Anti-Tumour TreatmentThe abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant
Introduction
Radiotherapy (RT) is highly effective anticancer treatment leading to local tumor control and potential cure for early stage cancer. Targeted ionizing irradiation has long been known to cause direct localized cell death. However, irradiation is also increasingly recognized to be able to induce tumor regression at non-irradiated, distant tumor sites. This phenomenon is called the “abscopal effect”, a term first introduced by Mole in 1953 and later on broadened by Andrews to include distant normal tissue effects [1], [2]. The existence of this type of effect is mainly described in sporadic case reports. Because documented abscopal regressions are rare, its clinical relevance is uncertain with current routinely used radiotherapy regimens. Nevertheless, recent insights regarding the immunogenic effects of RT and the biological mechanisms of the abscopal effect have provided renewed interest in the ability of radiotherapy to induce distant tumor regression leading to meaningful clinical benefit. The immune system has been proposed as the key component of abscopal effects after radiotherapy [3]. Local radiotherapy is known to induce an immunostimulatory form of cell death, called immunogenic cell death (ICD), leading to host immune responses [4], [5], [6], [7]. The concept of ICD relies mainly on the release of damage associated molecular patterns (DAMPs) which trigger an antigen engulfment of dendritic cells (DC). This subsequently results in an improved antigen presentation to the cytotoxic immune system [8], [9] (see Fig. 1). Irradiation is also known to alter the immune phenotype of the tumor by augmenting the presence of MHC I on the tumor cell surface, improving expression of cancer-testis antigens and upregulating the FAS/CD95 complex [10], [11], [12], [13]. Furthermore, RT is recognized to create a cytokine pattern that facilitates migration and function of effector CD8+ T cells [14], [15]. Therefore improved antigen expression and presentation as well as enhanced functioning of effector T cells provide a sound potential rationale for an immune mediated abscopal effect.
Here we overview the current state of knowledge of preclinical data and clinical experience regarding the abscopal effect. The aim of this review is to provide a systematic overview of the abscopal effect and identify links with the immunogenic properties of radiotherapy. Finally, we critically assess future therapeutic possibilities of radiotherapy in combination with the large number of emerging immunomodulatory agents [16].
Section snippets
Search strategy and selection criteria
References for this review were identified through searches of Medline and Embase with the broad search terms “abscopal”, “(non-targeted irradiation) OR (non-targeted radiotherapy)” and “distant bystander” from 1960 until July, 2014. Titles and abstracts were screened by the main author and papers that were selected were verified by the other authors. English, Dutch and French clinical papers were included if they met the following criteria: patients had to receive single or multiple fractions
Results
Using the described methodology, we identified 378 Medline and 555 Embase references in total (Fig. 2). Thirteen preclinical papers were retrieved that directly identified abscopal effects in vivo, which are summarized in Table 1. Eleven of these studies used radiotherapy in conjunction with an immune treatment to achieve an abscopal effect. Out of the 5 different mouse models, BALB/C and C57BL/6 were by far the most used (6 times each). Dose varied extensively, ranging from one fraction of 2 Gy
The effector T cell response is crucial for abscopal effects
Preclinical studies investigating the abscopal effect are relatively immature. As one of the first to demonstrate an abscopal effect in vivo, Chakravarty et al. set up a metastatic Lewis lung carcinoma (LLC) model in the feet of mice and irradiated only one tumor localization with a single dose of 60 Gy. Subsequently, this group administered Fms-like tyrosine kinase receptor 3 ligand (Flt3-L), a growth factor for dendritic cells (DC) [19]. Combination treatment improved disease-free survival at
Conclusion
In this review we conclude that an irradiation induced abscopal effect is based on antitumor immunity. Abscopal effects were observed at all ages, across a variety of tumor types and with substantial differences in radiotherapy regimens and techniques. However, they do seem to occur more in known immunogenic tumor types. At the same time, the rarity of documented reports and the preclinical research suggest that abscopal effects induced by RT alone are unlikely to have major clinical impact on
Author’s contribution
All authors approve the final article.
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Kobe Reynders: conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article.
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Tim Illidge: interpretation of data, revising the article critically for important intellectual content.
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Shankar Siva: interpretation of data, revising the article critically for important intellectual content.
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Joe Y. Chang: interpretation of data, revising the article critically for important intellectual content.
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Dirk De
Conflict of interest
None.
Acknowledgments/funding
This research was funded by the Flemish League against Cancer (Vlaamse Liga tegen Kanker, VLK) and a Grant for Diverse Research Actions (Diverse Onderzoeksacties, DOA) of the Special Research Fund from KU Leuven.
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