On the Twentieth Anniversary of Dendritic Cell Vaccines - Riding the Next Wave.
Cancer research
In the mid 1990's, a convergence of discoveries in dendritic cell (DC) biology and tumor antigen identification led investigators to study DCs as adjuvants for cancer vaccines. On the twentieth anniversary of a seminal clinical study by Jacques Banchereau and colleagues, we revisit the key events that prompted the initial wave of DC vaccine clinical studies and lessons learned that, in our opinion, helped forge the path for the field that we now call immuno-oncology. It is essential to recall that prior to the discovery of immune checkpoint therapy and chimeric antigen receptor (CAR) T-cell therapy, skepticism prevailed regarding the potential therapeutic benefit of immunotherapies. In hindsight, we can now appreciate how the early DC cancer vaccine trials helped investigators sustain their attention on adaptive immunity specific for malignant cells. These vaccines demonstrated clear evidence for induction of antigen-specific T cells and were well tolerated despite low rates of objective clinical response. In the context of the current era some 20 years later, harnessing DC vaccines has been shown to increase the breadth and diversity of tumor-specific T cells, and by trafficking to sites of metastases promote an inflamed tumor microenvironment. See related article by Banchereau and colleagues, Cancer Res 2001; 61:6451-8.
10.1158/0008-5472.CAN-21-4440
Dendritic cell vaccines for cancer therapy.
Sprinzl G M,Kacani L,Schrott-Fischer A,Romani N,Thumfart W F
Cancer treatment reviews
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.
10.1053/ctrv.2001.0221
Endogenous/Exogenous Nanovaccines Synergistically Enhance Dendritic Cell-Mediated Tumor Immunotherapy.
Advanced healthcare materials
Traditional dendritic cell (DC)-mediated immunotherapy is usually suppressed by weak immunogenicity in tumors and generally leads to unsatisfactory outcomes. Synergistic exogenous/endogenous immunogenic activation can provide an alternative strategy for evoking a robust immune response by promoting DC activation. Herein, Ti C MXene-based nanoplatforms (termed MXP) are prepared with high-efficiency near-infrared photothermal conversion and immunocompetent loading capacity to form endogenous/exogenous nanovaccines. Specifically, the immunogenic cell death of tumor cells induced by the photothermal effects of the MXP can generate endogenous danger signals and antigens release to boost vaccination for DC maturation and antigen cross-presentation. In addition, MXP can deliver model antigen ovalbumin (OVA) and agonists (CpG-ODN) as an exogenous nanovaccine (MXP@OC), which further enhances DC activation. Importantly, the synergistic strategy of photothermal therapy and DC-mediated immunotherapy by MXP significantly eradicates tumors and enhances adaptive immunity. Hence, the present work provides a two-pronged strategy for improving immunogenicity and killing tumor cells to achieve a favorable outcome in tumor patients.
10.1002/adhm.202203028
Nanovaccine-Based Strategies to Overcome Challenges in the Whole Vaccination Cascade for Tumor Immunotherapy.
Qin Lin,Zhang Huilin,Zhou Yang,Umeshappa Channakeshava Sokke,Gao Huile
Small (Weinheim an der Bergstrasse, Germany)
Nanovaccine-based immunotherapy (NBI) has received greater attention recently for its potential to prime tumor-specific immunity and establish a long-term immune memory that prevents tumor recurrence. Despite encouraging results in the recent studies, there are still numerous challenges to be tackled for eliciting potent antitumor immunity using NBI strategies. Based on the principles that govern immune response, here it is proposed that these challenges need to be addressed at the five critical cascading events: Loading tumor-specific antigens by nanoscale drug delivery systems (L); Draining tumor antigens to lymph nodes (D); Internalization by dendritic cells (DCs) (I); Maturation of DCs by costimulatory signaling (M); and Presenting tumor-peptide-major histocompatibility complexes to T cells (P) (LDIMP cascade in short). This review provides a detailed and objective overview of emerging NBI strategies to improve the efficacy of nanovaccines in each step of the LDIMP cascade. It is concluded that the balance between each step must be optimized by delicate designing and modification of nanovaccines and by combining with complementary approaches to provide a synergistic immunity in the fight against cancer.
10.1002/smll.202006000
Dendritic cells and immunotherapy for cancer.
International journal of hematology
Dendritic cells, nature's adjuvant, are antigen-presenting cells specialized to initiate and regulate immunity. Their potent antigen-presenting function has encouraged targeting of dendritic cells (DCs) for harnessing the immune system against cancer. DCs are efficient at activating not only CD4+ helper T-cells and CD8+ killer T-cells but also B-cells and innate effectors such as natural killer and natural killer T-cells. Early studies of adoptive transfer of tumor antigen-loaded DCs have shown promise. However, DC vaccination is at an early stage, and several parameters still need to be established. The complexity of the DC system brings about the necessity for its rational manipulation for achieving protective and therapeutic immunity in patients.
10.1007/BF02986611
Advances in dendritic cell-based vaccine of cancer.
Zhang Xueshu,Gordon John R,Xiang Jim
Cancer biotherapy & radiopharmaceuticals
Dendritic cells (DCs) are potent antigen presenting cells that exist in virtually every tissue, and from which they capture antigens and migrate to secondary lymphoid organs where they activate naïve T cells. Although DCs are normally present in extremely small numbers in the circulation, recent advances in DC biology have allowed the development of methods to generate large numbers of these cells in vitro. Because of their immunoregulatory capacity, vaccination with tumor antigen-presenting DCs has been proposed as a treatment modality for cancer. In animal models, vaccination with DCs pulsed with tumor peptides, lysates, or RNA or loaded with apoptotic/necrotic tumor cells could induce significant antitumor CTL responses and antitumor immunity. However, the results from early clinical trails pointed to a need for additional improvement of DC-based vaccines before they could be considered as practical alternatives to the existing cancer treatment strategies. In this regard, subsequent studies have shown that DCs that express transgenes encoding tumor antigens are more potent primers of antitumor immunity both in vitro and in vivo than DCs simply pulsed with tumor peptides. Furthermore, DCs that have been engineered to express certain cytokines or chemokines can display a substantially improved maturation status, capacity to migrate to secondary lymphoid organs in vivo, and abilities to stimulate tumor-specific T cell responses and induce tumor immunity in vivo. In this review we also discuss a number of factors that are important considerations in designing DC vaccine strategies, including (i) the type and concentrations of tumor peptides used for pulsing DCs; (ii) the timing and intervals for DC vaccination/boostable data on DC vaccination portends bright prospects for this approach to tumor immune therapy, either alone or in conjunction with other therapies.
10.1089/108497802320970217
Dendritic cells from bench to bedside and back.
Adema G J
Immunology letters
Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. They serve as the sentinels that capture antigens in the periphery, process them into peptides and present these to lymphocytes in lymph nodes. DCs play a key role in regulating immunity. Several DC-subsets exist, including myeloid-DCs (MDCs), plasmacytoid-DCs (PDCs) and Langerhans cells (LC). DCs not only instruct T- and B-lymphocytes, but also activate Natural Killer cells and produce interferons, thus linking the innate and adaptive immune system. Inflammatory-mediators and especially the Toll like receptor (TLR) family of proteins have been shown to play a pivotal role in inducing the immune activation program in DCs. TLRs recognize pathogen-associated-molecular-patterns (PAMPS) like LPS or flagellin and signal to alert immune cells in general, and DC in particular. DC activation, also referred to as DC maturation, thus results in immunity. In contrast, resting DC or DC receiving immune-inhibitory signals, like IL-10 and/or corticosteroids, induce immune tolerance via T cell deletion and induction of suppressive T cells, now termed regulatory T cells. Several mouse models have demonstrated that the immunological outcome is depending on the DC activation state; mature immune-activating DC protect mice from a tumor or pathogen while tolerogenic DC induces tolerance against transplanted tissues. Hence, DC acts at the interface of immunity and peripheral tolerance.
10.1016/j.imlet.2008.11.017
Dendritic cell-based immunotherapy: a basic review and recent advances.
Immunologic research
Dendritic cells (DCs) are considered a very promising arm to activate the immune system in immunotherapeutic strategies against cancer. DCs are the most powerful antigen-presenting cells (APCs), being highly efficient at generating robust immune responses. They are also considered the center of the immune system, since they provide a crucial link between both innate and adaptive immune responses. Thus, DC-based cancer immunotherapy aims to take advantage of these unique characteristics of DCs to better fight cancer. During the last decade, they have been the subject of numerous studies intending to develop immunotherapeutic strategies against cancer through vaccination. For this purpose, it is essential to gain a better insight into DC immunobiology, regulation of innate and adaptive immune systems, and tumor microenvironment, as well as applying the latest advances in science in order to boost their enormous anti-tumor immunotherapeutic potential. In this review, we will hold focus on DC immunobiology (from their origin, location, and special properties and distinct subsets to the innate and adaptive immunity), on the new concept of cancer immunoediting, and on the knowledge given by clinical trials using DC vaccines. Finally, future perspectives for this emerging field are highlighted.
10.1007/s12026-017-8931-1
Dendritic cell vaccination and immune monitoring.
Cancer immunology, immunotherapy : CII
We exploited dendritic cells (DC) to vaccinate melanoma patients. We recently demonstrated a statistical significant correlation between favorable clinical outcome and the presence of vaccine-related tumor antigen-specific T cells in delayed type hypersensitivity (DTH) skin biopsies. However, favorable clinical outcome is only observed in a minority of the treated patients. Therefore, it is obvious that current DC-based protocols need to be improved. For this reason, we study in small proof of principle trials the fate, interactions and effectiveness of the injected DC.
10.1007/s00262-008-0553-y
Dendritic Cell-Based Immunotherapy: State of the Art and Beyond.
Bol Kalijn F,Schreibelt Gerty,Gerritsen Winald R,de Vries I Jolanda M,Figdor Carl G
Clinical cancer research : an official journal of the American Association for Cancer Research
Dendritic cell (DC) vaccination in cancer patients aims to induce or augment an effective antitumor immune response against tumor antigens and was first explored in a clinical trial in the 1990s. More than two decades later, numerous clinical trials have been performed or are ongoing with a wide variety of DC subsets, culture protocols, and treatment regimens. The safety of DC vaccination and its ability to induce antitumor responses have clearly been established; however, although scattered patients with long-term benefit were reported, DC vaccines have not yet fulfilled their promise, perhaps mainly due to the lack of large-scale well-conducted phase II/III trials. To allow meaningful multicenter phase III trials, the production of DC vaccines should be standardized between centers which is now becoming feasible. To improve the efficacy of DC-based immunotherapy, it could be combined with other treatments.
10.1158/1078-0432.CCR-15-1399
Manipulation of Innate and Adaptive Immunity through Cancer Vaccines.
Journal of immunology research
Although cancer immunotherapy has shown significant promise in mediating efficacious responses, it remains encumbered by tumor heterogeneity, loss of tumor-specific antigen targets, and the regulatory milieu both regionally and systemically. Cross talk between the innate and adaptive immune response may be requisite to polarize sustained antigen specific immunity. Cancer vaccines can serve as an essential fulcrum in initiating innate immunity while molding and sustaining adaptive immunity. Although peptide vaccines have shown tepid responses in a therapeutic setting with poor correlates for immune activity, RNA vaccines activate innate immune responses and have shown promising effects in preclinical and clinical studies based on enhanced DC migration. While the mechanistic insights behind the interplay between innate and adaptive immunity may be unique to the immunotherapeutic being investigated, understanding this dynamic is important to coordinate the different arms of the immune response in a focused response against cancer antigens.
10.1155/2017/3145742
Immunotherapy of cancer with dendritic-cell-based vaccines.
Cancer immunology, immunotherapy : CII
Animal studies have shown that vaccination with genetically modified tumor cells or with dendritic cells (DC) pulsed with tumor antigens are potent strategies to elicit protective immunity in tumor-bearing animals, more potent than "conventional" strategies that have been tested in clinical settings with limited success. While both vaccination strategies are forms of cell therapy requiring complex and costly ex vivo manipulations of the patient's cells, current protocols using dendritic cells are considerably simpler and would be more widely available. Vaccination with defined tumor antigens presented by DC has obvious appeal. However, in view of the expected emergence of antigen-loss variants as well as natural immunovariation, effective vaccine formulations must contain mixtures of commonly, if not universally, expressed tumor antigens. When, or even if, such common tumor antigens will be identified cannot be, predicted, however. Thus, for the foreseeable future, vaccination with total-tumor-derived material as source of tumor antigens may be preferable to using defined tumor antigens. Vaccination with undefined tumor-derived antigens will be limited, however, by the availability of sufficient tumor tissue for antigen preparation. Because the mRNA content of single cells can be amplified, tumor mRNA, or corresponding cDNA libraries, offer an unlimited source of tumor antigens. DC transfected with tumor RNA were shown to engender potent antitumor immunity in animal studies. Thus, immunotherapy using autologous DC loaded with unfractionated tumor-derived antigens in the form of RNA emerges as a potentially powerful and broadly useful vaccination strategy for cancer patients.
10.1007/s002620050465
Advances in dendritic cell vaccination therapy of cancer.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Traditionally, vaccines have helped eradication of several infectious diseases and also saved millions of lives in the human history. Those prophylactic vaccines have acted through inducing immune responses against a live attenuated, killed organism or antigenic subunits to protect the recipient against a real infection caused by the pathogenic microorganism. Nevertheless, development of anticancer vaccines as valuable targets in human health has faced challenges and requires further optimizations. Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) that play essential roles in tumor immunotherapies through induction of CD8 T cell immunity. Accordingly, various strategies have been tested to employ DCs as therapeutic vaccines for exploiting their activity against tumor cells. Application of whole tumor cells or purified/recombinant antigen peptides are the most common approaches for pulsing DCs, which then are injected back into the patients. Although some hopeful results are reported for a number of DC vaccines tested in animal and clinical trials of cancer patients, such approaches are still inefficient and require optimization. Failure of DC vaccination is postulated due to immunosuppressive tumor microenvironment (TME), overexpression of checkpoint proteins, suboptimal avidity of tumor-associated antigen (TAA)-specific T lymphocytes, and lack of appropriate adjuvants. In this review, we have an overview of the current experiments and trials evaluated the anticancer efficacy of DC vaccination as well as focusing on strategies to improve their potential including combination therapy with immune checkpoint inhibitors (ICIs).
10.1016/j.biopha.2023.114954
Enhancing Dendritic Cell Cancer Vaccination: The Synergy of Immune Checkpoint Inhibitors in Combined Therapies.
International journal of molecular sciences
Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs' ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation used blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs), such as anticytotoxic T-lymphocyte Antigen 4 and antiprogrammed death-1 antibodies, has shown promise by enhancing T-cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs' efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T-cell receptors could further augment the antitumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.
10.3390/ijms25147509
Trial watch: anticancer vaccination with dendritic cells.
Oncoimmunology
Dendritic cells (DCs) are critical players at the intersection of innate and adaptive immunity, making them ideal candidates for anticancer vaccine development. DC-based immunotherapies typically involve isolating patient-derived DCs, pulsing them with tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs), and utilizing maturation cocktails to ensure their effective activation. These matured DCs are then reinfused to elicit tumor-specific T-cell responses. While this approach has demonstrated the ability to generate potent immune responses, its clinical efficacy has been limited due to the immunosuppressive tumor microenvironment. Recent efforts have focused on enhancing the immunogenicity of DC-based vaccines, particularly through combination therapies with T cell-targeting immunotherapies. This Trial Watch summarizes recent advances in DC-based cancer treatments, including the development of new preclinical and clinical strategies, and discusses the future potential of DC-based vaccines in the evolving landscape of immuno-oncology.
10.1080/2162402X.2024.2412876
DC-based cancer vaccines.
Gilboa Eli
The Journal of clinical investigation
Because of the large preexisting antigenic load and immunosuppressive environment within a tumor, inducing therapeutically useful antitumor immunity in cancer patients requires the development of powerful vaccination protocols. An approach gaining increasing popularity in the tumor vaccine field is to immunize cancer patients with their own DCs loaded ex vivo with tumor antigens. The underlying premise of this approach is that the efficiency and control over the vaccination process provided by ex vivo manipulation of the DCs generates an optimally potent APC and a superior method for stimulating antitumor immunity in vivo compared with the more conventional direct vaccination methods, offsetting the added cost and complexity associated with this form of customized cell therapy.
10.1172/JCI31205
Dendritic cell biology and its role in tumor immunotherapy.
Wang Yingying,Xiang Ying,Xin Victoria W,Wang Xian-Wang,Peng Xiao-Chun,Liu Xiao-Qin,Wang Dong,Li Na,Cheng Jun-Ting,Lyv Yan-Ning,Cui Shu-Zhong,Ma Zhaowu,Zhang Qing,Xin Hong-Wu
Journal of hematology & oncology
As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4 and CD8 T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovered to participate in antigen presentation. T cell microvillar dynamics and TCR conformational changes were demonstrated upon DC antigen presentation. Caspase-11-driven hyperactive DCs were recently reported to convert effectors into memory T cells. DCs were also reported to crosstalk with NK cells. Additionally, DCs are the most important sentinel cells for immune surveillance in the tumor microenvironment. Alongside DC biology, we review the latest developments for DC-based tumor immunotherapy in preclinical studies and clinical trials. Personalized DC vaccine-induced T cell immunity, which targets tumor-specific antigens, has been demonstrated to be a promising form of tumor immunotherapy in patients with melanoma. Importantly, allogeneic-IgG-loaded and HLA-restricted neoantigen DC vaccines were discovered to have robust anti-tumor effects in mice. Our comprehensive review of DC biology and its role in tumor immunotherapy aids in the understanding of DCs as the mentors of T cells and as novel tumor immunotherapy cells with immense potential.
10.1186/s13045-020-00939-6
Engineering dendritic cell vaccines to improve cancer immunotherapy.
Perez Caleb R,De Palma Michele
Nature communications
At the interface between the innate and adaptive immune system, dendritic cells (DCs) play key roles in tumour immunity and hold a hitherto unrealized potential for cancer immunotherapy. Here we review the role of distinct DC subsets in the tumour microenvironment, with special emphasis on conventional type 1 DCs. Integrating new knowledge of DC biology and advancements in cell engineering, we provide a blueprint for the rational design of optimized DC vaccines for personalized cancer medicine.
10.1038/s41467-019-13368-y
An immunogenic personal neoantigen vaccine for patients with melanoma.
Nature
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4 and CD8 T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
10.1038/nature22991
Dendritic Cells and Cancer Immunity.
Gardner Alycia,Ruffell Brian
Trends in immunology
Dendritic cells (DCs) are central regulators of the adaptive immune response, and as such are necessary for T-cell-mediated cancer immunity. In particular, antitumoral responses depend on a specialized subset of conventional DCs that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. DC maturation is necessary to provide costimulatory signals to T cells, but while DC maturation occurs within tumors, it is often insufficient to induce potent immunity, particularly in light of suppressive mechanisms within tumors. Bypassing suppressive pathways or directly activating DCs can unleash a T-cell response, and although clinical efficacy has proven elusive, therapeutic targeting of DCs continues to hold translational potential in combinatorial approaches.
10.1016/j.it.2016.09.006
Dendritic cell-based immunotherapy.
Sabado Rachel L,Balan Sreekumar,Bhardwaj Nina
Cell research
Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.
10.1038/cr.2016.157
Dendritic cells in cancer immunology and immunotherapy.
Wculek Stefanie K,Cueto Francisco J,Mujal Adriana M,Melero Ignacio,Krummel Matthew F,Sancho David
Nature reviews. Immunology
Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.
10.1038/s41577-019-0210-z