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At least 19 recordsLinked to original sources
PubMed2005

Aberrant T helper cell response in tumor-bearing mice limits the efficacy of dendritic cell vaccine.

Dendritic cell (DC) vaccine is a promising immunotherapy for malignancies, but its clinical efficacy has been questioned. Here we examined the mechanisms of treatment failure with DC vaccine in a murine colon cancer model. DC vaccination of naive mice prevents tumor implantation, but it is ineffective in tumor-bearing hosts despite the induction of tumor-specific CTL activity. Analyses of tumor-specific T helper cell type 1 (Th1)/T helper cell type 2 (Th2) responses showed that DC vaccine induced a mixed Th1/Th2 response in naive mice. Interestingly, CD4+ T cells from tumor-bearing mice showed a Th1-predominant response before DC vaccination but Th2 after DC vaccination. Furthermore, interleukin-10 production was higher in CD4+ T cells from vaccinated tumor-bearing mice than in CD4+ T cells from unvaccinated tumor-bearing mice. CD4+ T cells from mice treated with lipopolysaccharide (LPS)-matured DC fusion vaccine had lower production of interleukin-10 than CD4+ T cells from mice treated with non-LPS-treated DC vaccine. However, similar to the non-LPS-treated DC vaccine, the LPS-matured DC vaccine failed to suppress tumor growth and induced a Th2 predominant tumor-specific response in tumor-bearing mice. These results suggest that the presence of tumor in the host induces an aberrant CD4+ T cell response to DC vaccine, which may contribute to the failure of the vaccine to eradicate established tumors.

Animals↗
PubMed2003

Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines.

Dendritic cell (DC)-based vaccines have exhibited minimal effectiveness in treating established tumors, likely because of factors present in the tumor microenvironment. One such factor is transforming growth factor beta (TGF-beta), a cytokine that is produced by numerous tumor types and has been demonstrated to impair DC functions in vitro. We have evaluated the effect of TGF-beta on the immunostimulatory activities of DCs. We demonstrate that TGF-beta exposure inhibits the ability of DCs to present antigen, stimulate tumor-sensitized T lymphocytes, and migrate to draining lymph nodes. Neutralization of TGF-beta using the TGF-beta-neutralizing monoclonal antibody 2G7 enhanced the ability of DC vaccines to inhibit the growth of established 4T1 murine mammary tumors. Treatment of 4T1 tumors transduced with the antisense TGF-beta transgene (4T1-asT) with the combination of DC and 2G7 monoclonal antibody inhibited tumor growth and resulted in complete regression of tumors in 40% of the mice. These results demonstrate that neutralization of TGF-beta in tumor-bearing mice enhances the efficacy of DC-based vaccines.

Amino Acid Sequence↗
PubMed2000

Clinical applications of dendritic cell vaccines.

Dendritic cells play a central role in the presentation of antigen to naïve T-cells and the induction of primary immune responses. Preclinical studies have established that dendritic cells loaded with antigens ex vivo induce potent antitumor and antiviral immune responses in vitro and in vivo. This has lead to a proliferation of clinical trials testing their effectiveness in humans, particularly with advanced malignancies. The few reported studies suggest that clinically relevant immune responses may be induced against some types of malignancies. Many questions regarding the best type of dendritic cell, degree of maturity, choice of antigen, route and schedule of administration, targeting to lymphoid tissue and use of additional adjuvants will need to be answered in preclinical and clinical studies as the field of dendritic cell-based immunotherapy progresses.

Adjuvants, Immunologic↗
PubMed2006

Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine.

Dendritic cells (DC) are professional antigen-presenting cells that play a pivotal role in the induction of immunity. Ex vivo-generated, tumor antigen-loaded mature DC are currently exploited as cancer vaccines in clinical studies. However, antigen loading and maturation of DC directly in vivo would greatly facilitate the application of DC-based vaccines. We have previously shown that in situ tumor destruction by ablative treatments efficiently delivers antigens for the in vivo induction of antitumor immunity. In this article, we show that although 20% of the draining lymph node DCs acquire intratumorally injected model antigens after in situ cryoablation, only partial protection against a subsequent tumor rechallenge is observed. However, we also show that a combination treatment of cryoablation plus TLR9 stimulation via CpG-oligodeoxynucleotides is far more effective in the eradication of local and systemic tumors than either treatment modality alone. Analysis of the underlying mechanism revealed that in situ tumor ablation synergizes with TLR9 stimulation to induce DC maturation and efficient cross-presentation in tumor-bearing mice, leading to superior DC function in vivo. Therefore, in situ tumor destruction in combination with CpG-oligodeoxynucleotide administration creates a unique "in situ DC vaccine" that is readily applicable in the clinic.

Animals↗
PubMed2005

Development of cell-based tuberculosis vaccines: genetically modified dendritic cell vaccine is a much more potent activator of CD4 and CD8 T cells than peptide- or protein-loaded counterparts.

Genetically modified dendritic cell (DC)-based vaccines have not been explored for immunization against tuberculosis. A gene-modified DC vaccine expressing Mycobacterium tuberculosis (M.tb) antigen 85A (Ag85A) was developed by using a recombinant replication-deficient adenoviral gene transfer vector (AdAg85A). AdAg85A-transduced DC vaccine (AdAg85/DC) expressed higher levels of IL-12 and was much more immunogenic than Ag85 protein-loaded (pro/DC) or CD4/CD8 T cell peptide-loaded (pep/DC) DC vaccines. Compared to pro/DC or pep/DC, AdAg85/DC elicited a remarkably higher level of ex vivo IFN-gamma production by CD4 and CD8 T cells at weeks 2, 6, and 12 postimmunization, which was coupled with higher frequencies of antigen-specific T cells. By an in vivo CD8 or CD4 T cell cytotoxicity (CTL) assay, AdAg85/DC was shown to provoke much higher and more sustained levels of CD8 and CD4 CTL activity up to 12 weeks postimmunization. Intramuscular (im) AdAg85/DC immunization was more potent than the iv route of AdAg85/DC immunization. Such stronger immunogenicity of im AdAg85/DC vaccination was corroborated with better protection from M.tb challenge. Our results thus suggest that genetically modified DC-based TB vaccine is superior to subunit DC vaccines and has the potential for therapeutic applications.

Adenoviridae↗
PubMed2005

Adenovirus-mediated transgene-engineered dendritic cell vaccine of cancer.

Dendritic cells (DCs) are the most effective antigen presenting cells (APCs) to elicit both primary and secondary T-cell response that is critical for antitumor immunity and elimination of intracellular pathogens. Therefore, DCs pulsed ex vivo with antigens have the potential used as cell-based vaccines against tumors. Viral vectors derived from adenoviruses have been extensively used to pulse DCs ex vivo by delivering genes encoding immunomodulatory molecules and tumor antigens to DCs since these vectors are relatively safe, effective in inducing the maturation of DCs, and can accommodate large expression cassettes encoding antigens. One of the hurdles for gene delivery to DCs by adenovirus (Ad) vectors, however, is low transfection efficiency of DCs due to the paucity of Ad receptor on DCs. To overcome this obstacle, targeted Ad vectors have been made by modifying viral capsid proteins. These targeted Ad vectors not only enhance the gene delivery to DCs, but also allow in vivo gene delivery to DCs, thus avoiding ex vivo manipulation of DCs.

Adenoviridae↗
PubMed2004

Activated natural killer cell-mediated immunity is required for the inhibition of tumor metastasis by dendritic cell vaccination.

Immunization with dendritic cells (DCs) pulsed with tumor antigen can activate tumor-specific cytotoxic T lymphocytes (CTL), which is responsible for tumor protection and regression. In this study, we examined whether DCs pulsed with necrotic tumor lysates can efficiently prevent malignant melanoma tumor cell metastasis to the lung. DCs derived from mouse bone marrow were found to produce remarkably elevated levels of IL-12 after being pulsed with the tumor lysates. Moreover, immunization with these DCs induced CTL activation and protected mice from metastasis development by intravenously inoculated tumor cells. In addition, these DCs activated NK cells in vitro in a contact-dependent manner, and induced NK activities in vivo. Furthermore, NK cell depletion before DC vaccination significantly reduced the tumor-specific CTL activity, IFN-gamma production, and IFN-gamma- inducible gene expression, and eventually interfered with the antitumor effect of tumor-pulsed DCs. Finally, similar findings with respect to NK cell dependency were obtained in the C57BL/ 6J-bg/bg mice, which have severe deficiency in cytolytic activity of NK cells. These data suggest that the antitumor effect elicited by DC vaccination, at least in a B16 melanoma model, requires the participation of both cytolytic NK and CD8(+) T cells. The findings of this study would provide important data for the effective design of DC vaccines for cancer immunotherapy.

Animals↗
PubMed2003

Endogenous dendritic cells are required for amplification of T cell responses induced by dendritic cell vaccines in vivo.

Dendritic cells (DCs) loaded in vitro with Ag are used as cellular vaccines to induce Ag-specific immunity. These cells are thought to be responsible for direct stimulation of Ag-specific T cells, which may subsequently mediate immunity. In this study, in transgenic mouse models with targeted MHC class II expression specifically on DCs, we show that the DC vaccine is responsible only for partial CD4(+) T cell activation, but to obtain optimal expansion of T cells in vivo, participation of endogenous (resident) DCs, but not endogenous B cells, is crucial. Transfer of Ag to endogenous DCs seems not to be mediated by simple peptide diffusion, but rather by DC-DC interaction in lymph nodes as demonstrated by histological analysis. In contrast, injection of apoptotic or necrotic DC vaccines does not induce T cell responses, but rather represents an immunological null event, which argues that viability of DC vaccines can be crucial for initial triggering of T cells. We propose that viable DCs from the DC vaccine must migrate to the draining lymph nodes and initiate a T cell response, which thereafter requires endogenous DCs that present transferred Ag in order induce optimal T cell expansion. These results are of specific importance with regard to the applicability of DC vaccinations in tumor patients, where the function of endogenous DCs is suppressed by either tumors or chemotherapy.

Adoptive Transfer↗
PubMed2001

Recent advances in dendritic cell vaccines for cancer treatment.

Dendritic cells (DC) are special subsets of antigen presenting cells characterized by their unique abilities to efficiently take up, process, and present various forms of antigens to immunologically naive T cells. Recent advances in the understanding of molecular mechanisms regulating the functions of DC have allowed the investigators to "design" innovative DC-based vaccine formats for the treatment of cancer patients. In this article, we will review the most advanced DC vaccine strategies, focusing on three major areas: a) new ex vivo protocols for DC loading with tumor-associated antigens (TAA), b) genetic approaches to load skin-resident Langerhans cells (LC) with TAA, and c) chemokine-mediated LC entrapment and in situ loading of LC with TAA at the entrapment sites. We believe that these new classes of DC vaccine strategies will soon become applicable to the treatment of patients with malignant tumors.

Cancer Vaccines↗
PubMed2004

Immune response induced in vitro by CD16- and CD16+ monocyte-derived dendritic cells in patients with metastatic renal cell carcinoma treated with dendritic cell vaccines.

Monocyte-derived dendritic cells (mDC) are increasingly used as cancer vaccines. However, human monocytes are a heterogeneous cell population. We showed previously that DC derived from a monocyte subset expressing CD16 (16+mDC) stimulated allogeneic naïve T lymphocytes to secrete higher levels of IL-4 than DC derived from regular CD14(high)CD16(-) monocytes (16-mDC). Th1-type responses have been associated with effective antitumor responses, thus the use of mDC containing 16+mDC as cancer vaccines might be disadvantageous. Here, we evaluate the primary and memory immune response elicited in vitro by 16+mDC and 16-mDC in five patients with metastatic renal cell carcinoma vaccinated with autologous mDC pulsed with tumor lysates (TuLy) and keyhole limpet hemocyanin (KLH). After therapy, three of the five patients had stable disease. Surprisingly, patients with longer survival showed the highest amount of peripheral blood CD16+ monocytes. Analysis of KLH-specific antibodies revealed high titers of IgG2 in patients with longer survival. CD4+ T lymphocyte proliferation against KLH and TuLy increased after treatment, and some patients showed an augmented rate of CD4+ T lymphocyte proliferation against KLH (3/5) and TuLy (2/3) when 16+mDC were used as antigen presenting cells (APC). Before treatment, the IFN-gamma/IL-4 ratio against TuLy and KLH was higher when using 16-mDC as APC, but after vaccination four of five patients had an increased ratio for TuLy with 16+mDC. These results suggest that the immune response elicited by 16-mDC and 16+mDC is modified when memory or naïve T cells are stimulated, and 16+mDC could favor a stronger and more beneficial antitumoral Th1 memory response in vivo.

Adolescent↗
PubMed1999

Direct and indirect T cell priming by dendritic cell vaccines.

The mechanisms by which dendritic cell (DC) vaccines prime host T cells in vivo was analyzed. Mice were immunized with syngeneic bone marrow-derived DC and as surrogate antigen beta-galactosidase (beta-gal) was used. DC either pulsed with peptide, loaded with beta-gal antigen or gene-modified induced beta-gal-specific cytotoxic T lymphocytes (CTL) and moderate rejection of an in vivo challenge with beta-gal expressing tumors. In addition, beta-gal-specific CTL lysed the syngeneic DC that were used as vaccines. Using SCID mice reconstituted with F1 lymphocytes, direct priming by gene-modified DC vaccines was demonstrated by the presence of beta-gal-specific CTL of the haplotype exclusively expressed by DC while indirect priming by host antigen-presenting cells (APC) was shown by the detection of CTL of the haplotype exclusively present on host APC and absent on DC vaccines. Since DC immunization in syngeneic mice was associated with an increase in NK1.1+/Ly49C- cells and detectable lysis of DC in vitro by lymphokine-activated killer cells, DC vaccines appear to interact with host natural killer cells as well as with antigen-specific T cells. These effector cells in turn may lyse DC vaccines thereby leading to the release of antigens that can be taken up by host APC.

Animals↗
PubMed2006

Preparation of apoptotic tumor cells with replication-incompetent HSV augments the efficacy of dendritic cell vaccines.

The use of dendritic cells (DCs) loaded with apoptotic tumor cells is an attractive approach to tumor vaccination in the absence of well-characterized tumor antigens. Apoptotic tumor cells are a convenient source of polyvalent tumor antigen, but may induce only weak immunization. We tested the role of replication-incompetent recombinant herpes simplex virus (HSV) d106 lacking all immediate early genes except ICP0 in the generation of apoptotic cells for tumor vaccination, using ID8-VEGF, a syngeneic mouse model of ovarian carcinoma expressing high levels of VEGF, and TC-1, a human papillomavirus (HPV) 16 E6- and E7-transformed adenocarcinoma. HSVd106 killed tumor cells by apoptosis. Tumor cells infected by HSVd106 were engulfed more avidly by immature DCs, and induced DC maturation more efficiently than tumor cells killed by ultraviolet B (UVB) radiation. HSVd106 infection induced stronger upregulation of heat shock protein (Hsp) 70 and glucose-related protein (GRP) 94 than UVB in cells undergoing apoptosis. Immunization of mice with DCs loaded with HSVd106-killed cells elicited stronger antitumor T-cell response, including tumor-reactive interferon-gamma-secreting and cytotoxic T cells, and resulted in significantly stronger delay in tumor growth than immunization with DCs loaded with UVB-killed tumor cells. Moreover, in the TC-1 model, a protective effect of vaccination (40% tumor free animals) was observed only after immunization with DCs loaded with HSVd106-killed cells. Thus, the use of replication-incompetent HSV strains lacking immediate early genes except ICP0 offers possible advantages in the preparation of whole tumor cell antigen for DC-based tumor vaccination.

Animals↗
PubMed2006

Current state and perspectives of dendritic cell vaccination in cancer immunotherapy.

Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination.

Animals↗
PubMed2001

Dendritic cell vaccines for cancer therapy.

Dendritic cells (DC) are professional antigen-presenting cells whose primary function is the initiation of immune response. Based on the finding that the immune system usually fails to identify and kill cancer cells, DC have been recently used as vaccines for stimulation of tumour-specific immunity. This review focuses on pitfalls related to DC-based vaccination against solid tumours and on improvement of this immunotherapeutic approach for routine treatment of cancer disease.

Adjuvants, Immunologic↗
PubMed2003

Dendritic cell vaccination and viral infection--animal models.

Dendritic cells (DCs) play a pivotal role in the initiation and maintenance of immune responses against viruses and other microbial pathogens. Adoptively transferred, in vitro manipulated DCs presenting antigen derived from different viruses have been shown to elicit cytotoxic T cell (CTL) and T helper (Th) cell responses and to induce protective antiviral immunity. Furthermore, DC-based adoptive immunotherapies have the potential to specifically (re)activate antiviral immunity in chronic viral diseases such as HIV or hepatitis virus infections. Cellular dendritic cell vaccines, however, are not suitable for large-scale prophylactic immunization. Strategies for vaccine development should therefore aim at the specific delivery of microbial antigens to DCs in situ. Furthermore, appropriate mobilization and activation of DCs by the vaccine is important for the generation of optimal antimicrobial immune responses. Here, we discuss recent data on induction of antiviral immunity with various DC-vaccination approaches and outline future directions for the development of specific antigen targeting to DCs.

Animals↗
PubMed2006

Feasibility of clinical dendritic cell vaccination in acute myeloid leukemia.

Dendritic cells (DC) are increasingly being utilized for anti-cancer therapy. Acute myeloid leukemia (AML) blasts are able to differentiate towards leukemia-derived DC enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, clinical trials using AML-DC are hampered by patient inclusion criteria which allow selective entering of patients in second complete remission. Clinical relevant responses to DC-based immunotherapy are likely to only occur in non-end-stage patients. Application in early stage disease is mandatory to permit ultimate proof of clinical benefit of AML-DC vaccination strategy.

Acute Disease↗
PubMed2003

Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients.

PURPOSE: We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes. PATIENTS AND METHODS: We performed a randomized, phase I, dose-escalation study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses. RESULTS: Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8+ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8+ T cells that respond by cytokine secretion to peptide-pulsed targets (six [85.7%] of seven IN patients v two [33%] of six ID patients v none [0%] of six IV patients; P =.005) and de novo DTH (seven [87.5%] of eight IN patients v two [33.3%] of six ID patients v one [14.3%] of seven IV patients; P =.01) compared with other routes. CONCLUSION: Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.

Administration, Cutaneous↗
PubMed2005

A new dendritic cell vaccine generated with interleukin-3 and interferon-beta induces CD8+ T cell responses against NA17-A2 tumor peptide in melanoma patients.

Dendritic cells derived from monocytes cultured in the presence of type I interferon were found to induce efficient T cell responses against tumor antigens in vitro. We vaccinated eight stage III or IV melanoma patients with dendritic cells generated with interferon-beta and interleukin-3, activated by poly I: C, and pulsed with the tumor-specific antigen NA17.A2. This dendritic cell vaccine was well-tolerated with only minor and transient flu-like symptoms and inflammatory reactions at the injection sites. In most patients, isotopic imaging documented dendritic cells (DC) migration from the intradermal injection site to the draining lymph nodes. Finally, mixed lymphocyte-peptide culture under limiting dilution conditions followed by tetramer labeling indicated that three out of eight patients mounted a CD8 T cell response against the NA17.A2 antigenic peptide. We conclude that DC generated in type I-IFN represent an interesting alternative to DC generated in IL-4 and GM-CSF for cancer immunotherapy.

Adult↗