Aim: Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic... Show moreAim: Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling. Method: For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions. Results: Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin-6 (IL-6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases. Conclusion: This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target- and disease-specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL-6, Tumor Necrosis Factor alfa (TNF-alpha) and interleukin-1 beta (IL-1 beta) in diseases with systemic inflammation. Show less
Tumor growth and progression are linked to an altered lipid metabolism in the tumor microenvironment (TME), including tumor cells and tumor-associated macrophages (TAMs). A growing number of lipid... Show moreTumor growth and progression are linked to an altered lipid metabolism in the tumor microenvironment (TME), including tumor cells and tumor-associated macrophages (TAMs). A growing number of lipid metabolism targeting drugs have shown efficacy in anti-tumor therapy. In addition, exogenously applied lipids and lipid analogues have demonstrated anti-tumor activities in several cancers, including breast cancer. In this study, we investigated the anti-tumor efficacies of the natural lipids palmitic acid (PA), sphingomyelin (SM), ceramide (Cer) and docosahexaenoic acid (DHA) on breast cancer cells. All tested lipids reduced the malignancy of breast cancer cells in vitro by impairing cell proliferation, migration and invasiveness. PA showed superior anti-tumor properties, as it additionally impaired cancer cell viability by inducing apoptosis, without affecting healthy cells. Co-culture experiments further demonstrated that Cer and PA reduced the immunosuppressive phenotype of M2 macrophages and the M2 macrophage-promoted the epithelial-mesenchymal transition (EMT) and migration of breast cancer cells. At the molecular level, this coincided with the up-regulation of E-cadherin. Our results highlight a powerful role for exogenously applied PA and Cer in reducing breast cancer tumorigenicity by simultaneously targeting cancer cells and M2 macrophages. Our findings support the notion that lipids represent alternative biocompatible therapeutic agents for breast cancer. Show less
Atmar, K.; Tulling, A.J.; Lankester, A.C.; Bartels, M.; Smiers, F.J.; Burg, M. van der; Mohseny, A.B. 2022
BackgroundIn most patients with aplastic anemia (AA), the diagnosis is limited to a description of the symptoms. Lack of understanding of the underlying pathophysiological mechanisms causing bone... Show moreBackgroundIn most patients with aplastic anemia (AA), the diagnosis is limited to a description of the symptoms. Lack of understanding of the underlying pathophysiological mechanisms causing bone marrow failure (BMF), hampers tailored treatment. In these patients, auto-immune cell-mediated destruction of the bone marrow is often presumed to be the causative mechanism. The status of the bone marrow microenvironment, particularly the mesenchymal stromal cell (MSC) component, was recently suggested as a potential player in the pathophysiology of AA. Therefore, functional, and immune modulatory characteristics of bone marrow MSCs might represent important parameters for AA.ObjectiveTo conduct a systematic review to evaluate in vitro functional properties of MSCs derived from patients with AA compared to healthy controls.MethodsAccording to PRISMA guidelines, a comprehensive search strategy was performed by using online databases (Pubmed, ISI Web of Science, Embase, and the Cochrane Library). Studies reporting on phenotypical characterization, proliferation potential, differentiation capacity, immunomodulatory potential, and ability to support hematopoiesis were identified and screened using the Rayyan software tool.Results23 articles were included in this systematic review, describing a total of 324 patients with AA and 285 controls. None of the studies identified a significant difference in expression of any MSC surface marker between both groups. However, AA-MSCs showed a decreased proliferation potential, an increased tendency to differentiate into the adipogenic lineage and decreased propensity towards osteogenic differentiation. Importantly, AA-MSCs show reduced capacity of immunosuppression and hematopoietic support in comparison to healthy controls.ConclusionWe conclude that there are indications for a contribution of MSCs in the pathophysiology of AA. However, the current evidence is of poor quality and requires better defined study populations in addition to a more robust methodology to study MSC biology at a cellular and molecular level. Future studies on bone marrow microenvironment should aim at elucidating the interaction between MSCs, hematopoietic stem cells (HSCs) and immune cells to identify impairments associated with/causing BMF in patients with AA. Show less
Gruil, N. de; Pijl, H.; Burg, S.H. van der; Kroep, J.R. 2022
Simple Summary Stimulating our body's own immune response to fight cancer is important for the success of cancer treatment in general. To further improve current cancer therapy, preclinical... Show moreSimple Summary Stimulating our body's own immune response to fight cancer is important for the success of cancer treatment in general. To further improve current cancer therapy, preclinical research shows that short-term fasting diets enhance cancer therapy efficacy, such as chemotherapy. Short-term fasting diets are low-caloric and low in protein for 3-5 days; they are usually done every couple of weeks. This review summarizes preclinical and clinical evidence of fasting diets synergizing with cancer therapy by boosting antitumor immunity. Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy. Show less
Gu, Z.L.; Silva, C.G. da; Maaden, K. van der; Ossendorp, F.; Cruz, L.J. 2020
Cancer immunotherapy has shown remarkable progress in recent years. Nanocarriers, such as liposomes, have favorable advantages with the potential to further improve cancer immunotherapy and even... Show moreCancer immunotherapy has shown remarkable progress in recent years. Nanocarriers, such as liposomes, have favorable advantages with the potential to further improve cancer immunotherapy and even stronger immune responses by improving cell type-specific delivery and enhancing drug efficacy. Liposomes can offer solutions to common problems faced by several cancer immunotherapies, including the following: (1) Vaccination: Liposomes can improve the delivery of antigens and other stimulatory molecules to antigen-presenting cells or T cells; (2) Tumor normalization: Liposomes can deliver drugs selectively to the tumor microenvironment to overcome the immune-suppressive state; (3) Rewiring of tumor signaling: Liposomes can be used for the delivery of specific drugs to specific cell types to correct or modulate pathways to facilitate better anti-tumor immune responses; (4) Combinational therapy: Liposomes are ideal vehicles for the simultaneous delivery of drugs to be combined with other therapies, including chemotherapy, radiotherapy, and phototherapy. In this review, different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed. Show less
Hernandez, I.B.; Yu, Y.X.; Ossendorp, F.; Korbelik, M.; Oliveira, S. 2020
Photodynamic therapy (PDT) is an anticancer strategy utilizing light-mediated activation of a photosensitizer (PS) which has accumulated in tumor and/or surrounding vasculature. Upon activation,... Show morePhotodynamic therapy (PDT) is an anticancer strategy utilizing light-mediated activation of a photosensitizer (PS) which has accumulated in tumor and/or surrounding vasculature. Upon activation, the PS mediates tumor destruction through the generation of reactive oxygen species and tumor-associated vasculature damage, generally resulting in high tumor cure rates. In addition, a PDT-induced immune response against the tumor has been documented in several studies. However, some contradictory results have been reported as well. With the aim of improving the understanding and awareness of the immunological events triggered by PDT, this review focuses on the immunological effects post-PDT, described in preclinical and clinical studies. The reviewed preclinical evidence indicates that PDT is able to elicit a local inflammatory response in the treated site, which can develop into systemic antitumor immunity, providing long-term tumor growth control. Nevertheless, this aspect of PDT has barely been explored in clinical studies. It is clear that further understanding of these events can impact the design of more potent PDT treatments. Based on the available preclinical knowledge, recommendations are given to guide future clinical research to gain valuable information on the immune response induced by PDT. Such insights directly obtained from cancer patients can only improve the success of PDT treatment, either alone or in combination with immunomodulatory approaches. Show less
Chakraborty, T.; Thuer, E.; Heijink, M.; Toth, R.; Bodai, L.; Vagvolgyi, C.; ... ; Gacser, A. 2018
Schistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most... Show moreSchistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most antibodies raised during schistosome infection are directed against glycans, some of which are thought to be protective. Developing schistosomula are considered most vulnerable to immune attack, and better understanding of local antibody responses raised against glycans expressed by this life stage might reveal possible glycan vaccine candidates for future vaccine research. In this tehsis we adressed the spatial and temporal expression of glycans expressed during the critical larval stages of schistosome development and we studied the (protective) antibody responses against these glycans in animals and infected human populations. Together these studies thereby contribute to an important basis for the understanding of the anti-glycan antibody responses towards Schistosoma in general and towards the vulnerable schistosomulum in particular. Show less
