Sébastien Anguille

Clinical use of dendritic cells for cancer therapy

Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccination of patients with cancer. Dendritic cell-based immunotherapy is safe and can induce antitumour immunity, even in patients with advanced disease. However, clinical responses have been disappointing, with classic objective tumour response rates rarely exceeding 15%. Paradoxically, findings from emerging research indicate that dendritic cell-based vaccination might improve survival, advocating implementation of alternative endpoints to assess the true clinical potency of dendritic cell-based vaccination. We review the clinical effectiveness of dendritic cell-based vaccine therapy in melanoma, prostate cancer, malignant glioma, and renal cell carcinoma, and summarise the most important lessons from almost two decades of clinical studies of dendritic cell-based immunotherapy in these malignant disorders. We also address how the specialty is evolving, and which new therapeutic concepts are being translated into clinical trials to leverage the clinical effectiveness of dendritic cell-based cancer immunotherapy. Specifically, we discuss two main trends: the implementation of the next-generation dendritic cell vaccines that have improved immunogenicity, and the emerging paradigm of combination of dendritic cell vaccination with other cancer therapies.

Short-term cultured, interleukin-15 differentiated dendritic cells have potent immunostimulatory properties

BackgroundOptimization of the current dendritic cell (DC) culture protocol in order to promote the therapeutic efficacy of DC-based immunotherapy is warranted. Alternative differentiation of monocyte-derived DCs using granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-15 has been propagated as an attractive strategy in that regard. The applicability of these so-called IL-15 DCs has not yet been firmly established. We therefore developed a novel pre-clinical approach for the generation of IL-15 DCs with potent immunostimulatory properties.MethodsHuman CD14+ monocytes were differentiated with GM-CSF and IL-15 into immature DCs. Monocyte-derived DCs, conventionally differentiated in the presence of GM-CSF and IL-4, served as control. Subsequent maturation of IL-15 DCs was induced using two clinical grade maturation protocols: (i) a classic combination of pro-inflammatory cytokines (tumor necrosis factor-α, IL-1β, IL-6, prostaglandin E2) and (ii) a Toll-like receptor (TLR)7/8 agonist-based cocktail (R-848, interferon-γ, TNF-α and prostaglandin E2). In addition, both short-term (2-3 days) and long-term (6-7 days) DC culture protocols were compared. The different DC populations were characterized with respect to their phenotypic profile, migratory properties, cytokine production and T cell stimulation capacity.ResultsThe use of a TLR7/8 agonist-based cocktail resulted in a more optimal maturation of IL-15 DCs, as reflected by the higher phenotypic expression of CD83 and costimulatory molecules (CD70, CD80, CD86). The functional superiority of TLR7/8-activated IL-15 DCs over conventionally matured IL-15 DCs was evidenced by their (i) higher migratory potential, (ii) advantageous cytokine secretion profile (interferon-γ, IL-12p70) and (iii) superior capacity to stimulate autologous, antigen-specific T cell responses after passive peptide pulsing. Aside from a less pronounced production of bioactive IL-12p70, short-term versus long-term culture of TLR7/8-activated IL-15 DCs resulted in a migratory profile and T cell stimulation capacity that was in favour of short-term DC culture. In addition, we demonstrate that mRNA electroporation serves as an efficient antigen loading strategy of IL-15 DCs.ConclusionsHere we show that short-term cultured and TLR7/8-activated IL-15 DCs fulfill all pre-clinical prerequisites of immunostimulatory DCs. The results of the present study might pave the way for the implementation of IL-15 DCs in immunotherapy protocols.

Dendritic Cell-Based Cancer Gene Therapy

In view of their potent antigen-presenting capacity and ability to induce effective immune responses, dendritic cells (DCs) have become an attractive target for therapeutic manipulation of the immune system. The application of tumor-associated antigen (TAA)-expressing DCs for cancer therapy has been the subject of intensive translational investigation. Previous clinical trials demonstrated tumor-specific immune responses without any significant toxicity. However, the clinical success has been modest, because only a limited number of immunized patients demonstrated cancer regression. Considerable progress has been made in the knowledge of DC biology, which opens new avenues for the development of optimized clinical protocols. One such promising approach that might carve its place in the future of DC-based therapy is the use of gene-modified DCs. DCs engineered to express TAAs allow multiepitope presentation by both major histocompatibility complex (MHC) class I and II molecules of full-length TAAs independent of the patients HLA constitution, as opposed to peptide vaccination strategies. Besides transgene TAA expression, DCs can be genetically modified (1) to express a variety of immune-potentiating molecules (e.g., costimulatory molecules, cytokines, and chemokines) or (2) to downregulate negative modulators of DC functioning, all allowing an enhancement of their immunogenic potential. In the present review, gene delivery systems for DCs are discussed, as well as the various transgenes used for genetic modification of DCs. Moreover, a detailed review of the already published trials using gene-modified DCs is presented and future DC-based strategies targeting multiple layers of the complex cellular immune response are highlighted.

Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials.

A growing body of evidence points toward an important anti-cancer effect of bisphosphonates, a group of inexpensive, safe, potent, and long-term stable pharmacologicals that are widely used as osteoporosis drugs. To date, they are already used in the prevention of complications of bone metastases. Because the bisphosphonates can also reduce mortality in among other multiple myeloma, breast, and prostate cancer patients, they are now thoroughly studied in oncology. In particular, the more potent nitrogen-containing bisphosphonates have the potential to improve prognosis. The first part of this review will elaborate on the direct and indirect anti-tumoral effects of bisphosphonates, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion and invasion, anti-angiogenesis, synergism with anti-neoplastic drugs, and enhancement of immune surveillance (e.g., through activation of γδ T cells and targeting macrophages). In the second part, we shed light on the current clinical position of bisphosphonates in the treatment of hematological and solid malignancies, as well as on ongoing and completed clinical trials investigating the therapeutic effect of bisphosphonates in cancer. Based on these recent data, the role of bisphosphonates is expected to further expand in the near future outside the field of osteoporosis and to open up new avenues in the treatment of malignancies.

Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy

Although the earliest—rudimentary—attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy.

Tumoricidal activity of human dendritic cells

n n Dendritic cells (DCs) are a family of professional antigen-presenting cells (APCs) that are able to initiate innate and adaptive immune responses against pathogens and tumor cells. The DC family is heterogeneous and is classically divided into two main subsets, each with its unique phenotypic and functional characteristics: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). Recent results have provided intriguing evidence that both DC subsets can also function as direct cytotoxic effector cells; in particular, against cancer cells. In this review, we delve into this understudied function of human DCs and discuss why these so-called killer DCs might become important tools in future cancer immunotherapies.n n

Dendritic cell vaccination in acute myeloid leukemia.

The prognosis of patients with acute myeloid leukemia (AML) remains dismal, with a 5-year overall survival rate of only 5.2% for the continuously growing subgroup of AML patients older than 65 years. These patients are generally not considered eligible for intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation because of high treatment-related morbidity and mortality, emphasizing the need for novel, less toxic, treatment alternatives. It is within this context that immunotherapy has gained attention in recent years. In this review, we focus on the use of dendritic cell (DC) vaccines for immunotherapy of AML. DC are central orchestrators of the immune system, bridging innate and adaptive immunity and critical to the induction of anti-leukemic immunity. We discuss the rationale and basic principles of DC-based therapy for AML and review the clinical experience that has been obtained so far with this form of immunotherapy for patients with AML.

Interleukin-15 dendritic cells as vaccine candidates for cancer immunotherapy

Owing to their professional antigen-presenting capacity and unique potential to induce tumor antigen-specific T cell immunity, dendritic cells (DCs) have attracted much interest over the past decades for therapeutic vaccination against cancer. Clinical trials have shown that the use of tumor antigen-loaded DCs in cancer patients is safe and that it has the potential to induce anti-tumor immunity which, in some cases, culminates in striking clinical responses. Unfortunately, in a considerable number of patients, DC vaccination is unable to mount effective anti-tumor immune responses and, if it does so, the resultant immunity is often insufficient to translate into tangible clinical benefit. This underscores the necessity to re-design and optimize the current procedures for DC vaccine manufacturing. A new generation of DC vaccines with improved potency has now become available for clinical use as a result of extensive pre-clinical research. One of the promising next-generation DC vaccine candidates are interleukin (IL)-15-differentiated DCs. In this commentary, we will compile the research data that have been obtained by our group and other groups with these so-called IL-15 DCs and summarize the evidence supporting the implementation of IL-15 DCs in DC-based cancer vaccination regimens.

Induction of complete remission of acute myeloid leukaemia by pegylated interferon‐α‐2a in a patient with transformed primary myelofibrosis

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CD56 marks human dendritic cell subsets with cytotoxic potential.

Human plasmacytoid and myeloid dendritic cells (DCs), when appropriately stimulated, can express the archetypal natural killer (NK)-cell surface marker CD56. In addition to classical DC functions, CD56+ DCs are endowed with an unconventional cytotoxic capacity.