Fractionated Radiotherapy with 3 x 8 Gy Induces Systemic Anti-Tumour Responses and Abscopal Tumour Inhibition without Modulating the Humoral Anti-Tumour Response

Habets, Thomas H. P. M.; Oth, Tammy; Houben, A. W.; Huijskens, Mirelle J.A.J.; Senden-Gijsbers, Birgit L. M. G.; Schnijderberg, Melanie C. A.; Brans, Boudewijn; Dubois, Ludwig; Saint-Hubert, Marijke De; Germeraad, Wilfred T.V.; Tilanus, Marcel G.J.; Mottaghy, Felix M.; Bos, Gerard M.J.; Vanderlocht, Joris

doi:10.1371/journal.pone.0159515

Cited by 44 publications

(44 citation statements)

References 40 publications

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“…From these studies, it is also evident that different immunotherapeutic agents can boost abscopal responses by targeting different aspects of the immune-mediated response 9,17,27 . For example, FLT3L can be used to recruit and stimulate APCs 17,18,32 , anti-CD40 can be employed to increase activation of APCs 33 , and anti-CTLA4 or antibodies against programmed cell death protein 1 (PD1) can act as immune checkpoint inhibitors, increasing the T cell activity directed against tumour cells 23,26,34 .…”

Section: Boosting the Abscopal Effectmentioning

confidence: 99%

Using immunotherapy to boost the abscopal effect

et al. 2018

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More than 60 years ago, the effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the abscopal effect (from ‘ab scopus’, that is, away from the target). The abscopal effect has been connected to mechanisms involving the immune system. However, the effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the abscopal effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.

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Section: Boosting the Abscopal Effectmentioning

confidence: 99%

Using immunotherapy to boost the abscopal effect

et al. 2018

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“…A few studies also suggested that not exclusively T cells and their effective priming by DCs but also other factors contribute to abscopal anti‐tumor responses. For example, an involvement of NK cells and a negative regulation by intratumoral MDSCs have been proposed, whereas B cells appear to be dispensable . Furthermore, two groups reported on the tumor suppressor protein p53 as a mediator of RT‐stimulated abscopal effects.…”

Section: Critical Parameters Of Systemic Anti‐tumor Reactions and Absmentioning

confidence: 99%

“…For example, an involvement of NK cells and a negative regulation by intratumoral MDSCs have been proposed, 30,49,68,86,126 whereas B cells appear to be dispensable. 78,83 Furthermore, two groups reported on the tumor suppressor protein p53 as a mediator of RT-stimulated abscopal effects. Murine lung tumors and fibrosarcomas regressed upon excessive irradiation of distant healthy tissue in wildtype but not in p53 mutant mice.…”

Section: Mediators Of Systemic Abscopal Anti-tumor Effectsmentioning

confidence: 99%

Abscopal, immunological effects of radiotherapy: Narrowing the gap between clinical and preclinical experiences

Brix

Tiefenthaller

Anders

et al. 2017

Immunological Reviews

169

156

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SummaryRadiotherapy-despite being a local therapy that meanwhile is characterized by an impressively high degree of spatial accuracy-can stimulate systemic phenomena which occasionally lead to regression and rejection of non-irradiated, distant tumor lesions. These abscopal effects of local irradiation have been observed in sporadic clinical case reports since the beginning of the 20th century, and extensive preclinical work has contributed to identify systemic anti-tumor immune responses as the underlying driving forces. Although abscopal tumor regression still remains a rare event in the radiotherapeutic routine, increasing numbers of cases are being reported, particularly since the clinical implementation of immune checkpoint inhibiting agents. Accordingly, interests to systematically exploit the therapeutic potential of radiotherapy-stimulated systemic responses are constantly growing. The present review briefly delineates the history of radiotherapy-induced abscopal effects and the activation of systemic anti-tumor immune responses by local irradiation. We discuss preclinical and clinical reports with specific focus on the corresponding controversies, and we propose issues that should be addressed in the future in order to narrow the gap between preclinical knowledge and clinical experiences. K E Y W O R D Sabscopal effect, anti-tumor immunity, immunogenic cell death, radiotherapy | INTRODUCTIONTogether with surgery and chemotherapy, radiotherapy (RT) plays a central role in oncological treatment regimens. More than 60% of all cancer patients receive RT at one point during their medical attendance. 1 Traditionally, the efficacy of RT has been exclusively credited to its ability to induce cancer cell death and the notion that tumors are more prone to damage induced by ionizing radiation (IR) than non-malignant, normal tissues. According to the concept of the four R's of radiotherapy, repair (of IR-induced damage), reoxygenation, redistribution (to other cell cycle phases), and regeneration are the major determinants of a tissue's response toward IR.2 Importantly, tumors and non-malignant tissues are considered to differ in these characteristics, thus forming the rationale for the use of fractionated irradiation regimens with daily fractions over a period of 3-6 weeks in the clinical routine.It needs to be stressed that in the majority of all cases RT is applied in local settings with a high degree of spatial precision and the cardinal aim to achieve locoregional tumor control. However, there is accumulating evidence that-although applied locally-RT can induce systemic anti-tumor responses leading to regression and rejection of non-irradiated, distant tumor lesions. Collectively, these observations have been summarized under the term 'abscopal effects of RT', and meanwhile it is well accepted that immune mechanisms are the underlying driving forces. For distinct chemotherapeutics, the induction of such systemic, immune-mediated effects has been extensively analyzed by the groups of G. Kroemer and L. ZitvogeI....

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“…Strictly defined, the abscopal effect is the shrinkage or disappearance of metastatic deposits after treatment of the primary tumor mass. 42,43 Evidence of this effect has been demonstrated in both mouse 44 and human models, specifically in melanoma and renal cell carcinoma. 45,46 Despite documented evidence of this effect, to the best of our knowledge there have been a minimal number of clinical cases seen in practice.…”

Section: Immunomodulatory Effects Of Rt and Rationale For Its Use Witmentioning

confidence: 99%

“…Perhaps the most studied clinical correlate of the immunogenic effects of RT, the abscopal effect has been well documented in the literature. Strictly defined, the abscopal effect is the shrinkage or disappearance of metastatic deposits after treatment of the primary tumor mass . Evidence of this effect has been demonstrated in both mouse and human models, specifically in melanoma and renal cell carcinoma .…”

Section: Optimal Timing Of Chemotherapy With Rtmentioning

confidence: 99%