2059 - Hypofractionated FLASH Carbon Ion Radiotherapy Outperforms Standard Dose-Rate Treatment in Genetically Engineered Pancreatic Cancer Models: Impact of Adaptive Immune Responses
Presenter(s)
S. Eskandarian1, M. Moustafa2, M. Akbarpour2, F. Muenter3, I. Dokic2, J. Furkel2, N. Abdallah4, A. Osama4, S. Brons5, M. Knoll2, I. I. Verginadis6, S. Magdeldin4, C. Koumenis7, J. Debus8, and A. Abdollahi9; 1DKFZ/HIT/NCT/UKHD, Heidelberg, Germany, 2Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany, 3German Cancer Research Center (DKFZ), Heidelberg, Germany, 4Children Cancer Hospital Egypt 57357, Cairo, Egypt, 5Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany, 6Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 7Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 8Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany, 9Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Purpose/Objective(s): Ultra-high dose-rate (uHDR) irradiation seeks to expand the therapeutic window by harnessing the FLASH effect, potentially sparing normal tissue while demonstrating non-inferiority to standard dose-rate irradiation in terms of antitumor efficacy. Carbon ion radiation therapy (CIRT), characterized by high linear energy transfer (LET), has shown compelling activity in pancreatic ductal adenocarcinoma (PDAC). Here, we interrogate the impact of hypo-fractionated FLASH CIRT on tumor control in benchmark KPC tumors derived from an immunocompetent genetically engineered mouse model (GEMM) harboring activated KrasG12D and mutant p53R172H under pancreas-specific Pdx1-Cre expression
Materials/Methods: Two KPC-derived tumor cell lines, 2838c3 and 6419c5, were implanted subcutaneously into the right hind limb of female C57BL/6 mice. At a tumor volume of 80 ± 30 mm³, mice were randomized to three fractions of CIRT (3 × 8.5 Gy) delivered either at standard dose-rate (SDR, 4.2–4.3 Gy/s) or FLASH dose-rate (270–300 Gy/s) at the mid-region of the spread-out Bragg peak (SOBP, LETd 90 keV/µm).
Results: In the 6419c5 model, both SDR and FLASH CIRT delayed tumor growth versus controls, with FLASH inducing significantly slower growth (p = 0.002) and superior survival compared with SDR (p = 0.0008). The pronounced tumor growth delay with hypo-fractionated FLASH CIRT was independently confirmed in the 2838c3 model. Strikingly, the FLASH CIRT benefit was strongly attenuated when 2838c3 tumors were implanted in immunocompromised nude mice or upon CD8? T-cell depletion using anti-CD8 antibody, highlighting a pivotal role for adaptive immune responses in mediating FLASH efficacy. Single-cell immune profiling (CyTOF), spatial transcriptomics (Xenium), and integrative molecular analyses are underway to resolve the underlying mechanisms. In parallel, potential FLASH sparing of acute gastrointestinal (duodenal) toxicity is being assessed.
Conclusion: To our knowledge, this is the first demonstration that hypo-fractionated FLASH CIRT may confer superior antitumor efficacy in PDAC. The pivotal contribution of adaptive immunity may open powerful new avenues for immunomodulatory combination strategies.