Kris Thielemans

Kris Thielemans
Vrije Universiteit Brussel | VUB · Laboratory of Cellular and Molecular Immunology

MD, PhD

About

307
Publications
36,153
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16,863
Citations
Additional affiliations
January 2004 - present
Erasmus MC
January 2003 - December 2005
January 2002 - December 2009
Université Libre de Bruxelles

Publications

Publications (307)
Article
BACKGROUND: The development of a prophylactic vaccine against HIV-1 has so far not been successful. Therefore, attention has shifted more and more towards the development of novel therapeutic vaccines. Here, we evaluated a new mRNA based therapeutic vaccine against HIV-1 encoding activation signals (TriMix: CD40L+CD70+caTLRA4) combined with ration...
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Background: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. Methods: Freshly frozen melanoma metastases were collected from patients treated wit...
Article
The majority of metastatic cancers remain incurable since the current methods of treatment often fail to target the heterogeneous nature of each individual patient's tumor. Personalized approaches targeting each individual patient's tumor may therefore bring significant improvements. The Mutanome Engineered RNA Immuno-Therapy (MERIT) consortium wil...
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Cancer vaccines based on mRNA are extensively studied. The fragile nature of mRNA has instigated research into carriers that can protect it from ribonucleases and as such enable its systemic use. However, carrier-mediated delivery of mRNA has been linked to production of type I interferon (IFN) that was reported to compromise the effectiveness of m...
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Background: Recurrent glioblastoma is associated with a poor overall survival. Antiangiogenic therapy results in a high tumor response rate but has limited impact on survival. Immunotherapy has emerged as an efficient treatment modality for some cancers, and preclinical evidence indicates that anti-VEGF(R) therapy can counterbalance the immunosupp...
Chapter
Dendritic cells (DCs) are the orchestrators of the immune system and are frequently used in clinical trials in order to boost the immune system in cancer patients. Among several available techniques for DC modification, mRNA electroporation is an interesting technique due to the favorable characteristics of mRNA. Antigen expression level and durati...
Chapter
The immune system is a crucial player in the development of cancer. Once it is in imbalance and immunosuppressive mechanisms supporting tumor growth take over control, dendritic cell immunotherapy might offer a solution to restore the balance. There are several methods to manufacture dendritic cells but none of them has yet proven to be superior to...
Article
Purpose Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an immunoglobulin G1 monoclonal antibody directed against the cytotoxic T-lymphocyte-associated protein 4 receptor that co...
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The lack of appropriate mouse models is likely one of the reasons of a limited translational success rate of therapeutic vaccines against cervical cancer, as rapidly growing ectopic tumours are commonly used for preclinical studies. In this work, we demonstrate that the tumour microenvironment of TC-1 tumours differs significantly depending on the...
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Cross-presentation enables dendritic cells to present on their MHC class I molecules antigenic peptides derived from exogenous material, through a mechanism that remains partly unclear. It is particularly efficient with long peptides, which are used in cancer vaccines. We studied the mechanism of long-peptide cross-presentation using human dendriti...
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Recent advances in immunotherapy led to a breakthrough in cancer treatment, changing the algorithms of clinical cancer management. Notwithstanding this success, numerous immune escape mechanisms significantly hamper the long-term efficacy of immunotherapy. A growing body of evidence recognizes immunosuppressive tumor microenvironment (TME) as a maj...
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Modulating the activity of tumor-infiltrating dendritic cells (TiDCs) provides opportunities for novel cancer interventions. In this study, we report on the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (IT) delivery. We exploited this property to deliver mRNA encoding the co-stimulatory molecule CD70, the activation stimuli...
Article
Modification of dendritic cells (DC) with mRNA allows the loading of these cells with tumor antigens and the functional modification of the cellular vaccine. To reprogram immature DC towards potent and immunostimulatory antigen presenting cells, we provide three different molecular adjuvants to DCs with mRNA coding for caTLR4, mimicking TLR-activat...
Article
In situ modification of antigen-presenting cells (APCs) garnered interest in cancer immunotherapy. Therefore, we developed APC-targeted lentivectors (LVs). Unexpectedly, these LVs were inferior vaccines to broad tropism LVs. Since IL-12 is a potent mediator of antitumor immunity, we evaluated whether this pro-inflammatory cytokine could enhance ant...
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Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM pa...
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The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and e...
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The immunosuppressive tumor microenvironment (TME) is a major obstacle in cancer immunotherapy. Therefore, it has gained attention as a target site. mRNA emerged as a versatile drug class for cancer therapy. We reported that intratumoral administration of mRNA encoding the fusokine Fβ2 supports tumor-specific T-cell immunity. This study provides a...
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The identification of tumor-specific antigens and the immune responses directed against them has instigated the development of therapies to enhance antitumor immune responses. Most of these cancer immunotherapies are administered systemically rather than directly to tumors. Nonetheless, numerous studies have demonstrated that intratumoral therapy i...
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Melanoma patients are at high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the anti-tumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tum...
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Melanoma patients with a high risk of recurrence may benefit from immunotherapy with mRNA-electroporated autologous monocyte-derived dendritic cells (DCs). Further benefit may be found in combining DC-therapy with interferon alfa-2b. The long-term clinical outcome of AJCC stage III/IV melanoma patients who had no evidence of disease at the time of...
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Full-text available
Purpose: Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an immunoglobulin G1 monoclonal antibody directed against the cytotoxic T-lymphocyte-associated protein 4 receptor that...
Article
An increasing number of studies is focusing on the role of myeloid-derived suppressor cells (MDSCs) in the suppression of anti-tumor immune responses. Although the main site of action for MDSCs is most likely the tumor microenvironment, the study of these cells has been largely restricted to MDSCs derived from peripheral lymphoid organs. Only in a...
Article
It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8(+) cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral deliv...
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About 25 years ago, mRNA became a tool of interest in anticancer vaccination approaches. However, due to its rapid degradation in situ, direct application of mRNA was confronted with considerable skepticism during its early use. Consequently, mRNA was for a long time mainly used for the ex vivo transfection of dendritic cells, professional antigen-...
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It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8 + cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delive...
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Cancer immunotherapy has been proposed as a powerful treatment modality. Active immunotherapy aspires to stimulate the patient's immune system, particularly T cells. These cells can recognize and kill cancer cells and can form an immunological memory. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system. They tak...
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VEGF is a key mediator of pathological cancer associated neoangiogenesis and immunosuppression. VEGFR targeted therapy holds promise to counteract cancer associated neoangiogenesis but also to alleviate cancer associated immune suppression. Melanoma patients are at high risk for developing brain metastases. These lesions are strongly vascularized a...
Article
Dendritic cell (DC)-based cancer vaccines, where the patient’s own immune system is harnessed to target and destroy tumor tissue, has emerged as a potent therapeutic strategy. In the development of such DC vaccines, it is crucial to load the DCs with tumor antigens, and to simultaneously activate them to become more potent antigen-presenting cells....
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AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth...
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Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Im...
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Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play...
Article
Although the main site of action for myeloid-derived suppressor cells (MDSCs) is most likely the tumor-microenvironment, so far the study of these cells has been largely restricted to spleen-derived MDSCs. In this study we compared the suppressive capacity of splenic and tumor-derived MDSCs in different subcutaneous mouse tumor models. We investiga...
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Several galectins are released by tumor cells and macrophages and accumulate in the tumor microenvironment. Galectin-1 and -3 were found to bind to glycosylated receptors at the surface of tumor-infiltrating lymphocytes (TIL), forming glycoprotein-galectin lattices that could reduce the motility and therefore the functionality of surface molecules....
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To increase the safety and possibly efficacy of HIV-1 derived lentivectors (LVs) as an anti-cancer vaccine, we recently developed the Nanobody (Nb) display technology to target LVs to antigen presenting cells (APCs). In this study, we extend these data with exclusive targeting of LVs to conventional dendritic cells (DCs), which are believed to be t...
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The release of cytokines by T cells strongly defines their functional activity in vivo. The ability to produce multiple cytokines has been associated with beneficial immune responses in cancer and infectious diseases, while their progressive loss is associated with T-cell exhaustion, senescence and anergy. Consequently, strategies that enhance the...
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Tumor antigen-encoding mRNA for dendritic cell (DC)-based vaccination has gained increasing popularity in recent years. Within this context, two main strategies have entered the clinical trial stage: the use of mRNA for ex vivo antigen loading of DCs and the direct application of mRNA as a source of antigen for DCs in vivo. DCs transfected with mRN...
Article
This study aimed to evaluate HIV sequence evolution in whole genes and in CD8 T-cell epitope regions following immunotherapy and subsequent analytical treatment interruption (ATI). A second objective of this study was to analyze associations between vaccine-specific immune responses and epitope mutation rates. HIV-1-infected patients on combined an...
Article
Peripheral blood T cells transduced with a tumor-specific T cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the effi...
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Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3...
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Antigen-presenting cells are a heterogeneous group of cells that are characterized by their functional specialization. Consequently, targeting specific antigen-presenting cell subsets offers opportunities to induce distinct T cell responses. Here we report on the generation and use of nanobodies (Nbs) to target lentivectors specifically to human ly...
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Regulatory T cells (Tregs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)-based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the Treg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active...
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Full-text available
Regulatory T cells (Tregs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)-based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the Treg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active...
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Persistent activation of the transcription factor, signal transducer and activator of transcription 3 (Stat3) has been shown to mediate several oncogenic features in many types of cancers, including melanoma. In this study, we investigated whether lentiviral (LV) delivery of Stat3-targeting short hairpin RNA (shRNA; LV-shStat3) to K1735-C4 melanoma...
Article
Dendritic cell therapy has been optimized a lot aiming to induce a strong and broad immune response in terms of the recognized epitopes by both CD8+ and CD4+ T cells and the use of the patients' complete unique set of HLA molecules. We here give an overview of our approach for antigen loading and maturation of dendritic cells and describe the conse...
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Full-text available
Two decades ago, mRNA became the focus of research in molecular medicine and was proposed as an active pharmaceutical ingredient for the therapy of cancer. In this regard, mRNA has been mainly used for ex vivo modification of antigen-presenting cells (APCs), such as dendritic cells (DCs). This vaccination strategy has proven to be safe, well tolera...
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Full-text available
Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to mig...
Chapter
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It is well established that CD8 + cytotoxic T lymphocytes (CTLs) play a major role in eradicating tumor cells. The path from naive CD8 + T cell to effector CD8 + T cell is guided by antigen presenting cells, such as dendritic cells (DCs) that start a developmental program in the CD8 + T cells through the delivery of MHC/peptide complexes, co-stimul...