Review
Stereotactic ablative body radiotherapy combined with immunotherapy: Present status and future perspectivesAssociation de radiothérapie stéréotaxique ablative et d’immunothérapie : présent et avenir

https://doi.org/10.1016/j.canrad.2014.06.012Get rights and content

Abstract

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy.

Résumé

La radiothérapie, conjointement avec la chirurgie et la chimiothérapie, est une thérapeutique majeure du cancer. Elle est délivrée dans la tumeur primitive en situation néo-adjuvante ou adjuvante. Les techniques de radiothérapie ont beaucoup évolué au cours de la dernière décennie en autorisant la délivrance de fortes doses et en réduisant les effets secondaires dans les tissus sains adjacents. Sans oublier le contrôle de la tumeur, des efforts doivent être faits pour contrôler la maladie macroscopique et celle à distance, qui est finalement responsable de la progression tumorale. Cette revue traite de la possibilité d’association de radiothérapie et d’immunothérapie.

Section snippets

Stereotactic ablative body radiotherapy

Stereotactic ablative body radiotherapy is a form of high-precision radiotherapy delivering extremely high ablative doses of radiation, usually in three to eight fractions, combining reproducible patient immobilization, tumour motion tracking and steep dose gradients, resulting in reduced normal tissue toxicity [1]. Stereotactic ablative body radiotherapy achieves excellent local control rates in patients with stage I/II non-small cell lung cancer and liver metastases of colorectal cancer [2].

Tumorigenesis and the immune system

The immune system closely monitors the process of tumorigenesis first by registering the presence of cells undergoing neoplastic transformation, and second by interacting with neoplastic cells to mediate their destruction. Solid tumours have developed mechanisms to escape “cancer immunosurveillance”, i.e., detection by the immune system. This is achieved by, among other mechanisms, the secretion of potent immune-suppressive cytokines and the expression of T cell inhibitory molecules, which are

Breaking the immune tolerance using checkpoint modulators

Immune-checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system. These are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues, in order to minimize collateral tissue damage. It is now clear that tumours use certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against tumour antigen specific T cells. Examples of these immune-checkpoints are

Preclinical results

Several studies have focused on the immunogenic response of tumours to different dose schedules of radiotherapy. Lee et al. observed that a single dose of ablative radiotherapy (20 Gy) generated a CD8+ T cell-dependent immunity leading to tumour reduction and eradication of metastasis [37]. In comparison, mice treated with 4 × 5 Gy initially responded to radiotherapy but tumours relapsed over time. One possible explanation is that fractionated low-dose radiotherapy may kill infiltrating CD8+ T

Conclusion

In conclusion, these data show that immunogenic cell death caused by different strategies of radiotherapy can be used in combination with immunotherapy to induce a CD8+ T cell mediated anti-tumour response, which leads to tumour control of the irradiated tumour and often to tumour control outside the radiation field, i.e., an abscopal effect in different preclinical models. However, there is not yet a uniform combination strategy for the best radiotherapy schedule/dose and immunotherapeutic

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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