vaccine efficacy was correlated with increased percentages of CD8+ T cells expressing IFN-γ as well as potent killing responses of both CD8+ T and NK cells in the absence of detectable antibodies to ssDNA as a sign of autoimmunity. Antibody depletion of CD8+ T cells one day before vaccination completely abrogated therapeutic efficacy, whereas depletion of CD4+ T cells had no effect. Importantly, NK cell depletion had a moderate (∼50% reduction), but significant (p<0.05) effect on vaccine efficacy. Taken together, these results shed light on the mechanistic basis of the SA-4-1BBL/SVN subunit vaccine formulation in a lung carcinoma model and demonstrate the robust therapeutic efficacy of the prime-boost immunization strategy with important clinical implications. 相似文献
5.
Adoptive immuno-gene therapy of cancer with single chain antibody [scFv(Ig)] gene modified T lymphocytes 总被引:4,自引:0,他引:4
Lamers CH Sleijfer S Willemsen RA Debets R Kruit WH Gratama JW Stoter G 《Journal of biological regulators and homeostatic agents》2004,18(2):134-140
Adoptive transfer of antigen-specific T cells has recently shown therapeutic successes in the treatment of viral infections and tumors. T cells specific for the antigen of interest can be generated in vitro, and adoptively transferred back to provide patients with large numbers of immune-competent T cells. Adoptive T cell therapy, however, is a patient-tailored treatment that unfortunately is not universally applicable to treat viral infections and tumors. We and others have demonstrated that the transfer of genes encoding antigen-specific receptors into T cells (i.e., genetic retargeting) represents an attractive alternative to induce antigen-specific immunity. Currently, we evaluate this concept in a clinical protocol to treat patients with metastatic renal cell cancer (RCC) using autologous RCC-specific gene-modified T lymphocytes. 相似文献
6.
Noriaki Nakai Gunther Hartmann Saburo Kishimoto Norito Katoh 《Pigment cell & melanoma research》2010,23(5):607-619
Eleven years have passed since the start of the first trial of dendritic cell (DC) vaccination for melanoma. A review of 54 trials was performed to evaluate the relationship between clinical effects and vaccine parameters. Significant differences were found between use of immature and mature DCs with regard to progressive disease (PD), between stage III and IV for clinical response, between use and non-use of adjuvants with regard to stable disease (SD) in treatment with tumor/tumor lysate-pulsed DCs, between positive and negative delayed-type hypersensitivity (DTH) for PD, and between increased and unchanged interferon (IFN)-γ-secreting T cells for clinical response. These results are consistent with the partial efficacy of vaccination with mature DCs in early stage melanoma and the partial correlation of efficacy with positive DTH and increased IFN-γ-secreting T cells. DC vaccination alone had a limited clinical effect and a modified regimen is needed to enhance antigen-specific cytotoxic T cells and decrease immunosuppression. 相似文献
7.
Sofía Grille Andreína Brugnini Martha Nese Esteban Corley Frank W. Falkenberg Daniela Lens José A. Chabalgoity 《Cancer immunology, immunotherapy : CII》2010,59(4):519-527
Therapeutic vaccination holds great potential as complementary treatment for non-Hodgkin’s lymphoma. Here, we report that
a therapeutic whole cell vaccine formulated with IL-2 adsorbed onto aluminum hydroxide as cytokine-depot formulation elicits
potent antitumor immunity and induces delayed tumor growth, control of tumor dissemination and longer survival in mice challenged
with A20-lymphoma. Therapeutic vaccination induced higher numbers of tumor’s infiltrating lymphocytes (CD4+ and CD8+ T cells and NK cells), and the production of IFN-γ and IL-4 by intratumoral CD4+ T cells. Further, strong tumor antigen-specific cellular responses were detected at systemic level. Both the A20-derived
antigenic material and the IL-2 depot formulation were required for induction of an effective immune response that impacted
on cancer progression. All mice receiving any form of IL-2, either as part of the vaccine or alone as control, showed higher
numbers of CD4+CD25+/highFoxp3+ regulatory T cells (Treg) in the tumor, which might have a role in tumor progression in these animals. Nevertheless, for
those animals that received the cytokine as part of the vaccine formulation, the overall effect was improved immune response
and less disseminated disease, suggesting that therapeutic vaccination overcomes the potential detrimental effect of intratumoral
Treg cells. Overall, the results presented here show that a simple vaccine formulation, that can be easily prepared under
GMP conditions, is a promising strategy to be used in B-cell lymphoma and may have enough merit to be tested in clinical trials. 相似文献
8.
9.
Anticancer vaccines have been extensively studied in animal models and in clinical trials. While vaccination can lead to tumor protection in numerous murine models, objective tumor regressions after anticancer vaccination in clinical trials have been rare. B16 is a poorly immunogenic murine melanoma that has been extensively used in anticancer vaccination experiments. Because B16 has been widely used, different vaccination strategies can be compared. We reviewed the results obtained when B16 was treated with five common vaccine types: recombinant viral vaccines, DNA vaccines, dendritic cell vaccines, whole-tumor vaccines, and peptide vaccines. We also reviewed the results obtained when B16 was treated with vaccines combined with adoptive transfer of tumor antigen-specific T cells. We found several characteristics of vaccination regimens that were associated with antitumor efficacy. Many vaccines that incorporated xenogeneic antigens exhibited more potent anticancer activity than vaccines that were identical except that they incorporated the syngeneic version of the same antigen. Interleukin-2 enhanced the antitumor efficacy of several vaccines. Finally, several effective regimens generated large numbers of tumor antigen-specific CD8(+) T cells. Identification of vaccine characteristics that are associated with antitumor efficacy may aid in the development of more effective anticancer vaccination strategies. 相似文献
10.
Vaccine and antibody-directed T cell tumour immunotherapy 总被引:3,自引:0,他引:3
Dermime S Gilham DE Shaw DM Davidson EJ Meziane el-K Armstrong A Hawkins RE Stern PL 《Biochimica et biophysica acta》2004,1704(1):11-35
Clearer evidence for immune surveillance in malignancy and the identification of many new tumour-associated antigens (TAAs) have driven novel vaccine and antibody-targeted responses for therapy in cancer. The exploitation of active immunisation may be particularly favourable for TAA where tolerance is incomplete but passive immunisation may offer an additional strategy where the immune repertoire is affected by either tolerance or immune suppression. This review will consider how to utilise both active and passive types of therapy delivered by T cells in the context of the failure of tumour-specific immunity by presenting cancer patients. This article will outline the progress, problems and prospects of several different vaccine and antibody-targeted approaches for immunotherapy of cancer where proof of principle pre-clinical studies have been or will soon be translated into the clinic. Two examples of vaccination-based therapies where both T cell- and antibody-mediated anti-tumour responses are likely to be relevant and two examples of oncofoetal antigen-specific antibody-directed T cell therapies are described in the following sections: (1) therapeutic vaccination against human papillomavirus (HPV) antigens in cervical neoplasia; (2) B cell lymphoma vaccines including against immunoglobulin idiotype; (3) oncofoetal antigens as tumour targets for redirecting T cells with antibody strategies. 相似文献
11.
Lisa M. Ebert Sarah E. MacRaild Damien Zanker Ian D. Davis Jonathan Cebon Weisan Chen 《PloS one》2012,7(10)
Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIXTM cancer vaccine. All patients tested had Treg (CD25bright FoxP3+ CD127neg) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1157–170 epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1115–132 peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials. 相似文献
12.
Kobayashi H Azumi M Kimura Y Sato K Aoki N Kimura S Honma M Iizuka H Tateno M Celis E 《Cancer immunology, immunotherapy : CII》2009,58(6):931-940
Background Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis
that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and
ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of
malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune
cellular responses.
Methods To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC
class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients.
Results Two synthetic peptides, FAK143–157 and FAK1,000–1,014, induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing
tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient’s
CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients.
Conclusions Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based
immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors. 相似文献
13.
A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《Molecular medicine (Cambridge, Mass.)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
F. M. Batliwalla B. A. Bateman D. Serrano D. Murray S. Macphail V. C. Maino J. C. Ansel P. K. Gregersen C. A. Armstrong 《Molecular medicine (Cambridge, Mass.)》1998,4(12):783-794
BACKGROUND: The development of effective adjuvant therapies for the treatment of high-risk melanoma patients is critical for the prevention of metastatic disease and improvement of patient survival. Active specific immunotherapy has been tested as an adjuvant treatment in numerous clinical trials with overall limited, but occasionally promising, success rates. Newcastle disease virus (NDV) oncolysate has been utilized as an adjunctive immunotherapeutic agent in the postsurgical management of these patients. A phase II study initiated in 1975 using adjuvant vaccine therapy composed of allogeneic and autologous human melanoma cells infected with live NDV (NDV oncolysate) in patients with AJCC stage III melanoma following therapeutic lymph node dissection has shown >60% survival rate at 10 years with no adverse effects. Continued long-term analysis of trials with promising early results as well as assessment of immunologic responses generated in these patients may result in improved therapeutic decisions for clinical trials in the future. MATERIALS AND METHODS: We analyzed the 15-year survival of patients treated postsurgically with NDV oncolysate in the phase II study described above. In an attempt to understand the immunological effects of this treatment, we have also carried out a comprehensive analysis of the peripheral blood T cell repertoire in these patients. RESULTS: The overall 15-year survival of this group of patients is 55%. Previous studies have suggested that improved outcome in patients undergoing immunotherapy is correlated with increased numbers of CD8(+)CD57(+) cells. In surviving patients, we observed a striking oligoclonality in the CD8(+) T cell population in peripheral blood, which reflects clonal expansions in the CD8(+)CD57(+) subset. CONCLUSIONS: The data suggest that adjuvant vaccination with NDV oncolysates is associated with prolonged survival of patients with lymph node-positive malignant melanoma and that CD8(+) T cells may be an important component of therapeutic efficacy. 相似文献
14.
Johnson LE Frye TP Chinnasamy N Chinnasamy D McNeel DG 《Cancer immunology, immunotherapy : CII》2007,56(6):885-895
Prostatic acid phosphatase (PAP) is a prostate cancer tumor antigen and a prostate-specific protein shared by rats and humans.
Previous studies indicated that Copenhagen rats immunized with a recombinant vaccinia virus expressing human PAP (hPAP) developed
PAP-specific cytotoxic T cells (CTL) with cross reactivity to rat PAP (rPAP) and evidence of prostate inflammation. Viral
delivery of vaccine antigens is an active area of clinical investigation. However, a potential difficulty with viral-based
immunizations is that immune responses elicited to the viral vector might limit the possibility of multiple immunizations.
In this paper, we investigate the ability of another genetic immunization method, a DNA vaccine encoding PAP, to elicit antigen-specific
CD8+ T cell immune responses. Specifically, Lewis rats were immunized with either a plasmid DNA-based (pTVG-HP) or vaccinia-based
(VV-HP) vaccine each encoding hPAP. We determined that rats immunized with a DNA vaccine encoding hPAP developed a Th1-biased
immune response as indicated by proliferating PAP-specific CD4+ and CD8+ cells and IFNγ production. Rats immunized with vaccinia
virus encoding PAP did not develop a PAP-specific response unless boosted with a heterologous vaccination scheme. Most importantly,
multiple immunizations with a DNA vaccine encoding the rat PAP homologue (pTVG-RP) could overcome peripheral self-tolerance
against rPAP and generate a Th1-biased antigen-specific CD4+ and CD8+ T cell response. Overall, DNA vaccines provide a safe
and effective method of generating prostate antigen-specific T cell responses. These findings support the investigation of
PAP-specific DNA vaccines in human clinical trials. 相似文献
15.
Heike Pohla Alexander Buchner Birgit Stadlbauer Bernhard Frankenberger Stefan Stevanovic Steffen Walter Ronald Frank Tim Schwachula Sven Olek Joachim Kopp Gerald Willimsky Christian G Stief Alfons Hofstetter Antonio Pezzutto Thomas Blankenstein Ralph Oberneder Dolores J Schendel 《Molecular medicine (Cambridge, Mass.)》2012,18(1):1499-1508
Our previously reported phase I clinical trial with the allogeneic gene–modified tumor cell line RCC-26/CD80/IL-2 showed that vaccination was well tolerated and feasible in metastatic renal cell carcinoma (RCC) patients. Substantial disease stabilization was observed in most patients despite a high tumor burden at study entry. To investigate alterations in immune responses that might contribute to this effect, we performed an extended immune monitoring that included analysis of reactivity against multiple antigens, cytokine/chemokine changes in serum and determination of the frequencies of immune suppressor cell populations, including natural regulatory T cells (nTregs) and myeloid-derived suppressor cell subsets (MDSCs). An overall immune response capacity to virus-derived control peptides was present in 100% of patients before vaccination. Vaccine-induced immune responses to tumor-associated antigens occurred in 75% of patients, demonstrating the potent immune stimulatory capacity of this generic vaccine. Furthermore, some patients reacted to peptide epitopes of antigens not expressed by the vaccine, showing that epitope-spreading occurred in vivo. Frequencies of nTregs and MDSCs were comparable to healthy donors at the beginning of study. A significant decrease of nTregs was detected after vaccination (p = 0.012). High immune response rates, decreased frequencies of nTregs and a mixed T helper 1/T helper 2 (TH1/TH2)-like cytokine pattern support the applicability of this RCC generic vaccine for use in combination therapies. 相似文献
16.
Lang JM Kaikobad MR Wallace M Staab MJ Horvath DL Wilding G Liu G Eickhoff JC McNeel DG Malkovsky M 《Cancer immunology, immunotherapy : CII》2011,60(10):1447-1460
Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond
to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates,
including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded
with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current
report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with
low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit
an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however,
two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day
8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated
from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2
T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration
of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2
T cell in patients with metastatic RCC. 相似文献
17.
18.
Hörig H Lee DS Conkright W Divito J Hasson H LaMare M Rivera A Park D Tine J Guito K Tsang KW Schlom J Kaufman HL 《Cancer immunology, immunotherapy : CII》2000,49(9):504-514
The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope
and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC)
constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study
in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses.
Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an
ALVAC-CEA-B7.1 vaccine (4.5 × 106, 4.5 × 107, and 4.5 × 108 plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored
for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA- B7.1 at doses up to 4.5 × 108 PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable
disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-γ enzyme-linked immunoassay
spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses.
This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted
in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific
T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1
to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with
tolerable toxicity.
Received: 6 May 2000 / Accepted: 13 July 2000 相似文献
19.
Background
CD4+CD25+ regulatory T cells (Tregs) suppress adaptive T cell-mediated immune responses to self- and foreign-antigens. Tregs may also suppress early innate immune responses to vaccine antigens and might decrease vaccine efficacy. NK and NKT cells are the first responders after plasmid DNA vaccination and are found at the site of inoculation. Earlier reports demonstrated that NKT cells could improve plasmid DNA efficacy, a phenomenon not found for NK cells. In fact, it has been shown that under certain disease conditions, NK cells are suppressed by Tregs via their release of IL-10 and/or TGFβ. Therefore, we tested the hypothesis that NK cell function is suppressed by Tregs in the setting of plasmid DNA vaccination.Methodology/Principal Findings
In this study we show that Tregs directly inhibit NK cell function during plasmid DNA vaccination by suppressing the potentially 10-fold, NK cell-mediated, augmentation of plasmid DNA antigen-specific CD8+ T cells. We found that this phenomenon is dependent on the secretion of cytokine TGFβ by Tregs, and independent of IL-10.Conclusions
Our data indicate a crucial function for Tregs in blocking plasmid DNA vaccine-elicited immune responses, revealing potentially novel strategies for improving the efficiency of plasmid DNA vaccines including chemical- or antibody-induced localized blockage of Treg-mediated suppression of NK cells at the site of plasmid DNA vaccine inoculation. 相似文献20.
Debapriya Bhattacharya Ved Prakash Dwivedi Santosh Kumar Madhava C. Reddy Luc Van Kaer Prashini Moodley Gobardhan Das 《The Journal of biological chemistry》2014,289(48):33404-33411
Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy. 相似文献