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FLASH radiation therapy (FLASH-RT) is a promising radiation technique that uses ultrahigh doses of radiation to increase the therapeutic window of the treatment. FLASH-RT has been observed to provide normal tissue sparing at high dose rates and similar tumor control compared with conventional RT, yet the biological processes governing these radiobiological effects are still unknown. In this study, we sought to investigate the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model. We cranially irradiated rats with a single high dose (25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s). We first assessed the protective FLASH effect that resulted in our setup through behavioral studies in naïve rats. This was followed by a comprehensive analysis of immune cells in blood, healthy tissue of the brain, and tumor microenvironment by flow cytometry. Proton FLASH-RT spared memory impairment produced by conventional high-dose proton therapy and induced a similar tumor infiltrating lymphocyte recruitment. Additionally, a general neuroinflammation that was similar in both dose rates was observed. Overall, this study demonstrated that FLASH proton therapy offers a neuro-protective effect even at high doses while mounting an effective lymphoid immune response in the tumor. [ABSTRACT FROM AUTHOR]

Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT. Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation. The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation. Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy. [ABSTRACT FROM AUTHOR]

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference. [ABSTRACT FROM AUTHOR]

• Advantages and current limitations of FLASH and spatially fractionated radiotherapy (SFRT). • Similarities and differences between FLASH and SFRT. • Devices for simultaneous application of FLASH and SFRT: current status and perspectives. FLASH radiotherapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are two new therapeutical strategies that use non-standard dose delivery methods to reduce normal tissue toxicity and increase the therapeutic index. Although likely based on different mechanisms, both FLASH-RT and SFRT have shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. With the therapeutic potential having been established separately for each technique, the combination of FLASH-RT and SFRT could therefore represent a winning alliance. In this review, we discuss the state of the art, advantages and current limitations, potential synergies, and where a combination of these two techniques could be implemented today or in the near future. [ABSTRACT FROM AUTHOR]