Anti-Tumor Immune Response and Long-Term Immunological Memory Induced by Minibeam Radiation Therapy: A Pilot Study

Abstract

<h3>Purpose/Objective(s)</h3> Minibeam radiation therapy (MBRT) is a novel therapeutic approach that uses narrow beams (0.5 to 1 mm) to create a distinct spatial modulation of the dose, featuring alternating regions of high dose (peaks) and low dose (valleys). MBRT with both x-rays and protons was shown to provide a remarkable normal (skin and brain) tissue preservation in preclinical experiments, including sparing of cognitive, emotional, and motor processes. Equivalent or superior (glioma) tumor control compared to conventional radiation therapy was observed, and that even with highly heterogeneous dose distributions in small animal experiments. The underlying biological mechanisms under MBRT efficiency remain elusive. The aim of this work was to investigate the possible participation of the immune system in the anti-tumor response of MBRT. We also hypothesized the possible establishment of a long-term anti-tumor immunity. <h3>Materials/Methods</h3> We collected original <b>in vivo</b> radiopathological data in rats, thanks to the implementation of MBRT on a small animal radiation system. Firstly, we compared the response to MBRT of RG2-bearing nude (athymic) rats versus immunocompetent (Fischer) rats. The dose prescription was 30 Gy (average) in one fraction, with approximately one half of the tumor volume receiving (valley) doses of 6 Gy. Secondly, RG2-bearing rats having survived to the first part of the study were reinjected with the same tumor cell line and tumor development was monitored by MRI and bioluminescence imaging. <h3>Results</h3> While a significant increase of lifespan was observed in the irradiated immunocompetent rats with respect to non-irradiated controls, the irradiated nude rats showed no response to the treatment, pointing out a determinant role of T-cells in MBRT efficiency. Quantification of immune cells is ongoing. Additionally, the irradiated and cured immunocompetent RG2-bearing rats were rechallenged with RG2 tumor cells (3 to 6 months after irradiation). While naïve controls developed tumor normally, this was not the case for any of the previously irradiated animals. <h3>Conclusion</h3> These results suggest that T cells play a central role in tumor cell killing in MBRT. Moreover, MBRT seems to act as an anti-tumor vaccine. The remarkable reduction in neurotoxicity along with the potential activation of the immune system makes MBRT an ideal candidate to achieve an effective radio-immunotherapy in very infiltrative and immunosuppressive brain tumors, such as high-grade gliomas (GBM).