Viscum album neutralizes tumor-induced immunosuppression in a human in vitro cell model

Steinborn, Carmen; Zimmermann-Klemd, Amy Marisa; Sanchez-Campillo, Ann-Sophie; Rieger, Sabine; Scheffen, Marieke; Sauer, Barbara; Garcia-Käufer, Manuel; Urech, Konrad; Follo, Marie; Ücker, Annekathrin; Kienle, Gunver S.; Huber, Roman; Gründemann, Carsten

doi:10.1371/journal.pone.0181553

Cited by 34 publications

(26 citation statements)

References 28 publications

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“…This is in line with published tolerability results of studies analyzing the safety profile of mAb and ICI therapies without and with add-on VA therapy [ 35 ]. The specific underlying mechanisms of VA’s toxicity-ameliorating effects in the present study remain elusive, and the well-published VA-mediated immune-stimulatory [ 57 , 58 ], anti-proliferative [ 59 , 60 , 61 , 62 ], anti-angiogenic [ 63 ], and anti-invasive [ 64 ] effects may not sufficiently explain them. VA extracts have been shown to in vitro and in vivo improve DNA-repair of radiation-, ultraviolet radiation- and cyclophosphamide-induced damage of lymphocytes of breast cancer patients [ 65 , 66 , 67 , 68 , 69 ] and further in the gamma-ray damaged peripheral blood mononuclear cells of breast cancer patients [ 70 ] and this may serve as a hypothesis for the mechanism of the improvement in adverse events experienced by cancer patients.…”

Section: Discussionmentioning

confidence: 84%

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients

et al. 2018

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Background: Despite improvement of tumor response rates, targeted therapy may induce toxicities in cancer patients. Recent studies indicate amelioration of adverse events (AEs) by add-on mistletoe (Viscum album L., VA) in standard oncological treatment. The primary objective of this multicenter observational study was to determine the safety profile of targeted and add-on VA therapy compared to targeted therapy alone. Methods: Demographic and medical data were retrieved from the Network Oncology registry. Allocation to either control (targeted therapy) or combinational group (targeted/add-on VA) was performed. Safety-associated variables were evaluated by adjusted multivariable analyses. Results: The median age of the study population (n = 310) at first diagnosis was 59 years; 67.4% were female. In total, 126 patients (40.6%) were in the control and 184 patients (59.4%) in the combination group. Significant differences were observed between both groups with respect to overall AE frequency (χ2 = 4.1, p = 0.04) and to discontinuation of standard oncological treatment (χ2 = 4.8, p = 0.03) with lower rates in the combinational group (20.1%, 35% respectively) compared to control (30.2%, 60.5%, respectively). Addition of VA to targeted therapy significantly reduced the probability of oncological treatment discontinuation by 70% (Odds ratio (OR) 0.30, p = 0.02). Conclusions: Our results indicate a highly significant reduction of AE-induced treatment discontinuation in all-stage cancer patients when treated with VA in addition to targeted therapy.

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Section: Discussionmentioning

confidence: 84%

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients

et al. 2018

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“…DAMPs elicit an immune response by activating dendritic cells (DC), promoting the release of proinflammatory factors and by recruiting immune cells that infiltrate the tumor area [ 50 ]. In this context it has been published that mistletoe extracts stimulated the maturation of DCs [ 22 , 51 ]. Finally, in immunocompetent mice serial ISCADOR Qu injection might induce the production of antibodies that either positively or negatively modulate immunoreactivity [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…Beyond this, mistletoe extracts trigger monocyte-derived macrophage activity, dendritic cell (DC) maturation, and induce a specific T-helper cell reaction [ 20 , 21 ]. Additionally, they neutralize tumor-induced immunosuppression, at least in vitro [ 22 ]. In vivo both, extracts and purified MLs, increased the number of leucocytes and granulocytes and enhanced the blood level of granulocyte-macrophage colony stimulating factor (GM-CSF), interferon (IFN)- γ , and interleukin (IL)-5 [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Adjuvant Therapy Using Mistletoe Containing Drugs Boosts the T‐Cell‐Mediated Killing of Glioma Cells and Prolongs the Survival of Glioma Bearing Mice

Schötterl

Huber

Lentzen³

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Viscum album L. extracts (VE) are applied as complementary cancer therapeutics for more than one century. Extracts contain several compounds like mistletoe lectins (ML) 1-3 and viscotoxins, but also several minor ingredients. Since ML-1 has been described as one of the main active components harboring antitumor activity, purified native or recombinant ML-1 has been also used in clinical trials in the last years. The present study examined and compared the immunoboosting effects of three ML-1 containing drugs (the extract ISCADOR Qu, the recombinant ML-1 Aviscumine, and purified native ML-1) in the context of the T-cell mediated killing of glioma cells. Additionally we examined the possible underlying T-cell stimulating mechanisms. Using cocultures of immune and glioma cells, a PCR-based microarray, quantitative RT-PCR, and an antibody-based array to measure cytokines in blood serum, immunosupporting effects were determined. A highly aggressive, orthotopic, immunocompetent syngeneic mouse glioma model was used to determine the survival of mice treated with ISCADOR Qu alone or in combination with tumor irradiation and temozolomide (TMZ). Treatment of glioblastoma (GBM) cells with ISCADOR Qu that contains a high ML concentration, but also viscotoxins and other compounds, as well as with Aviscumine or native ML-1, enhanced the expansion of cancer cell-specific T-cells as well as T-cell-mediated tumor cell lysis, but to a different degree. In GBM cells all three ML-1-containing preparations modulated the expression of immune response associated genes. In vivo, subcutaneous ISCADOR Qu injections at increasing concentration induced cytokine release in immunocompetent VM/Dk-mice. Finally, ISCADOR Qu, if applied in combination with tumor irradiation and TMZ, further prolonged the survival of glioma mice. Our findings indicate that ML-1 containing drugs enhance anti-GBM immune responses and work in synergy with radiochemotherapy. Therefore, adjuvant mistletoe therapy should be considered as an auspicious treatment option for glioma patients.

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“…The failure of cytokine therapy should also be discussed in the context of alternative and complementary cancer medicine, which is associated with reduced OS 17. Mistletoe extracts, for example, are widely used with the promise of immune-stimulation and have been shown to promote IFN-γ release 18. Such an action on the immune system could, however, lead to opposing and undesired effects which, in turn, deteriorate prognosis.…”

Section: Cytokinesmentioning

confidence: 99%

Immunotherapy in ovarian cancer: fake news or the real deal?

Marth¹,

Wieser

Tsibulak

et al. 2019

Int J Gynecol Cancer

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Cancer immunotherapy has emerged as one of the most promising approaches in oncology, and comprises the activation of the immune system to induce tumor immune surveillance or to reverse the tumor immune escape. Different therapeutic strategies for ovarian carcinoma have evolved over the years. Already 30 years ago, the first clinical studies focused on modulating the tumor cytokine network with special attention to interferon-mediated immune responses. With the exploration of specific tumor antigens such as NY-ESO-1, which is expressed in ovarian carcinoma and other malignancies, the development of therapeutic cancer vaccines has been pursued initiating the era of personalized anti-cancer medicine. Almost at the same time, the adoptive transfer of genetically modified autologous tumor-reactive T-cells occurred, but response rates in ovarian carcinoma were disappointing. Today, probably the most promising therapeutic approach in this context is the blockade of immune checkpoints, such as programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) or cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4), which has demonstrated impressive response rates in malignant melanoma and non-small cell lung cancer. Despite increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. Here, we summarize different immunotherapy approaches in ovarian cancer and discuss why immunotherapy in ovarian cancer is still in its infancy.

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Viscum album neutralizes tumor-induced immunosuppression in a human in vitro cell model

Cited by 34 publications

References 28 publications

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients

Adjuvant Therapy Using Mistletoe Containing Drugs Boosts the T‐Cell‐Mediated Killing of Glioma Cells and Prolongs the Survival of Glioma Bearing Mice

Immunotherapy in ovarian cancer: fake news or the real deal?

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