S2524
Radiobiology – Immuno-radiobiology
ESTRO 2026
optimizing ICB dosing schedules that maintain efficacy while reducing treatment burden and toxicity. Material/Methods: Subcutaneous and orthotopic tumor models were established using MC38, CT26, and TSA cell lines. Mice were treated with anti-PD-1 or anti-PD-L1 antibodies (10 mg/kg, intraperitoneally) either once (1 dose) or four times (4 doses), in combination with a single (MC38, CT26) or triple (TSA) 8 Gy irradiation schedule using a small-animal radiation platform. To confirm whether the therapeutic effect is more dependent on receptor occupancy or cumulative effects, we conducted a series of efficacy experiments at different settings. We treated mice with different dosages (0.5- 1-2-5-10 mg/kg) at varying frequencies (1 vs. 4 doses). Tumor growth and survival were monitored to evaluate therapeutic efficacy. Mechanistic analyses were performed on samples collected on the day after the first or fourth injection, including flow cytometry, multiplex cytokine profiling to assess receptor occupancy, immune activation, and cytotoxic function. We also conducted experiments to determine the relationship between tumor burden and the toxicity induced by anti-PD-L1 in TSA models. Results: A single anti-PD-1/PD-L1 dose combined with irradiation achieved comparable anti-tumor efficacy to four doses in all three models. However, repeated anti-PD-L1 dosing caused lethal toxicity in TSA-bearing mice, especially after the 4th injection. Dose– escalation experiments revealed non-linear relationships, where intermediate doses (e.g., 5 mg/kg) provided optimal outcomes. Increasing injection frequency produced minimal additional benefit, indicating limited cumulative effects for both anti-PD-1 (0.5 mg/kg) and anti-PD-L1 (1 mg/kg) regimens. Mechanistic and toxicity-related investigations are ongoing. Conclusion: A single administration of anti-PD-1 or anti-PD-L1 antibodies provided comparable efficacy to standard multi-dose regimens across different doses, suggesting that reduced dosing frequency may sustain therapeutic benefit while lowering toxicity and treatment burden. Keywords: Immuno-radiotherapy Optimization
ATRA or 9-cis-RA, upregulated CD98hc and LAT1 via direct RAR α interaction. When radioresistant tumor spheroids and PDTOs were targeted, CD98hc TM increased UniCAR infiltration and tumor spheroid elimination. The combination of fractionated RT showed a synergistic anti-tumor effect (2, 3). In vivo, administration of UniCAR cells near the tumor site, combined with intraperitoneal CD98hc TM, significantly improved tumor infiltration. When combined with fractionated radiochemotherapy (5 × 2Gy), UniCARs significantly delayed tumor growth and improved tumor-free survival. Conclusion: Our study suggests that the CD98hc–AAT axis sustains CSC-driven radioresistance and serves as a predictive biomarker and promising target for combination therapies (Figure 1A). A biomarker-guided combination of transporter-directed UniCAR immunotherapy with radiochemotherapy is a promising multimodal strategy for patients with HPV- negative HNSCC (Figure 1B).
References: 1. Digomann et al., Clin Cancer Res 2019.2. Köseer et al., Cancers 2022.3. Köseer et al., Cancers 2023. Keywords: immunotherapy, HNSCC, cancer stem cells
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Optimization of immune checkpoint inhibitor (anti-PD-1/PD-L1) dosing regimens in combination with radiotherapy Liu SHI 1 , Marine GERBE-DE-THORE 1 , Lisa SITTERLE 1 , Michele MONDINI 1 , Eric DEUTSCH 1,2 , Lydia MEZIANI 1 1 INSERM U1030, Gustave Roussy, Villejuif, France. 2 Department of Radiotherapy, Gustave Roussy, Villejuif, France Purpose/Objective: This study aims to determine whether reduced immune checkpoint blockade (ICB) dosing regimens can achieve comparable anti-tumor efficacy to standard repeated dosing when combined with radiotherapy. Specifically, we compared 1-dose versus 4-dose anti-PD-1/PD-L1 treatments at various concentrations in preclinical tumor models to assess how dosing frequency and dosage influence therapeutic outcomes, T cell activation, and the immune landscape. By defining the immunological mechanisms underlying dose-dependent responses, this work seeks to provide a scientific rationale for
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Developing a preclinical mouse model to study image-guided stereotactic ablative radiotherapy and systemic treatment Stephanie May 1,2 , Katrina H Stevenson 2,3 , Bashaer Alqarafi 1 , Kyi Lai Yin Swe 1 , Agata Mrowinska 1 , Gaurav Malviya 1 , Alge Bloom 1,3 , Miryam Mueller 1 , Anastasia Georgakopoulou 1,2 , Christos Kiourtis 1,2 , Thomas
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