The routine methods used to treat oncological diseases have a number of drawbacks, including non-specific action and severe side effects for patients. Furthermore, tumor diseases are associated with a suppression of the immune system that often leads to the inefficiency of standard treatment methods. The development of novel immunotherapeutic approaches having specific antitumor action and that activate the immune system is of crucial importance. Vaccines based on dendritic cells DCs loaded with tumor antigens ex vivo that can activate antitumor cytotoxic T-cell responses stand out among different antitumor immunotherapeutic approaches. This review is focused on analyzing different methods of DC-based vaccine preparation and current research in antitumor DC-based vaccines using animal tumor models and in clinical trials.
Hong Y. J Immunother. Therefore, NAs are delivered into DCs using physical methods e. Mainly, they take part in regulating caspase 1 family proteins, Bj rn bernemann NLRP3 receptor is responsible for recognizing double-stranded ds RNAs. Pascolo, S. J Leukoc Biol. Shimizu K, Fujii S. Laflamme M. In comparison to protein pharmaceuticals mRNA gives more prolonged therapeutic effect. Nichols J.
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Zhu MZJ. It has not been shown to work with adult fibroblasts yet, and expression of the EBNA1 protein may raise concerns of immune rejection if the vector is retained in the reprogrammed cells [ 46 ]. A comparative study on collagen type I and hyaluronic acid dependent cell behavior for osteochondral tissue bioprinting. They concluded the potential benefits of PSA berhemann and earlier definitive cancer therapy did not outweigh the increased risks of side effects and complications from overtreatment. Transplant renal artery stenosis. Inform patients that PSA recurrence after surgery is Vintage aeroplane with a higher risk for metastatic prostate cancer and with increased mortality risk clinical principle. As a highly effective and accurate method to fabricate artificial tissue in vitro, printing achieves these three necessary components. It is possible that the sustained FIG. If adverse pathologic signs are found at Bj rn bernemann, gernemann adjuvant radiation therapy to bernemannn patient standard; evidence strength, Grade A. Lorber et al. Stem Cell Reports In a Bj rn bernemann trial, Kim and colleagues [ 20 ] reported that rats grafted with ES en DA neurons showed significant improvements in several behavioral tests and that the cells exhibited electrophysiological properties typical of midbrain DA neurons. The recently established M.
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The routine methods used to treat oncological diseases have a number of drawbacks, including non-specific action and severe side effects for patients. Furthermore, tumor diseases are associated with a suppression of the immune system that often leads to the inefficiency of standard treatment methods. The development of novel immunotherapeutic approaches having specific antitumor action and that activate the immune system is of crucial importance. Vaccines based on dendritic cells DCs loaded with tumor antigens ex vivo that can activate antitumor cytotoxic T-cell responses stand out among different antitumor immunotherapeutic approaches.
This review is focused on analyzing different methods of DC-based vaccine preparation and current research in antitumor DC-based vaccines using animal tumor models and in clinical trials. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT The routine methods used to treat oncological diseases have a number of drawbacks, including non-specific action and severe side effects for patients. Dendritic cells DCs are professional antigen-presenting cells whose key function is antigen capture, processing, and presentation to naive T cells to activate an immune response against the captured antigen.
The discovery of tumor-associated antigens TAAs , i. Today, antitumor DC-based vaccines are actively studied using both murine models in vivo and clinical trials. In , the U. Food and Drug Administration approved the first therapeutic vaccine, Sipuleucel-T,.
Hence, there are good reasons to develop highly efficient antitumor immunotherapy approaches based on the application of modified dendritic cells in the near future. This review focuses on strategies using DCs activated by various TAAs both in murine tumor models in vivo and in clinical trials. The approaches to antitumor therapy using DCs can be classified into four main groups: 1 injections of DCs loaded with tumor-associated antigens ex vivo, 2 systemic administration of tumor-associated antigens to load DCs in vivo, 3 injections of non-modified mature DCs, and 4 injections of DC-derived exosomes.
In this review, we discuss the conventional DC-based vaccines prepared by loading DCs with tumor-associated antigens ex vivo. Bone marrow-derived cells for the murine models and peripheral monocytes in clinical trials are commonly used as DC precursors pre-DCs when preparing DC-based vaccines.
The effectiveness of the antitumor immune response activated by modified DCs is strongly affected by the TAAs used to load immature DCs. Immature DCs can capture tumor antigens via a number of mechanisms, such as phagocytosis, macropi-nocytosis, receptor-mediated endocytosis, etc.
Hence, tumor-associated antigens of protein nature proteins, peptides, and lysates or apoptotic tumor cells are delivered into DCs by passively adding TAAs to immature DCs.
NAs are hydro-philic polyanionic molecules that interact with the negatively charged plasma membrane with a poor efficiency and cannot penetrate the cells through the hy-drophobic lipid bilayer of the plasma membrane. Furthermore, unprotected NAs are rapidly degraded by nucleases in body fluids. Therefore, NAs are delivered into DCs using physical methods e. Tables 1 and 2 summarize the results of the investigations of DC-based antitumor vaccines in murine models studies carried out in and clinical trials When selecting the studies to be listed, we.
We would like to take notice of the great diversity of sources of TAAs for loading DCs used in studies on murine tumor models, from the conventional tumor peptides and lysates to neuraminic acid derivatives and living tumor cells.
First of all, antigens of protein nature tumor cell lysates, proteins, and peptides were used as the main sources of TAAs for loading DCs in clinical trials. Various routes of vaccine administration intradermal, intravenous, vaccination into the lymph nodes, etc. Below, we discuss the results of 15 studies focused on DC-based vaccines in murine models and performed in Eight of them were devoted to therapeutic DC-based vaccines, where DCs were administered to tumor-bearing mice, four studies focused on preventive DC-based vaccines with DCs administered to animals before tumor grafting, and three studies were devoted to both types of DC-based vaccines.
The antitumor potential of DCs was studied in murine tumor models such as colorectal cancer [47, 48], hepatocellular carcinoma [49, 50], Dalton's lymphoma  and EL4 lymphoma , FBL3 leukemia, 4T1 breast carcinoma , B16 melanoma [30, ], Lewis lung carcinoma [58, 59], and SCCVII squamous cell lung cancer models  Table 1.
Both therapeutic and preventive DC-based vaccines were administered to animals 2 or 3 times with a 7-day interval, preferentially via subcutaneous injections or, less frequently, intraperitoneal or intravenous injections. Protein antigens first of all, lysate and the total protein of tumor cells were the most typically used as a source of TAAs to load DCs.
The vaccines being used can be subdivided into 1 DC-based vaccines without additional stimuli B16 melanoma  and Lewis lung carcinoma  ; 2 DC-based vaccines additionally treated with siRNA against immunosuppressive enzyme indolamine 2,3-dioxygenase 4T1 breast carcinoma  or with plant-based immunostimulatory polysaccharide EL4 lymphoma  ; and 3 DC-based vaccines combined with injections of cucurbitacin I that selectively inhibits STAT3 in tumor cells Dalton's lymphoma .
In addition, AH1 tumor peptide gp70 fragment in combination with the non-tumor helper peptide ovalbumin , whose key function was to increase the stability and efficiency of antigen presentation to T cells by DCs, was used as a source of TAAs. CTL activation. The preventive regimen ensures complete protection against tumor propagation. The therapeutic regimen ensures increased animal lifespan . In the model of hepatocellular carcinoma, a fusion protein carboanhy-drase 9 linked to the membrane protein of Acinetobac-ter baumannii was used to load DCs .
N-phenylacetyl-D-neuraminic acid, a synthetic derivative of neuraminic acid the models of FBL3 leukemia and B16 melanoma  , and living tumor cells B16 melanoma model [56, 57] are the novel sources of TAAs used for the activation of DCs. All the DC-based vaccines under consideration showed significant efficacy and reduced tumor size 1. In addition, injection of preventive DC-based vaccines transfected with mRNA encoding pol-ypeptide P2m-tumor peptide-TLR4  or prepared using living B16 melanoma cells as a source of TAA  fully protected animals against the development of B16 melanoma.
Antitumor DC-based vaccines significantly reduced the number of metastases in mice [30, 53, 57, 59, 60], considerably increased the lifespan of tumor-bearing animals [47, 49, 51, 53, 55, 58, 60], and induced the development of a strong antitumor response from cytotoxic T lymphocytes [, , 58, 60].
Hence, the highly promising results for both the therapeutic and preventive application of DC-based vaccines obtained using murine tumor models attest to their high potential and provide grounds for hoping.
The promising results obtained using murine models in vivo encouraged researchers to proceed to the clinical trials of antitumor DC-based vaccines as early as in the s. The safety of antitumor DC-based immunother-apy has been documented in the clinical trials that have been carried out in the past 20 years.
DC vaccination is well tolerated  and has minor side effects, such as local inflammation reaction at the injection site and in lymph nodes [62, 63]; manifestations similar to influenza symptoms are sometimes observed [63, 64].
Nevertheless, despite its safety and high potential, immunovac-cination of cancer patients with DC-based vaccines in most cases has proved less efficacious than in experiments using murine models. There can be various reasons for this, including the fact that in most studies, DC vaccination was used for terminal patients with extremely aggressive tumors that do not respond to conventional therapy and also the fact that human tumors have a stronger immunosuppressive activity.
Although there have not been that many impressive clinical results, further development of antitumor DC-based vaccines continues: our understanding of the DC function is being deepened, novel sources of tumor antigens and immunostimulatory agents for loading and activating DC are being tested, and the potential of combining DC-based vaccines with other approaches is being evaluated.
We have made an attempt to assess the variety and clinical efficacy of DC-based vaccines for tumors of different origins. With this aim in mind, we analyzed the results reported in 20 studies performed in ; in most of them, DC-based vaccines were in phase I and II clinical trials Table 2.
These studies were conducted for cancers of different nosological entities. Various tumor antigens loaded into DCs, treatment regimens, and combination of DC-based vaccines with other therapeutic approaches were employed. Pancreatic cancer I 10 WT-1 peptide. Combination with gemcitabine. Days 8 and ID injection, 1x DCs. No clinical response .
Combination with cytokine-induced killer cells CIKs. No clinical response. I 8 Autologous melanoma cell lysate; TNF-a. Combination with tumor-infiltrating T cells. Preliminary chemotherapy. DCs injected ID, 3 times with a day interval. Mean relapse-free survival time is 22 months. Group B: 4-month chemotherapy course The overall two-year survival rate in groups A and B is Combination with chemotherapy.
Cyclophosphamide, 7 days 2. DCs, SC injection, cells, 12 times within the first year 2 times with a 2-week interval 3. Docetaxel every 3 weeks until toxicity is achieved. The mean survival time is 19 months. The antitumor potential of DC-based vaccines was evaluated in patients with a cancer of the gastrointestinal tract liver, pancreatic, and colorectal cancer , brain glioblastoma , blood myeloid leukemia, lym-phocytic leukemia, lymphoma , bone tissue osteosar-coma , the reproductive system ovarian or prostate cancer , skin melanoma , and lungs non-small cell cancer both after the tumors had been surgically resected and patients had undergone conventional chemo- or radiotherapy and in treatment-naive patients Table 2.
The adequacy of DC-based vaccines was evaluated using two criteria: the immunological criterion and the clinical one.
Table 2. Unconventional DC-based vaccines were used as antitumor vaccines undergoing phase III clinical trials: DCs isolated from pulmonary lymph nodes were used in non-small cell lung cancer ; the Sipuleucel-T vaccine a cellular agent isolated from leukapheresis-derived products that included DCs was used in patients with prostate cancer [5, 83].
Protein antigens peptides, synthetic proteins, and tumor cell lysates were used most frequently 15 out of 20 publications as a source of TAAs to load DCs. In the case of hepatocellular carcinoma, DCs were loaded with fusion proteins containing TAAs such as a-fetoprotein, glypican-3 and MAGE-3, each of those connected to a cytoplasmic transduction peptide .
Tumor cell lysates were used to prepare DC-based vaccines against osteosarcoma  and melanoma [76, 78, 80]; the lysate was most often prepared from autologous tumor cells. DCs were also often loaded with apoptotic tumor cells e. It is known that injection of immature DCs into a tumor-bearing organism can cause the development of tolerance of the immune system to tumor antigens, ultimately resulting in an even greater tumor progression .
Therefore, much attention is paid to agents that stimulate DC maturation in almost all clinical trials of DC-based vaccines. Both single pro-inflammatory cytokines TNF-a or IFN-y and cocktails containing a combination of pro-inflammatory cytokines, prosta-glandin E2, and in some cases poly I:C oligonucleotides, low-virulence S.
Despite the variety of protocols for tumor immu-notherapy with DC-based vaccines, common features can also be listed. DCs are preferentially administered either intradermally or subcutaneously times with a 7- to day interval. The mean dose is DCs. In some cases, DC vaccination can be combined with chemotherapy gemcitabine for pancreatic tumor , cyclophosphamide for lymphocytic leukemia  and ovarian cancer , and docetaxel for prostate cancer  , with the application of other immune cells e.
However, despite the substantial immune response, the clinical efficacy of antitumor DC-based therapy is less impressive. The clinical response is either rather weak or absent, which manifests itself in a large number of relapses and tumor progression. Immunotherapy using this vaccine resulted in remission in none of the patients; disease progression was observed in most cases, although patient survival increased 1. Hence, a conclusion can be drawn that activation of a tumor-specific immune response after DC vaccination does not necessarily provide significant clinical outcomes.
First of all, this can be attributed to the negative effect of the tumor on the immune system. Even provided that antitumor T cells are properly activated by DC-based vaccines, immunotherapy may fail, since the tumor can evade immune surveillance by suppressing the functional activity of immunocompetent cells, including T cells and DCs, via various mechanisms .
Tumor remission in a number of patients is indicative of the clinical significance of DC vaccination. This is one of the highest indices of clinical efficacy of DC-based vaccines in the studies covered in this review. During the mean follow-up 6. The mean relapse-free survival time was 22 months. Four out of 10 patients showed an immune response against melanoma-associated antigens . Either complete or partial remission of melanoma was also observed after patients had undergone im-munotherapy with DC-based vaccines with lysates of.
It is noteworthy that melanoma is used appreciably often in clinical studies of the antitumor activity of DCs and is relatively more susceptible to immunotherapy than other tumor types.
He looks otherwise healthy. Freude, Poul Hyttel. His bone scan for metastasis is negative. PLoS Biol ;7:e It appears to offer improved sensitivity and specificity over standard imaging by combining molecular activity testing with conventional morphologically based radiographic studies.
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