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Pharmaceutics
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Dendritic Cell Vaccines
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Dendritic Cell Vaccines

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (10 December 2019) | Viewed by 50149

Special Issue Editors

Dr. Maria Teresa Cruz

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Guest Editor
Faculty of Pharmacy and Center for Neurosciences and Cell Biology, University of Coimbra, 3004-531 Coimbra, Portugal
Interests: immunopharmacology; pharmacotoxicology; innate immune cells; inflammation; immunotherapy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Bruno Miguel Neves

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Guest Editor
Department of Medical Sciences and Institute of Biomedicine – iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: immunobiology of innate immune cells; signal transduction; cell-based therapies
Special Issues, Collections and Topics in MDPI journals
Dr. Mylène Carrascal

E-Mail Website
Guest Editor
Tecnimede Group – Tecnimede SA, Sintra, Portugal
Interests: tumor immunotherapy; dendritic cells biology; cell-based vaccines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dendritic cells (DCs) are professional antigen-presenting cells displaying an odd capacity to induce and regulate T-cell responses. Due to their immunoregulatory capacities, these cells have been extensively tested in pre-clinical and clinical studies for their capacity to amplify immune responses against cancer. While clinical trials provide evidence that DC vaccines are safe and elicit immunological responses in most patients, few complete tumor remissions have been reported. To improve their clinical efficacy, it is mandatory to design novel and improved strategies that can boost adaptive and innate immunity against cancer, helping to overcome tumor immunoescape mechanisms.

This Special Issue of Pharmaceutics focuses on new approaches to improve the immunogenic profile of DCs towards tumor cells paving the way to the development of new DCs-based immunotherapeutic strategies. We welcome articles concerning all aspects covering the key biological qualities of DCs for immunotherapy, the wide range of adjuvants available, the multiple forms of tumor antigen and its loading, and different modes of vaccine delivery. The potential to fortify responses with other anti-cancer combinatorial approaches to boost the clinical potency of DC-based vaccines is also welcome.

We invite experts from academia or industry to contribute to this Special Issue with original research articles, reviews, or commentaries.

Dr. Maria Teresa Cruz
Prof. Dr. Bruno Miguel Neves
Dr. Mylène Carrascal
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Keywords

  • dendritic cells
  • cancer vaccines
  • immunotherapy
  • cell-based therapy
  • tumor antigens

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Related Special Issue

Published Papers (9 papers)

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Research

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21 pages, 2768 KiB  
Article
MHC Class I Stability is Modulated by Cell Surface Sialylation in Human Dendritic Cells
by Zélia Silva, Tiago Ferro, Danielle Almeida, Helena Soares, José Alexandre Ferreira, Fanny M. Deschepper, Paul J. Hensbergen, Martina Pirro, Sandra J. van Vliet, Sebastian Springer and Paula A. Videira
Pharmaceutics 2020, 12(3), 249; https://doi.org/10.3390/pharmaceutics12030249 - 10 Mar 2020
Cited by 18 | Viewed by 6664
Abstract
Maturation of human Dendritic Cells (DCs) is characterized by increased expression of antigen presentation molecules, and overall decreased levels of sialic acid at cell surface. Here, we aimed to identify sialylated proteins at DC surface and comprehend their role and modulation. Mass spectrometry [...] Read more.
Maturation of human Dendritic Cells (DCs) is characterized by increased expression of antigen presentation molecules, and overall decreased levels of sialic acid at cell surface. Here, we aimed to identify sialylated proteins at DC surface and comprehend their role and modulation. Mass spectrometry analysis of DC’s proteins, pulled down by a sialic acid binding lectin, identified molecules of the major human histocompatibility complex class I (MHC-I), known as human leucocyte antigen (HLA). After desialylation, DCs showed significantly higher reactivity with antibodies specific for properly folded MHC-I-β2-microglobulin complex and for β2-microglobulin but showed significant lower reactivity with an antibody specific for free MHC-I heavy chain. Similar results for antibody reactivities were observed for TAP2-deficient lymphoblastoid T2 cells, which express HLA-A*02:01. Using fluorescent peptide specifically fitting the groove of HLA-A*02:01, instead of antibody staining, also showed higher peptide binding on desialylated cells, confirming higher surface expression of MHC-I complex. A decay assay showed that desialylation doubled the half-life of MHC-I molecules at cell surface in both DCs and T2 cells. The biological impact of DC´s desialylation was evaluated in co-cultures with autologous T cells, showing higher number and earlier immunological synapses, and consequent significantly increased production of IFN-γ by T cells. In summary, sialic acid content modulates the expression and stability of complex MHC-I, which may account for the improved DC-T synapses. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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13 pages, 1950 KiB  
Article
PGE2 Is Crucial for the Generation of FAST Whole- Tumor-Antigens Loaded Dendritic Cells Suitable for Immunotherapy in Glioblastoma
by Sara Nava, Daniela Lisini, Simona Frigerio, Simona Pogliani, Serena Pellegatta, Laura Gatti, Gaetano Finocchiaro, Anna Bersano and Eugenio Agostino Parati
Pharmaceutics 2020, 12(3), 215; https://doi.org/10.3390/pharmaceutics12030215 - 2 Mar 2020
Cited by 4 | Viewed by 2889
Abstract
Dendritic cells (DC) are the most potent antigen-presenting cells, strongly inducers of T cell-mediated immune responses and, as such, broadly used as vaccine adjuvant in experimental clinical settings. DC are widely generated from human monocytes following in vitro protocols which require 5–7 days [...] Read more.
Dendritic cells (DC) are the most potent antigen-presenting cells, strongly inducers of T cell-mediated immune responses and, as such, broadly used as vaccine adjuvant in experimental clinical settings. DC are widely generated from human monocytes following in vitro protocols which require 5–7 days of differentiation with GM-CSF and IL-4 followed by 2–3 days of activation/maturation. In attempts to shorten the vaccine’s production, Fast-DC protocols have been developed. Here we reported a Fast-DC method in compliance with good manufacturing practices for the production of autologous mature dendritic cells loaded with antigens derived from whole tumor lysate, suitable for the immunotherapy in glioblastoma patients. The feasibility of generating Fast-DC pulsed with whole tumor lysate was assessed using a series of small-scale cultures performed in parallel with clinical grade large scale standard method preparations. Our results demonstrate that this Fast protocol is effective only in the presence of PGE2 in the maturation cocktail to guarantee that Fast-DC cells exhibit a mature phenotype and fulfill all requirements for in vivo use in immunotherapy approaches. Fast-DC generated following this protocol were equally potent to standard DC in inducing Ag-specific T cell proliferation in vitro. Generation of Fast-DC not only reduces labor, cost, and time required for in vitro clinical grade DC development, but can also minimizes inter-preparations variability and the risk of contamination. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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10 pages, 2188 KiB  
Article
Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA
by Alvaro Moreira, Michael Erdmann, Ugur Uslu, Verona Vass, Gerold Schuler and Beatrice Schuler-Thurner
Pharmaceutics 2020, 12(3), 210; https://doi.org/10.3390/pharmaceutics12030210 - 1 Mar 2020
Cited by 6 | Viewed by 2792
Abstract
Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to [...] Read more.
Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA. Methods: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears. Results: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2–111 months), compared to a median of 20 months (range 0–119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06). Conclusion: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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16 pages, 5194 KiB  
Article
Decellularized Lymph Node Scaffolding as a Carrier for Dendritic Cells to Induce Anti-Tumor Immunity
by Hung-Jun Lin, Weu Wang, Yi-You Huang, Wei-Tsen Liao, Ting-Yu Lin, Shyr-Yi Lin and Der-Zen Liu
Pharmaceutics 2019, 11(11), 553; https://doi.org/10.3390/pharmaceutics11110553 - 26 Oct 2019
Cited by 14 | Viewed by 4298
Abstract
In recent decades, the decellularized extracellular matrix (ECM) has shown potential as a promising scaffold for tissue regeneration. In this study, an organic acid decellularized lymph node (dLN) was developed as a carrier for dendritic cells (DCs) to induce antitumor immunity. The dLNs [...] Read more.
In recent decades, the decellularized extracellular matrix (ECM) has shown potential as a promising scaffold for tissue regeneration. In this study, an organic acid decellularized lymph node (dLN) was developed as a carrier for dendritic cells (DCs) to induce antitumor immunity. The dLNs were prepared by formic acid, acetic acid, or citric acid treatment. The results showed highly efficient removal of cell debris from the lymph node and great preservation of ECM architecture and biomolecules. In addition, bone marrow dendritic cells (BMDCs) grown preferably inside the dLN displayed the maturation markers CD80, CD86, and major histocompatibility complex (MHC)-II, and they produced high levels of interleukin (IL)-1β, IL-6, and IL-12 cytokines when stimulated with ovalbumin (OVA) and CpG oligodeoxynucleotides (CPG-ODN). In an animal model, the BMDC-dLN completely rejected the E.G7-OVA tumor. Furthermore, the splenocytes from BMDC-dLN-immunized mice produced more interferon gamma, IL-4, IL-6, and IL-2, and they had a higher proliferation rate than other groups when re-stimulated with OVA. Hence, BMDC-dLN could be a promising DC-based scaffold for in vivo delivery to induce potent antitumor immunity. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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Review

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83 pages, 4451 KiB  
Review
Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy
by Lukas Amon, Lukas Hatscher, Lukas Heger, Diana Dudziak and Christian H. K. Lehmann
Pharmaceutics 2020, 12(7), 663; https://doi.org/10.3390/pharmaceutics12070663 - 14 Jul 2020
Cited by 23 | Viewed by 6179
Abstract
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the [...] Read more.
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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28 pages, 1116 KiB  
Review
Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity
by María Julia Lamberti, Annunziata Nigro, Fátima María Mentucci, Natalia Belén Rumie Vittar, Vincenzo Casolaro and Jessica Dal Col
Pharmaceutics 2020, 12(3), 256; https://doi.org/10.3390/pharmaceutics12030256 - 12 Mar 2020
Cited by 64 | Viewed by 6755
Abstract
The safety and feasibility of dendritic cell (DC)-based immunotherapies in cancer management have been well documented after more than twenty-five years of experimentation, and, by now, undeniably accepted. On the other hand, it is equally evident that DC-based vaccination as monotherapy did not [...] Read more.
The safety and feasibility of dendritic cell (DC)-based immunotherapies in cancer management have been well documented after more than twenty-five years of experimentation, and, by now, undeniably accepted. On the other hand, it is equally evident that DC-based vaccination as monotherapy did not achieve the clinical benefits that were predicted in a number of promising preclinical studies. The current availability of several immune modulatory and targeting approaches opens the way to many potential therapeutic combinations. In particular, the evidence that the immune-related effects that are elicited by immunogenic cell death (ICD)-inducing therapies are strictly associated with DC engagement and activation strongly support the combination of ICD-inducing and DC-based immunotherapies. In this review, we examine the data in recent studies employing tumor cells, killed through ICD induction, in the formulation of anticancer DC-based vaccines. In addition, we discuss the opportunity to combine pharmacologic or physical therapeutic approaches that can promote ICD in vivo with in situ DC vaccination. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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20 pages, 2049 KiB  
Review
Dendritic Cell Vaccines for Cancer Immunotherapy: The Role of Human Conventional Type 1 Dendritic Cells
by João Calmeiro, Mylène A. Carrascal, Adriana Ramos Tavares, Daniel Alexandre Ferreira, Célia Gomes, Amílcar Falcão, Maria Teresa Cruz and Bruno Miguel Neves
Pharmaceutics 2020, 12(2), 158; https://doi.org/10.3390/pharmaceutics12020158 - 15 Feb 2020
Cited by 74 | Viewed by 8671
Abstract
Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations [...] Read more.
Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their development, regulation and heterogeneity. We also address the role of this functionally thrilling DC subset in anti-tumor immune responses and the most recent efforts to apply it in cancer immunotherapy. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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24 pages, 2946 KiB  
Review
Endoplasmic Reticulum-Associated Degradation-Dependent Processing in Cross-Presentation and Its Potential for Dendritic Cell Vaccinations: A Review
by Jun Imai, Sayaka Ohashi and Takahiro Sakai
Pharmaceutics 2020, 12(2), 153; https://doi.org/10.3390/pharmaceutics12020153 - 13 Feb 2020
Cited by 7 | Viewed by 3647
Abstract
While the success of dendritic cell (DC) vaccination largely depends on cross-presentation (CP) efficiency, the precise molecular mechanism of CP is not yet characterized. Recent research revealed that endoplasmic reticulum (ER)-associated degradation (ERAD), which was first identified as part of the protein quality [...] Read more.
While the success of dendritic cell (DC) vaccination largely depends on cross-presentation (CP) efficiency, the precise molecular mechanism of CP is not yet characterized. Recent research revealed that endoplasmic reticulum (ER)-associated degradation (ERAD), which was first identified as part of the protein quality control system in the ER, plays a pivotal role in the processing of extracellular proteins in CP. The discovery of ERAD-dependent processing strongly suggests that the properties of extracellular antigens are one of the keys to effective DC vaccination, in addition to DC subsets and the maturation of these cells. In this review, we address recent advances in CP, focusing on the molecular mechanisms of the ERAD-dependent processing of extracellular proteins. As ERAD itself and the ERAD-dependent processing in CP share cellular machinery, enhancing the recognition of extracellular proteins, such as the ERAD substrate, by ex vivo methods may serve to improve the efficacy of DC vaccination. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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33 pages, 1047 KiB  
Review
Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update
by Jan Dörrie, Niels Schaft, Gerold Schuler and Beatrice Schuler-Thurner
Pharmaceutics 2020, 12(2), 92; https://doi.org/10.3390/pharmaceutics12020092 - 23 Jan 2020
Cited by 53 | Viewed by 6793
Abstract
Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) [...] Read more.
Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) one method is to introduce mRNA coding for the desired antigens. To target the whole antigenic repertoire of a tumor, even the total tumor mRNA of a macrodissected biopsy sample can be used. To date, reports have been published on a total of 781 patients suffering from different tumor entities and HIV-infection, who have been treated with DCs loaded with mRNA. The majority of those were melanoma patients, followed by HIV-infected patients, but leukemias, brain tumors, prostate cancer, renal cell carcinomas, pancreatic cancers and several others have also been treated. Next to antigen-loading, mRNA-electroporation allows a purposeful manipulation of the DCs’ phenotype and function to enhance their immunogenicity. In this review, we intend to give a comprehensive summary of what has been published regarding clinical testing of ex vivo generated mRNA-transfected DCs, with respect to safety and risk/benefit evaluations, choice of tumor antigens and RNA-source, and the design of better DCs for vaccination by transfection of mRNA-encoded functional proteins. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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