Die Rolle der Strahlentherapie bei der Induktion von Antitumor-Immunantworten

Multhoff, Gabriele; Gaipl, Udo S.; Niedermann, Gabriele

doi:10.1007/s00066-012-0206-0

Cited by 11 publications

(7 citation statements)

References 21 publications

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“…They found out, amongst others, that there are significant differences in the gene response depending on the fractionation of radiation: 10 Gy delivered in fractions lead to a more stable induction of genes ( 34 ). Multhoff et al hypothesized that conventional fraction schemes over several weeks are thought to be rather negative for radiation-induced anti-tumor immune responses as tumor-infiltrating immune lymphocytes might be killed by the repeating irradiation ( 35 ). Dewan et al investigated the effects of RT with immune modulatory anti-CTLA4-antibodies on induction of anti-tumor immune responses.…”

Section: Impact Of the Fractionation Of Radiation On Anti-tumor Respomentioning

confidence: 99%

Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses – Pre-Clinical Evidence and Ongoing Clinical Applications

et al. 2015

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Radiotherapy (RT) primarily aims to locally destroy the tumor via the induction of DNA damage in the tumor cells. However, the so-called abscopal, namely systemic and immune–mediated, effects of RT move over more and more in the focus of scientists and clinicians since combinations of local irradiation with immune therapy have been demonstrated to induce anti-tumor immunity. We here summarize changes of the phenotype and microenvironment of tumor cells after exposure to irradiation, chemotherapeutic agents, and immune modulating agents rendering the tumor more immunogenic. The impact of therapy-modified tumor cells and damage-associated molecular patterns on local and systemic control of the primary tumor, recurrent tumors, and metastases will be outlined. Finally, clinical studies affirming the bench-side findings of interactions and synergies of radiation therapy and immunotherapy will be discussed. Focus is set on combination of radio(chemo)therapy (RCT) with immune checkpoint inhibitors, growth factor inhibitors, and chimeric antigen receptor T-cell therapy. Well-deliberated combination of RCT with selected immune therapies and growth factor inhibitors bear the great potential to further improve anti-cancer therapies.

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Section: Impact Of the Fractionation Of Radiation On Anti-tumor Respomentioning

confidence: 99%

Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses – Pre-Clinical Evidence and Ongoing Clinical Applications

et al. 2015

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“…We have previously revealed that mEHT at <42°C can dominantly induce a caspase-independent programmed cell death in HT29 colorectal cancer xenografts as a result of cell stress synergistically induced by the electric field and heat (Andocs et al 2009a;Meggyeshazi et al 2014). Other groups have demonstrated that mild whole-body hyperthermia of tumors between~38 and 42°C can generate immunogenic host response (Frey et al 2012;Mace et al 2012) and local hyperthermia can cause heat shock protein (Hsp) 70 increment along with high-mobility group box 1 (HMGB1) protein release due to stress and necrosis (Frey et al 2012;Multhoff et al 2012;Schildkopf et al 2010). These signs were suggestive of programmed cell death-related damage signals which may lead to immunogenic tumor cell death (ICD) (Garg et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia

Andócs

Meggyesházi

Balogh

et al. 2015

Cell Stress and Chaperones

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In modulated electrohyperthermia (mEHT) the enrichment of electric field and the concomitant heat can selectively induce cell death in malignant tumors as a result of elevated glycolysis, lactate production (Warburg effect), and reduced electric impedance in cancer compared to normal tissues. Earlier, we showed in HT29 colorectal cancer xenografts that the mEHTprovoked programmed cell death was dominantly caspase independent and driven by apoptosis inducing factor activation. Using this model here, we studied the mEHT-related cell stress 0-, 1-, 4-, 8-, 14-, 24-, 48-, 72-, 120-, 168-and 216-h post-treatment by focusing on damage-associated molecular pattern (DAMP) signals.

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“…Pre-clinical mouse models often suggest a more beneficial outcome if higher doses are used in hypofractionated schemes ( 84 , 85 ). Multhoff et al, thus, support the assumption that long-lasting, daily repeating RT leads to lymphocyte death ( 53 ) and longer breaks during the radiation are needed to give the immune system time to act and re-act ( 86 ). Dewan et al report that fractionated, but not single doses induce immune-mediated abscopal effects in combination with a CTLA-4 antibody ( 84 ).…”

Section: Radiation and Immunogenic Tumor Cell Deathmentioning

confidence: 95%

“…Currently, the influences of present RT concepts on the immune system are still only fragmentarily understood and it would be beneficial to gain a better insight about the effects of week-long RT on a molecular, cellular, and tissue level ( 4 ) as well as its effects on immune cells ( 53 ). While classical radiobiology has created a general understanding about survival curves based on varying radiation doses and treatment volumes, and extensive research concerning DNA damage and repair capacities following RT has been carried out, there is still a lack of data in pre-clinical and clinical studies with regard to radiation and its effects on the immune system ( 51 , 57 , 58 ).…”

Section: Influence Of Distinct Rt Concepts On Immune Activationmentioning

confidence: 99%

“…Necrotic cells also release the so-called danger signals, such as Hsp70 or HMGB1. These bind to receptors, e.g., to toll-like receptors (TLRs) on APCs such as DCs, induce their maturation and promote cross-presentation of tumor antigens ( 53 , 74 ). Another inflammatory molecule associated with immunogenic cancer cell death is adenosine triphosphate (ATP).…”

Section: Radiation and Immunogenic Tumor Cell Deathmentioning

confidence: 99%

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Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation

et al. 2016

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Even though there is extensive research carried out in radiation oncology, most of the clinical studies focus on the effects of radiation on the local tumor tissue and deal with normal tissue side effects. The influence of dose fractionation and timing particularly with regard to immune activation is not satisfactorily investigated so far. This review, therefore, summarizes current knowledge on concepts of modern radiotherapy (RT) and evaluates the potential of RT for immune activation. Focus is set on radiation-induced forms of tumor cell death and consecutively the immunogenicity of the tumor cells. The so-called non-targeted, abscopal effects can contribute to anti-tumor responses in a specific and systemic manner and possess the ability to target relapsing tumor cells as well as metastases. The impact of distinct RT concepts on immune activation is outlined and pre-clinical evidence and clinical observations on RT-induced immunity will be discussed. Knowledge on the radiosensitivity of immune cells as well as clinical evidence for enhanced immunity after RT will be considered. While stereotactic ablative body radiotherapy seem to have a beneficial outcome over classical RT fractionation in pre-clinical animal models, in vitro model systems suggest an advantage for classical fractionated RT for immune activation. Furthermore, the optimal approach may differ based on the tumor site and/or genetic signature. These facts highlight that clinical trials are urgently needed to identify whether high-dose RT is superior to induce anti-tumor immune responses compared to classical fractionated RT and in particular how the outcome is when RT is combined with immunotherapy in selected tumor entities.

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Die Rolle der Strahlentherapie bei der Induktion von Antitumor-Immunantworten

Cited by 11 publications

References 21 publications

Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses – Pre-Clinical Evidence and Ongoing Clinical Applications

Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses – Pre-Clinical Evidence and Ongoing Clinical Applications

Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia

Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation

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