Efficacy Of Dendritic Cell Vaccination Research Articles

Unlocking Dendritic Cell-Based Vaccine Efficacy through Genetic Modulation-How Soon Is Now?

The dendritic cell (DC) vaccine anti-cancer strategy involves tumour-associated antigen loading and maturation of autologous ex vivo cultured DCs, followed by infusion into the cancer patient. This strategy stemmed from the idea that to induce a robust anti-tumour immune response, it was necessary to bypass the fundamental immunosuppressive mechanisms of the tumour microenvironment that dampen down endogenous innate immune cell activation and enable tumours to evade immune attack. Even though the feasibility and safety of DC vaccines have long been confirmed, clinical response rates remain disappointing. Hence, the full potential of DC vaccines has yet to be reached. Whether this cellular-based vaccination approach will fully realise its position in the immunotherapy arsenal is yet to be determined. Attempts to increase DC vaccine immunogenicity will depend on increasing our understanding of DC biology and the signalling pathways involved in antigen uptake, maturation, migration, and T lymphocyte priming to identify amenable molecular targets to improve DC vaccine performance. This review evaluates various genetic engineering strategies that have been employed to optimise and boost the efficacy of DC vaccines.

Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector Tcells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Since OVM upregulates PD-L1 in DCs, combining PD-L1 blockade with DC vaccines and OVM further enhances antitumor activity. Overall, OVM strengthens the antitumor efficacy of DC vaccines by targeting the SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.

Metabolic glycan labeling immobilizes dendritic cell membrane and enhances antitumor efficacy of dendritic cell vaccine

Dendritic cell (DC) vaccine was among the first FDA-approved cancer immunotherapies, but has been limited by the modest cytotoxic T lymphocyte (CTL) response and therapeutic efficacy. Here we report a facile metabolic labeling approach that enables targeted modulation of adoptively transferred DCs for developing enhanced DC vaccines. We show that metabolic glycan labeling can reduce the membrane mobility of DCs, which activates DCs and improves the antigen presentation and subsequent T cell priming property of DCs. Metabolic glycan labeling itself can enhance the antitumor efficacy of DC vaccines. In addition, the cell-surface chemical tags (e.g., azido groups) introduced via metabolic glycan labeling also enable in vivo conjugation of cytokines onto adoptively transferred DCs, which further enhances CTL response and antitumor efficacy. Our DC labeling and targeting technology provides a strategy to improve the therapeutic efficacy of DC vaccines, with minimal interference upon the clinical manufacturing process.

Tubeimuside I improves the efficacy of a therapeutic Fusobacterium nucleatum dendritic cell-based vaccine against colorectal cancer.

Fusobacterium nucleatum (F. nucleatum) infection has been confirmed to be associated with the development, chemoresistance, and immune evasion of colorectal cancer (CRC). The complex relationship between the microorganism, host cells, and the immune system throughout all stages of CRC progression, which makes the development of new therapeutic methods difficult. We developed a new dendritic cell (DC) vaccine to investigate the antitumor efficacy of CRC immunotherapy strategies. By mediating a specific mode of interaction between the bacteria, tumor, and host, we found a new plant-derived adjuvant, tubeimuside I (TBI), which simultaneously improved the DC vaccine efficacy and inhibited the F. nucleatum infection. Encapsulating TBI in a nanoemulsion greatly improved the drug efficacy and reduced the drug dosage and administration times. The nanoemulsion encapsulated TBI DC vaccine exhibited an excellent antibacterial and antitumor effect and improved the survival rate of CRC mice by inhibiting tumor development and progression. In this study, we provide a effective strategy for developing a DC-based vaccine against CRC and underlies the importance of further understanding the mechanism of CRC processes caused by F. nucleatum.

Development of in vitro laboratory models of the tumor immune microenvironment to evaluate quality parameters and specific efficacy of the dendritic cell vaccine

Purpose of the study: development of in vitro laboratory models to evaluate quality parameters and specific efficacy of dendritic cell vaccine (DCV).Material and Methods. Biological samples of malignant tumor patients treated with autologous dendritic cell vaccine (DC) were included into the study. Immature DCs (n=46) and mature DCs (n=56) were used to induce proliferation of antigen-specific T lymphocytes (n=227). Autologous tumor cells from skin melanoma (n=10) or sarcoma (n=8) patients in the xCELLigence® assay system were used to study the in vitro antitumor cytotoxic activity of generated CTLs (n=18). The secretion of cytokines and cytolytic proteins was studied by multiplex analysis. The subpopulation composition of effector T-lymphocytes was determined by flow cytometry.Results. We revealed that mature DCs (CD83+CD1a-) had a high expression of antigen presenting molecules (HLA-DR) and those providing migration of DCs into lymph nodes (CCR7) as well as costimulatory molecules CD80 and CD86 as compared to immature DCs (CD83-CD1a+). Induction of mature DCs was found to stimulate an increase in the relative content of proliferating T cells compared with stimulation of immature DCs (p<0.001) and specific PTA+ tumor lysate (p<0.001). When studying cytotoxic activity of effector T-lymphocytes, we developed 2D in vitro models using xCELLigence® analytical system and revealed 2 types of interaction: 1) in vitro model № 1 – decrease in cell index (CI) of autologous tumor cell culture in the presence of activated effector T lymphocytes; 2) in vitro model № 2 – no change in CI of autologous tumor cell culture when co-cultured with activated effector T cells compared to control (72 h observation). The results demonstrated cytotoxic activity of antigen-specific T lymphocytes due to high content of terminally differentiated cytotoxic T lymphocytes (TEMRA), GrB-producing CTLs, and cytokine secretion profile.Conclusion. Requirements for the quality of personalized autologous DCs, including control of immunophenotypic characteristics were developed, and functional activity of Tlymphocytes during induction of mature vaccine DCs was evaluated. A laboratory procedure was developed for quantitative assessment of cytotoxic activity of antigen-specific T-lymphocytes against autologous tumor using the xCELLigence® analytical system, thus allowing for personalized monitoring and predicting the effectiveness of DСV treatment.

A Novel Therapeutic Tumor Vaccine Targeting MUC1 in Combination with PD-L1 Elicits Specific Anti-Tumor Immunity in Mice.

Dendritic cells (DCs), as professional antigen-presenting cells (APCs), play a key role in the initiation and regulation of humoral and cellular immunity. DC vaccines loaded with different tumor-associated antigens (TAAs) have been widely used to study their therapeutic effects on cancer. A number of clinical trials have shown that DCs are safe as an antitumor vaccine and can activate certain anti-tumor immune responses; however, the overall clinical efficacy of DC vaccine is not satisfactory, so its efficacy needs to be enhanced. MUC1 is a TAA with great potential, and the immune checkpoint PD-L1 also has great potential for tumor treatment. Both of them are highly expressed on the surface of various tumors. In this study, we generated a novel therapeutic MUC1-Vax tumor vaccine based on the method of PD-L1-Vax vaccine we recently developed; this novel PD-L1-containing MUC1-Vax vaccine demonstrated an elevated persistent anti-PD-L1 antibody production and elicited a much stronger protective cytotoxic T lymphocyte (CTL) response in immunized mice. Furthermore, the MUC1-Vax vaccine exhibited a significant therapeutic anti-tumor effect, which significantly inhibited tumor growth by expressing a high MUC1+ and PD-L1+ level of LLC and Panc02 tumor cells, and prolonged the survival of cancer-bearing animals. Taken together, our study provides a new immunotherapy strategy for improving the cross-presentation ability of therapeutic vaccine, which may be applicable to pancreatic cancer, lung cancer and for targeting other types of solid tumors that highly express MUC1 and PD-L1.

Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

ABSTRACT 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.

Matrine Combined with Mammalian Target of Rapamycin Inhibitor Enhances Anti-Tumor Efficacy of dendritic cell Vaccines in hepatocellular carcinoma

ABSTRACT Dendritic cells (DCs), as the most important antigen-presenting cells, play a crucial role in T cell activation. The latest research showed that inhibition of the mammalian target of rapamycin (mTOR) could enhance DCs maturation, promoting antigen presentation. Matrine has been identified as one of the key alkaloids isolated from the roots of Sophora flavescens. In present study, we combined matrine and mTOR inhibitor KU0063794 to observe the DCs functions, especially the antigen presentation ability. DCs were activated by phosphate-buffered saline (PBS), lipopolysaccharide (LPS), LPS+KU0063794, LPS+Matrine, and LPS+KU0063794+Matrine. The surface markers in DCs, proliferation of T cells and cytokines were detected by flow cytometry, cell counting kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA), respectively. The lactate dehydrogenase (LDH) release test was used to detect the antitumor efficacy. The tumor growth curves were plotted by calculating tumor volume. The apoptosis was detected by Terminal-deoxynucleoitidyl Transferase-Mediated Nick End Labeling (TUNEL) method. Matrine combined with KU0063794 could enhance the maturity of DCs, T cells proliferation and cytokines secretion (P < 0.05). The cytotoxic T lymphocytes (CTL) killing efficacy of LPS+KU0063794+Matrine group was higher than other groups (P < 0.05). In vivo, the tumor weights and volumes in LPS+KU0063794+Matrine group were lower than other groups. The detections of tumor apoptosis were increased in LPS+KU0063794+Matrine group (P < 0.05). DC vaccine with mTOR inhibitor and matrine could significantly improve the efficacy of antitumor immunity in vitro and vivo. These findings illustrated that mTOR inhibitor and matrine, as two immunomodulators, could enhance DC activation and differentiation.

207 Dendritic Cells Immunotherapy in the Treatment of Glioblastoma

INTRODUCTION: Immunotherapy is gradually being established as a relevant adjuvant therapy against cancer. Cell vaccination is a promising strategy for the treatment of glioblastoma (GBM). CarT and dendritic cells (DC) have been associated with partial response therapy in recent publications. METHODS: Clinical data were evaluated including overall survival, disease-free survival, global health scales, and quality of life in neuro-oncology. Analysis of overall survival and survival after recurrence and after vaccination is presented. Immunological panel with CD4/CD8 T-cell counts and lymphokines count were obtained on each vaccination session. RESULTS: A significant increase in overall survival was observed in the vaccinated group (33.16 ± 9.42 months, versus 13.56 ± 0.95 months in the previous group control (log rank p = 0.0021). The median overall survival from the first recurrence for the vaccinated population was 8.1 ± 1.9 months, and 5.0 ± 1.4 counted from the start of vaccination. The immunological data strengthen the importance of Th1 response pattern for tumor control, and Th-17 pattern linked to recurrence. CONCLUSION: The preliminary data support the safety and possible efficacy of DC vaccination in increasing overall survival in patients with recurrent GBM. The immune data provide important insights on the mechanisms beyond tumor control and recurrence.

Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions.

Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.

Cholesterol modified DP7 and pantothenic acid induce dendritic cell homing to enhance the efficacy of dendritic cell vaccines

Dendritic cell (DC)-based cancer vaccines have so far achieved good therapeutic effects in animal experiments and early clinical trials for certain malignant tumors. However, the overall objective response rate in clinical trials rarely exceeds 15%. The poor efficiency of DC migration to lymph nodes (LNs) (< 5%) is one of the main factors limiting the effectiveness of DC vaccines. Therefore, increasing the efficiency of DC migration is expected to further enhance the efficacy of DC vaccines. Here, we used DP7-C (cholesterol modified VQWRIRVAVIRK), which can promote DC migration, as a medium. Through multiomics sequencing and biological experiments, we found that it is the metabolite pantothenic acid (PA) that improves the migration and effectiveness of DC vaccines. We clarified that both DP7-C and PA regulate DC migration by regulating the chemokine receptor CXCR2 and inhibiting miR-142a-3p to affect the NF-κB signaling pathway. This study will lay the foundation for the subsequent use of DP7-C as a universal substance to promote DC migration, further enhance the antitumor effect of DC vaccines, and solve the bottleneck problem of the low migration efficiency and unsatisfactory clinical response rate of DC vaccines.

The Efficacy of Dendritic Cell Vaccine for Newly Diagnosed Glioblastoma: A Meta-analysis of Randomized Controlled Studies.

The efficacy of dendritic cell vaccine for newly diagnosed glioblastoma remains controversial. We conduct a systematic review and meta-analysis to explore the influence of dendritic cell vaccine on treatment efficacy for newly diagnosed glioblastoma. We search PubMed, EMBASE, Web of science, EBSCO, and Cochrane library databases through December 2019 for randomized controlled trials assessing the efficacy and safety of dendritic cell vaccine for newly diagnosed glioblastoma. This meta-analysis is performed using the random effect model. Three randomized controlled trials are included in the meta-analysis. Overall, compared with control group for newly diagnosed glioblastoma, dendritic cell vaccine shows no substantial effect on median overall survival [standard mean difference, 0.11; 95% confidence interval (CI), -0.18 to 0.41; P = 0.45], median progression-free survival (standard mean difference, 0.12; 95% CI, -0.24 to 0.48; P = 0.50), progression-free survival rate [risk ratio (RR), 1.29; 95% CI, 0.82-2.04; P = 0.27], overall survival rate (RR, 1.29; 95% CI, 0.61-2.72; P = 0.50), or nervous system disorders (RR, 0.80; 95% CI, 0.59-1.08; P = 0.14). Dendritic cell vaccine may provide no obvious benefits for the newly diagnosed glioblastoma.

Large-Sized Graphene Oxide Nanosheets Increase DC-T-Cell Synaptic Contact and the Efficacy of DC Vaccines against SARS-CoV-2.

Dendritic cell (DC) vaccines are used for cancer and infectious diseases, albeit with limited efficacy. Modulating the formation of DC–T‐cell synapses may greatly increase their efficacy. The effects of graphene oxide (GO) nanosheets on DCs and DC–T‐cell synapse formation are evaluated. In particular, size‐dependent interactions are observed between GO nanosheets and DCs. GOs with diameters of >1 µm (L‐GOs) demonstrate strong adherence to the DC surface, inducing cytoskeletal reorganization via the RhoA‐ROCK‐MLC pathway, while relatively small GOs (≈500 nm) are predominantly internalized by DCs. Furthermore, L‐GO treatment enhances DC–T‐cell synapse formation via cytoskeleton‐dependent membrane positioning of integrin ICAM‐1. L‐GO acts as a “nanozipper,” facilitating the aggregation of DC–T‐cell clusters to produce a stable microenvironment for T cell activation. Importantly, L‐GO‐adjuvanted DCs promote robust cytotoxic T cell immune responses against SARS‐CoV‐2 spike 1, leading to >99.7% viral RNA clearance in mice infected with a clinically isolated SARS‐CoV‐2 strain. These findings highlight the potential value of nanomaterials as DC vaccine adjuvants for modulating DC–T‐cell synapse formation and provide a basis for the development of effective COVID‐19 vaccines.

The efficacy of dendritic cell vaccine for newly diagnosed glioblastoma: A meta-analysis of randomized controlled studies

IntroductionThe efficacy of dendritic cell vaccine to treat glioblastoma remained elusive and therefore we conducted a meta-analysis to explore the influence of dendritic cell vaccine on treatment efficacy of glioblastoma. MethodsPubMed, EMbase, Web of science, EBSCO and Cochrane library databases have been searched through October 2020, and we included randomized controlled trials (RCTs) assessing the efficacy of dendritic cell vaccine for glioblastoma. ResultsFour RCTs and 267 patients were included in the meta-analysis. Compared to control group for glioblastoma, dendritic cell vaccine demonstrated no obvious impact on overall survival (HR=0.59; 95% CI=0.34 to 1.04; P=0.07), progression-free survival (PFS, HR=0.72; 95% CI=0.52 to 1.00; P=0.05), nervous system disorders (OR=0.61; 95% CI=0.29 to 1.29; P=0.20), or adverse events (OR=1.44; 95% CI=0.82 to 2.50; P=0.20). ConclusionsDendritic cell vaccine may be not effective to treat glioblastoma.

Therapeutic efficacy of dendritic cell vaccine combined with programmed death 1 inhibitor for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a serious cause of cancer-related deaths worldwide. Developing new therapeutic strategies is urgently needed to improve the outcomes of HCC patients. Dendritic cell (DC)-based vaccines and programmed death 1 (PD-1) immune checkpoint inhibitors have been regarded as potential immunotherapeutics for HCC. However, the therapeutic efficacy of combining these two treatments for HCC remains to be evaluated. In this study, DCs were derived from mouse bone marrow and pulsed with mouse HCC cell lysates to generate a DC vaccine. A monoclonal antibody that blocks the interaction of mouse PD-1 with its ligands was used as a PD-1 inhibitor. An orthotopic HCC mouse model was established to assess the effect of a DC vaccine in combination with a PD-1 inhibitor on overall survival and tumor volume. Compared with the untreated control, single treatment with a DC vaccine or PD-1 inhibitor prolonged the overall survival and reduced the tumor volume of HCC mice. Further, compared with the single treatment with the DC vaccine or the PD-1 inhibitor, a combination treatment using both agents elicited a higher cytotoxicity of T cells against HCC cells and resulted in a better overall survival, smaller tumor volume, and greater tumor cell apoptosis in HCC mice. Our results suggest that a combination treatment with DC vaccine and PD-1 inhibitor may be a promising therapeutic strategy for HCC.

Therapeutic Antitumor Efficacy of Cancer Stem Cell-Derived DRibble Vaccine on Colorectal Carcinoma.

Dendritic cell (DC)-based immunotherapy has been a promising strategy for colon cancer therapy, but the efficacy of dendritic cell vaccines is in part limited by immunogenicity of loaded antigens. In this study, we aimed to identify a putative tumor antigen that can generate or enhance anti-tumor immune responses against colon cancer. CD44+ colon cancer stem cells (CCSCs) were isolated from mouse colorectal carcinoma CT-26 cell cultures and induced to form defective ribosomal products-containing autophagosome-rich blebs (DRibbles) by treatment with rapamycin, bortezomib, and ammonium chloride. DRibbles were characterized by western blot and transmission electron microscopy. DCs generated from the mice bone marrow monocytes were cocultured with DRibbles, then surface markers of DCs were analyzed by flow cytometry. Meanwhile, the efficacy of DRibble-DCs was examined in vivo. Our results showed that CCSC-derived DRibbles upregulated CD80, CD86, major histocompatibility complex (MHC)-I, and MHC-II on DCs and induced proliferation of mouse splenic lymphocytes and CD8+ T cells. In a model of colorectal carcinoma using BALB/c mice with robust tumor growth and mortality, DC vaccine pulsed with CCSC-derived DRibbles suppressed tumor growth and extended survival. A lactate dehydrogenase test indicated a strong cytolytic activity of cytotoxic T-cells derived from mice vaccinated with CCSC-derived DRibbles against CT-26 cells. Furthermore, flow cytometry analyses showed that the percentages of IFN-γ-producing CD8+ T-cells were increased in SD-DC group compare with the other groups. These findings provide a rationale for novel immunotherapeutic anti-tumor approaches based on DRibbles derived from colon cancer stem cells.

Irreversible electroporation ablation overcomes tumor-associated immunosuppression to improve the efficacy of DC vaccination in a mice model of pancreatic cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is associated with highly immunosuppressive tumor microenvironment (TME) that can limit the efficacy of dendritic cell (DC) vaccine immunotherapy. Irreversible electroporation (IRE) is a local ablation approach. Herein, we test the hypothesis that IRE ablation can overcome TME immunosuppression to improve the efficacy of DC vaccination using KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) orthotopic mouse model of PDAC. The median survival for mice treated with the combined IRE and DC vaccination was 77 days compared with sham control (35 days), DC vaccination (49 days), and IRE (44 days) groups (P = .006). Thirty-six percent of the mice treated with combination IRE and DC vaccination were still survival at the end of the study period (90 days) without visible tumor. The changes of tumor apparent diffusion coefficient (ΔADC) were higher in mice treated with combination IRE and DC vaccination than that of other groups (all P < .001); tumor ΔADC value positively correlated with tumor fibrosis fraction (R = 0.707, P < .001). IRE induced immunogenic cell death and alleviation of immunosuppressive components in PDAC TME when combined with DC vaccination, including increased tumor infiltration of CD8+ T cells and Granzyme B+ cells (P = .001, and P = .007, respectively). Our data show that IRE ablation can overcome TME immunosuppression to improve the efficacy of DC vaccination in PDAC. Combination IRE ablation and DC vaccination may enhance therapeutic efficacy for PDAC.

Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma

ABSTRACT Dendritic cell (DC) vaccination has proven to be an effective and safe adjuvant for cancer immunotherapies. As the presence of DCs within the tumor microenvironment promotes adaptive antitumor immunity, enhancement of DC migration toward the tumor microenvironment following DC vaccination might represent one possible approach to increase its therapeutic efficacy. While recent findings suggest the activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) as critical regulator of DC migration in the context of autoimmune diseases, we aimed to investigate the impact of Arc/Arg3.1 expression for DC-based cancer vaccines. To this end, DC migration capacity as well as the induction of T cell-mediated antitumor immunity was assessed in an experimental B16 melanoma model with Arc/Arg3.1−/- and Arc/Arg3.1-expressing BMDCs applied as a subcutaneous vaccine. While antigen presentation on DCs was critical for unleashing effective T cell mediated antitumor immune responses, Arc/Arg3.1 expression enhanced DC migration toward the tumor and secondary lymphoid organs. Moreover, Arc/Arg3.1-expressing BMDCs shape the tumor immune microenvironment by facilitating tumor recruitment of antigen-specific effector T cells. Thus, Arc/Arg3.1 may represent a novel therapeutic target in DCs in order to increase the therapeutic efficacy of DC vaccination.

A Perspective on Cell Therapy and Cancer Vaccine in Biliary Tract Cancers (BTCs).

Simple SummaryIn this review, we discuss treatment strategies in biliary tract cancers (gallbladder cancer, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma). In particular, we will describe advances in cellular therapies and cancer vaccines for biliary tract cancers, followed by our local experience with combining a melanoma-associated antigen (MAGE)-positive cell lysate-based autologous dendritic cell vaccine and anti-angiogenic therapy (bevacizumab) in a case of stage IV gallbladder cancer.Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many cancers with a similar unmet need. Therefore, we reviewed current understanding of the tumor immune microenvironment and recent advances in cellular immunotherapy and therapeutic cancer vaccines against BTC. We illustrated the efficacy of dendritic cell vaccination in one patient with advanced, chemorefractory, melanoma-associated antigen (MAGE)-positive gallbladder carcinoma, who was given multiple injections of an allogenic MAGE antigen-positive melanoma cell lysate (MCL)-based autologous dendritic cell vaccine combined with sequential anti-angiogenic therapy. This resulted in good radiological and tumor marker response and an overall survival of 3 years from diagnosis. We postulate the potential synergism of adding anti-angiogenic therapy, such as bevacizumab, to immunotherapy in BTC, as a rational scientific principle to positively modulate the tumor microenvironment to augment antitumor immunity.

The Evolution of Dendritic Cell Immunotherapy against HIV-1 Infection: Improvements and Outlook.

Dendritic cells (DC) are key phagocytic cells that play crucial roles in both the innate and adaptive immune responses against the human immunodeficiency virus type 1 (HIV-1). By processing and presenting pathogen-derived antigens, dendritic cells initiate a directed response against infected cells. They activate the adaptive immune system upon recognition of pathogen-associated molecular patterns (PAMPs) on infected cells. During the course of HIV-1 infection, a successful adaptive (cytotoxic CD8+ T-cell) response is necessary for preventing the progression and spread of infection in a variety of cells. Dendritic cells have thus been recognized as a valuable tool in the development of immunotherapeutic approaches and vaccines effective against HIV-1. The advancements in dendritic cell vaccines in cancers have paved the way for applications of this form of immunotherapy to HIV-1 infection. Clinical trials with patients infected with HIV-1 who are well-suppressed by antiretroviral therapy (ART) were recently performed to assess the efficacy of DC vaccines, with the goal of mounting an HIV-1 antigen-specific T-cell response, ideally to clear infection and eliminate the need for long-term ART. This review summarizes and compares methods and efficacies of a number of DC vaccine trials utilizing autologous dendritic cells loaded with HIV-1 antigens. The potential for advancement and novel strategies of improving efficacy of this type of immunotherapy is also discussed.