Dendritic Cell-based Strategies Research Articles

Dendritic Cell-Based and Other Vaccination Strategies for Pediatric Cancer.

Dendritic cell-based and other vaccination strategies that use the patient’s own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death among children past infancy in the Western world, the hope is that this form of active specific immunotherapy can play an important role in the pediatric population as well. Since children have more vigorous and adaptable immune systems than adults, therapeutic cancer vaccines are expected to have a better chance of creating protective immunity and preventing cancer recurrence in pediatric patients. Moreover, in contrast to conventional cancer treatments such as chemotherapy, therapeutic cancer vaccines are designed to specifically target tumor cells and not healthy cells or tissues. This reduces the likelihood of side effects, which is an important asset in this vulnerable patient population. In this review, we present an overview of the different therapeutic cancer vaccines that have been studied in the pediatric population, with a main focus on dendritic cell-based strategies. In addition, new approaches that are currently being investigated in clinical trials are discussed to provide guidance for further improvement and optimization of pediatric cancer vaccines.

Overcoming Oncogenic Mediated Tumor Immunity in Prostate Cancer.

Immunotherapy is being tested intensively in clinical trials for prostate cancer; it includes immune checkpoint inhibition, prostate specific antigen (PSA) vaccines and dendritic cell-based strategies. Despite increasing evidence for clinical responses, the consensus of multiple trials is that prostate cancers are poorly responsive to immunotherapy. Prostate cancer has a high degree of pathological and genetic heterogeneity compared to other cancer types, which may account for immunotherapeutic resistance. This hypothesis also implies that select types of prostate tumors may be differentially responsive to immune-based strategies and that the clinical stage, pathological grade and underlying genetic landscape may be important criteria in identifying tumors that respond to immune therapies. One strategy is to target oncogenic driver pathways in combination with immunotherapies with the goal of overcoming tumor immunity and broadening the number of patients achieving a clinical response. In this analysis, we address the hypothesis that driver oncogenic signaling pathways regulate cancer progression, tumor immunity and resistance to current immune therapeutics in prostate cancer. We propose that increased responsiveness may be achieved through the combined use of immunotherapies and inhibitors targeting tumor cell autonomous pathways that contribute towards anti-tumor immunity in patients with prostate cancer.

Toward a cure for HIV--Seeking effective therapeutic vaccine strategies.

This review article focuses on the rationale and evaluation of therapeutic vaccines against HIV. This strategy has been developed in order to restore or restimulate HIV-specific immunity in patients treated with antiretroviral therapies. Despite the lack of good candidate vaccines against HIV, two objectives have been targeted during the past 15 years. Therapeutic immunization was first proposed to help control virus relapses during treatment interruptions. More recently, the concept of therapeutic immunization has been boosted by efforts to reach HIV remission or cure, in combination to HIV reactivating agents, to help purge HIV reservoirs in a "shock and kill" strategy. This review analyses the rationales for these strategies and the results of the most widely therapeutic vaccines designed to generate T-cell immunity, i.e. recombinant viral vectors and dendritic cell-based strategies, while extremely few strategies targeted HIV-specific Abs. Only marginal control of HIV was obtained with cellular-based strategies, suggesting that approaches targeting or using broadly neutralizing Abs, should be of benefit for future efforts of therapeutic immunization against HIV in the quest toward a cure for HIV.

Induction of Immunological Tolerance to Adenoviral Vectors by Using a Novel Dendritic Cell-Based Strategy

The success of helper-dependent adenoviral (HD-Ad) vector-mediated lung gene therapy is hampered by the host immune response, which limits pulmonary transgene expression following multiple rounds of vector readminstration. Here, we show that HD-Ad-mediated pulmonary gene expression is sustained even upon three rounds of readministration to immunodeficient mice, highlighting the need to suppress the adaptive immune response for sustained gene expression following vector readministration. Therefore, we devised a dendritic cell (DC)-based strategy for induction of immunological tolerance toward HD-Ad vectors. DCs derived in the presence of interleukin-10 (IL-10) are refractory to HD-Ad-induced maturation and instead facilitate generation of IL-10-producing Tr1 regulatory T cells which suppress HD-Ad-induced T cell proliferation. Delivery of HD-Ad-pulsed, IL-10-modified DCs to mice induces long-lasting immunological tolerance to HD-Ad vectors, whereby pulmonary DC maturation, the T cell response, and antibody response to HD-Ad vectors are suppressed even after three rounds of pulmonary HD-Ad readministration. Moreover, sustained transgene expression is also observed in the lungs of mice immunized with HD-Ad-pulsed, IL-10-modified DCs even after three rounds of pulmonary HD-Ad delivery. Taken together, these studies identify the use of DCs generated in the presence of IL-10 as a novel strategy to induce long-lasting immune tolerance to HD-Ad vectors.

Recent Advances in Antigen-Loaded Dendritic Cell-Based Strategies for Treatment of Minimal Residual Disease in Acute Myeloid Leukemia

Therapeutic vaccination with dendritic cells (DCs) is recognized as an important experimental therapy for the treatment of minimal residual disease in acute myeloid leukemia. Many sources of leukemia-associated antigens and different methods for antigen loading of DCs have been used in an attempt to optimize anti-tumor responses. For instance, monocyte-derived DCs have been loaded with apoptotic whole-cell suspensions, necrotic cell lysates, tumor-associated peptides, eluted peptides and cellular DNA or RNA. Furthermore, monocyte-derived DCs can be chemically or electrically fused with leukemic blasts, and DCs have been cultured out of leukemic blasts. However, it remains a challenge in cancer immunotherapy to identify which of these methods is the most optimal for antigen loading and activation of DCs. This review discusses recent advances in DC research and the application of this knowledge towards new strategies for antigen loading of DCs in the treatment of minimal residual disease in acute myeloid leukemia.

Dendritic Cell-Ewing’s Sarcoma Cell Hybrids Enhance Antitumor Immunity

Given the effective immunotherapy of DC-based vaccine in other cancers, we hypothesized DC-based vaccines would induce effective immune responses against Ewing's sarcoma. To verify this hypothesis and develop the most effective dendritic cell vaccine against Ewing's sarcoma, we evaluated the antitumor efficacy of dendritic cell-Ewing's sarcoma hybrids and dendritic cells pulsed with other antigen-loading methods, including cell lysates and the characteristic EWS-FLI1 gene of Ewing's sarcoma, using an A673 cell line as a model. The hybrids were generated by electrofusion with fusion efficiency and viability determined by flow cytometry and fluorescent microscopy analyses. By interferon-gamma secretion assay, the capacity of hybrids to stimulate cytotoxic T-lymphocytes (CTLs) is higher than that of other antigen-loading methods showing stronger tumor antigen-specific CTL cytotoxicity to A673. By in vivo experiment in SCID mice, all dendritic cell-based strategies induced specific immune responses to Ewing's sarcoma after mice-human immune system reconstitution by inoculating human peripheral blood mononuclear cells into the peritoneal cavity of SCID mice. However, the hybrids most inhibited the subcutaneous tumor growth in SCID mice compared with dendritic cells pulsed with other loading methods. The data suggest A673 cells respond to dendritic cell-based immunotherapy.