Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8+/CD4+ T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications.

• MeSH
• Antigens, Neoplasm MeSH
• Dendritic Cells MeSH
• Immunotherapy MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Cancer Vaccines * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

• MeSH
• Dendritic Cells metabolism   MeSH
• Carcinoma, Ovarian Epithelial drug therapy   MeSH
• Humans MeSH
• Lung Neoplasms * drug therapy   therapy   MeSH
• Ovarian Neoplasms * genetics   therapy   MeSH
• Cancer Vaccines * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Owing to their central role in the initiation and regulation of antitumor immunity, dendritic cells (DCs) have been widely tested for use in cancer immunotherapy. Despite several encouraging clinical applications, existing DC-based immunotherapy efforts have yielded inconsistent results. Recent work has identified strategies that may allow for more potent DC-based vaccines, such as the combination with antitumor agents that have the potential to synergistically enhance DC functions. Selected cytotoxic agents may stimulate DCs either by directly promoting their maturation or through the induction of immunogenic tumor cell death. Moreover, they may support DC-induced adaptive immune responses by disrupting tumor-induced immunosuppressive mechanisms via selective depletion or inhibition of regulatory subsets, such as myeloid-derived suppressor cells and/or regulatory T cells (Tregs). Here, we summarize our current knowledge on the capacity of anticancer chemotherapeutics to modulate DC phenotype and functions and the results of ongoing clinical trials evaluating the use of DC-based immunotherapy in combination with chemotherapy in cancer patients.

• MeSH
• Dendritic Cells immunology   MeSH
• Immunotherapy MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Cancer Vaccines immunology   MeSH
• Vaccination * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Dendritic cells (DCs) are believed to be the most potent antigen-presenting cells able to link the innate and adaptive immune systems. Many studies have focused on different immunotherapeutic approaches to applying DCs as tools to improve anticancer therapy. Although a number of investigations suggesting the benefit of DC-based vaccination during anticancer therapy have been reported, the general knowledge regarding the ultimate methods of DC-vaccine preparation is still unsatisfactory. In this article, the perspectives of DC-based anti-tumor immunotherapy and optimizing strategies of DC vaccination in humans in light of results obtained in mouse models are discussed.

• MeSH
• Immunotherapy, Active * MeSH
• Antigens, Neoplasm immunology   MeSH
• Cell Differentiation MeSH
• Cytokines genetics   MeSH
• Dendritic Cells cytology   immunology   transplantation   MeSH
• Neoplasms, Experimental immunology   therapy   MeSH
• Genetic Therapy MeSH
• Genetic Vectors therapeutic use   MeSH
• Mice, Inbred Strains MeSH
• Injections, Intradermal MeSH
• Injections, Intralymphatic MeSH
• Injections, Subcutaneous MeSH
• Combined Modality Therapy MeSH
• Cells, Cultured immunology   transplantation   MeSH
• Mice MeSH
• Organ Specificity MeSH
• Forecasting MeSH
• Antigen Presentation MeSH
• Cancer Vaccines * therapeutic use   MeSH
• Drug Screening Assays, Antitumor MeSH
• Vaccination MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Surgery and chemotherapy are standard treatments in ovarian cancer, but patients have a high rate of relapse. Dendritic cell (DC)-based vaccines are a new treatment option for elimination of residual tumor disease. We aim to explore the feasibility and immunogenicity of DC vaccines pulsed with autologous irradiated tumor cells from ovarian cancer patients. Monocyte-derived DC were generated and pulsed with autologous tumor-derived bodies, matured and subsequently cocultured with autologous lymphocytes. The ability of DC to activate lymphocytes was evaluated by proliferation and IFN-gamma ELISPOT. Induction of tumor cell apoptosis was optimal at 24 h, and DC pulsing optimal at 4 h. Maturation of DC and proliferation of lymphocytes were achieved in 75% of patients tested. Lymphocyte IFN-gamma production increased in response to tumor antigen-pulsed DC. We show the feasibility of preparing individual DC-based vaccines in ovarian cancer patients and the potential for induction of lymphocyte responses.

• MeSH
• Lymphocyte Activation immunology   MeSH
• Immunotherapy, Active methods   MeSH
• Antigens, Neoplasm immunology   MeSH
• Apoptosis physiology   MeSH
• Cytokines biosynthesis   MeSH
• Dendritic Cells immunology   MeSH
• Adult MeSH
• Phagocytosis immunology   MeSH
• Financing, Organized MeSH
• Immunoenzyme Techniques MeSH
• Interferon-gamma biosynthesis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Ovarian Neoplasms therapy   MeSH
• Cancer Vaccines immunology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH

High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4+CD25+Foxp3+ T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4+ and CD8+ T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8+ and CD4+ T cell responses were detected in NSCLC patient's against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8+ T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.

• MeSH
• CD4-Positive T-Lymphocytes immunology   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Dendritic Cells immunology   MeSH
• Hydrostatic Pressure MeSH
• Immunotherapy methods   MeSH
• Interferon-gamma metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Lung Neoplasms therapy   MeSH
• Carcinoma, Non-Small-Cell Lung therapy   MeSH
• Cancer Vaccines immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

PURPOSE: The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937). PATIENTS AND METHODS: We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC. RESULTS: Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood. CONCLUSIONS: Our findings suggest that while patients with highly infiltrated, "hot" EOCs benefit from chemotherapy, women with "cold" EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.

• MeSH
• Dendritic Cells MeSH
• Carcinoma, Ovarian Epithelial * genetics   therapy   MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor MeSH
• Ovarian Neoplasms * genetics   therapy   MeSH
• Cancer Vaccines * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Řada klinických studií byla realizována nebo v současnosti probíhá s cílem ověřit terapeutický potenciál vakcín na bázi dendritických buněk (dendritic cell – DC) u pacientů se zhoubnými nádory. V tomto sdělení se zabýváme publikovanými výsledky uvedených klinických studií u pacientů s nemalobuněčným karcinomem plic (non-small cell lung cancer – NSCLC). Přestože se nejedná o velké počty studií a i počet zařazených pacientů je limitovaný, z dosažených výsledků je možné dojít k závěru, že podávání DC, a to jakýmkoliv způsobem, je bezpečné, a že existují pacienti, u kterých byl po aplikaci pozorován klinický přínos. Tyto počáteční výsledky podporují pokračování výzkumu s DC, v rámci kterého jsou testovány různé strategie použití DC, které by vedly k co největší imunitní odpovědi proti tomuto smrtelnému onemocnění.

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic cell-based vaccines on cancer patients. Herewith, we describe the clinical trials of non‑small cell lung cancer (NSCLC) published in the literature. Although the number of clinical trials and NSCLC patients enrolled in these studies is small, it is possible to conclude that the administration of dendritic cells (DCs) by any route is safe and that a clinical benefit after their administration can be observed. These initial results encourage continued investigation in clinical trials into the benefit of DCs along with different strategies to enhance their immune response in this deadly disease. Key words: dendritic cells – non-small cell lung cancer – cancer – immunotherapy The author declare he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 15. 3. 2014 Přijato: 7. 6. 2014

• MeSH
• Dendritic Cells * immunology   MeSH
• Immunotherapy, Adoptive methods   MeSH
• Humans MeSH
• Lung Neoplasms therapy   MeSH
• Carcinoma, Non-Small-Cell Lung * therapy   MeSH
• Cancer Vaccines * adverse effects   therapeutic use   MeSH
• Check Tag
• Humans MeSH

Despite efforts to develop novel treatment strategies, refractory and relapsing sarcoma, and high-risk neuroblastoma continue to have poor prognoses and limited overall survival. Monocyte-derived dendritic cell (DC)-based anti-cancer immunotherapy represents a promising treatment modality in these neoplasias. A DC-based anti-cancer vaccine was evaluated for safety in an academic phase-I/II clinical trial for children, adolescents, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors, mainly sarcomas and neuroblastomas. The DC vaccine was loaded with self-tumor antigens obtained from patient tumor tissue. DC vaccine quality was assessed in terms of DC yield, viability, immunophenotype, production of IL-12 and IL-10, and stimulation of allogenic donor T-cells and autologous T-cells in allo-MLR and auto-MLR, respectively. Here, we show that the outcome of the manufacture of DC-based vaccine is highly variable in terms of both DC yield and DC immunostimulatory properties. In 30% of cases, manufacturing resulted in a product that failed to meet medicinal product specifications and therefore was not released for administration to a patient. Focusing on the isolation of monocytes and the pharmacotherapy preceding monocyte harvest, we show that isolation of monocytes by elutriation is not superior to adherence on plastic in terms of DC yield, viability, or immunostimulatory capacity. Trial patients having undergone monocyte-interfering pharmacotherapy prior to monocyte harvest was associated with an impaired DC-based immunotherapy product outcome. Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters. Searching for a surrogate marker predicting an adverse outcome of DC manufacture in the peripheral blood complete blood count prior to monocyte harvest, we observed an association between an increased number of immature granulocytes in peripheral blood and decreased potency of the DC-based product as quantified by allo-MLR. We conclude that the DC-manufacturing yield and the immunostimulatory quality of anti-cancer DC-based vaccines generated from the monocytes of patients were not influenced by the monocyte isolation modality but were detrimentally affected by the specific combination of anti-cancer agents used prior to monocyte harvest.

• Publication type
• Journal Article MeSH

Projekt je zaměřen na přípravu individuálních nádorových vakcín na principu dendritických buněk (DC). V projektu bude dopracována optimální metodika k pěstování zralýchfunkčních DC schopných indukovat protinádorovou reakci in vitro. V dalším kroku bude ověřena funkčnost DC kultivovaných z monocytů od onkologických pacientů po chemoterapii nebo jiných formách protinádorové terapie. Paralelně budou vypracovány metody na optimální formu a koncentraci nádorových antigenů. Na základě výsledků in vitro studiíbude vypracován protokol pro zahájení fáze I. a II. klinických pokusů s imunoterapí dendritickými buňkami u vybraných onkologických pacientů.; Project focuses on the development of dendritic cell-based vyccines for use in the immunotherapy of cancers. We will define a protocol permitting the generation of great numbers of fully mature DC, capabable of inducing antitumor immunity in vitro. We will also investigate the functional characteristics of DC generated from peripheral blood monocytes of patients undergoing chemotherapy or other standard anticancer treatment. Simultaneously, we will determine the optimal conditions for pulsing of DC Based on the results of the in vitro studies, we will elaborate a protocol permitting the initiation of Phase I, Phase II clinical trials based on the administration of DC-based vaccines to selected oncologic patients.

• MeSH
• Cytotoxicity, Immunologic MeSH
• Dendritic Cells MeSH
• Immunotherapy MeSH
• Neoplasms MeSH
• Vaccines MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• alergologie a imunologie
• epidemiologie
• onkologie
• neurologie
• NML Publication type
• závěrečné zprávy o řešení grantu IGA MZ ČR