Abstract 1105: Carbon ion radiotherapy eradicates glioblastoma via tumor immune environment reprograming

Background and purpose: Glioblastoma multiforme (GBM) is a stroma rich immune cold tumor with still dismal prognosis of despite multimodal therapy consisting of postoperative surgery and radiochemotherapy. Consequently, all randomized Phase III clinical GBM trials attempting to integrate immune checkpoint blockade (ICB) have failed to demonstrate efficacy. We have recently shown that tumor immune microenvironment (TIME) reprograming via Bintrafusp alpha (Anti-PD-L1/TGF-beta bispecific molecule) combined with conventional photon radiotherapy elicits beneficial effects and prolong survival in experimental models (Lan, Knoll, Moustafa et al. Cancer Cell 2021). Moreover, eradication of radioresistant i.e., stem cell like, invasive and hypoxic tumor subpopulations by high linear energy transfer (LET) carbon ion radiotherapy (CIRT) was shown to generate an immune permissive niche in experimental GBM models (Chiblak et al. JCI Insight 2019, Tang et al. IJRBP 2022). Therefore, we aimed to systematically study the effect of CIRT vs. conventional photon radiotherapy (RT) in two (GL261 and SB28) orhotopic syngeneic mouse GBM models. Methods: Tumor growth monitoring was conducted longitudinally by means of bioluminescence and small animal MR-imaging. Mice were irradiated in five fractions (Fx) with a total dose of 15Gy RT vs. 5, 10 and 15Gy CIRT. Results: Intriguingly, all GL261 harbouring mice were cured after 5 × 3Gy Fx CIRT with no sign of tumor recurrence up to 80 days post irradiation. In contrast, no tumor control was found after 5 × 3Gy Fx RT led despite a significant prolongation of OS. The tumor control probability 50% (TCP50) for CIRT in GL261 was estimated to be 10Gy in 5 Fx. To asses if the curative effect was related to tumor eradication or reconstitution of immune surveillance. GL261 tumor cells were implanted in the contralateral hemisphere of cured mice. Single cell and Bulk RNAseq as well as immunostaining were conducted to deconvolute TIME effects post CIRT. Conclusions: In line with mechanistic studies, lack of tumor growth indicating persistent immunity against GL261 was found in CIRT cured mice. Similar experiments are conducted in SB28 model and will be presented. Together, these encouraging data indicate potential benefits for high-LET CIRT in immune modulation of GBM in experimental models that warrants for study and optimization towards clinical translation. Citation Format: Federica Ciamarone, Sarah Meister, Jennifer Furkel, Maximilian Knoll, Christian Schwager, Jovana Bojcevski, Yannik Streibel, Christel Herold-Mende, Michael Breckwoldt, Juergen Debus, Ivana Dokic, Amir Abdollahi, Katharina Schregel. Carbon ion radiotherapy eradicates glioblastoma via tumor immune environment reprograming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1105.