A first evaluation of the efficacy of minibeam radiation therapy combined with an immune check point inhibitor in a model of glioma-bearing rats

Abstract

Glioblastoma multiforme (GBM) continues to be a hopeless case today. Its treatment involves the use of multiple modalities. One of them is radiation therapy (RT), that is limited by normal tissue tolerances in GBM patients. GBM is widely recognized to induce local and systemic immunosuppression, which is a hindrance to the use of immune-modulating therapies. One possible strategy is to ally immunotherapy (IT) with novel RT approaches able to revert the immunosuppressive nature of GBM. One example is minibeam radiation therapy (MBRT). Preclinical experiments have shown that MBRT leads to a remarkable widening of the therapeutic window for GBM and elicits an effective immune priming. The main hypothesis of this study is that the activation of the immune system by MBRT would synergize with IT enhancing tumour control and minimizing toxicities. To validate it, in vivo experiments in a glioma rat model were performed. The goal was to assess the gain in survival of animals treated with MBRT, MBRT plus an immune check point inhibitor (ICI) versus conventional RT (CRT) or ICI alone. All treatments (ICI alone, CRT, CRT + ICI, MBRT and MBRT + ICI) increased survival with respect to the non-irradiated controls. However, the high radiation dose (30 Gy) delivered in one fraction in CRT is highly detrimental for normal tissues contrary to MBRT. The combination of CRT plus ICI appeared to be toxic. MBRT + ICI surpassed the survival rate with respect to ICI alone. When ICI was used with high-dose conventional irradiation, tumor eradication was observed in 6 out 8 animals. However, the survival was statistically equivalent to MBRT plus ICI, with a tendency to reduce survival in comparison with CRT alone, suggesting acute toxicity associated with this multimodal treatment.

In conclusion, our results suggest some advantages for MBRT in combination with ICI. We need to conduct further work to determine the optimal RT-IT combination and schedule for ICI injection and MBRT irradiation.