S2537
Radiobiology – Immuno-radiobiology
ESTRO 2026
adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial. Lung Cancer. 2022 2 E. S. M. van Aken et al. ESMO-ESTRO consensus statements on the safety of combining radiotherapy with immune checkpoint inhibitors, VEGF(R) inhibitors, or multitargeted tyrosine kinase inhibitors. Annals of Oncology. 20253 Gassert FT et al. X-ray Dark-Field CT for early detection of radiation-induced lung injury in a murine model. Radiology. 2022 Keywords: lung injury, immune checkpoint inhibition Poster Discussion 3254 Elective Nodal irradiation in Head - and - Neck Cancer Radiotherapy induces Lymphopenia: Exploratory Results of a Prospective Randomized Trial Justus Kaufmann 1 , Sophia Drabke 1 , Ahmed Salah 1,2 , Stephanie Göller 1 , Nina Gercek 1 , Laura Oebel 1 , Heinz Schmidberger 1 , Sebastian Zahnreich 1 1 Department of Radiation Oncology, University Medical Center Mainz, Mainz, Germany. 2 Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany Purpose/Objective: Chemoradiotherapy (CRT) for head-and-neck squamous cell carcinoma (HNSCC) frequently causes hematologic alterations, including treatment-related lymphopenia, which may compromise immune competence and decrease the efficacy of combined radio-immunotherapy strategies. Given the radiosensitivity of peripheral blood lymphocytes, elective nodal irradiation (ENI) may contribute substantially to systemic hematologic adverse events. Here, we performed an exploratory analysis to assess whether ENI-sparing preserves hematologic integrity. Material/Methods: In this prospective randomized trial (DRKS00034747) twenty-one patients with HNSCC (excluding nasopharyngeal and p16-positive oropharyngeal carcinoma) scheduled for definitive or adjuvant platinum-based CRT between 04/2024 and 09/2025, were randomized using block randomization to: (i) standard CRT with ENI from the outset (n = 10) or (ii) an upfront boost to the gross tumour volume and involved nodes without ENI, followed by conventional ENI after 2 fractions (adjuvant) or after 5 fractions (definitive) (n = 11) (Figure 1). Venous blood was drawn before RT and weekly during treatment. Differential blood counts were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE).
combination results in enhanced immune activation, thereby driving additively or synergistically increased lung toxicity. 1,2 Material/Methods: We used a lung metastases model (B16-OVA melanoma) to investigate anti-tumor immune responses, survival, and lung toxicity in tumor-bearing mice after thorax irradiation (1x15gy) ± ICI with anti- PD-1 and anti-CTLA-4 (four weeks). In non-tumor bearing mice, the right thorax of C57BL/6 and BALB/c mice received either an unfractionated (1x15 Gy or 1x30 Gy) or a fractionated (5x9 Gy) course of RT ± anti- PD-1, anti-CTLA-4, or their combination. In selected experiments, CD8 T cells were depleted during radioimmunotherapy using anti-CD8. Peripheral blood immune cells were analyzed monthly by flow cytometry. Four months after RT, lungs were examined by histopathological staining and computed tomography (CT), including dark-field analyses ³ . Additionally, we performed bulk lung tissue RNA-seq analysis and high-dimensional single-cell immune phenotyping (cytometry by time-of-flight, CyTOF) one month after RT. Results: Tumor-bearing mice exhibit improved tumor control and CD8 T cell activation following RT combined with ICI. Combination therapy resulted in improved survival compared with RT controls; however, almost all mice developed severe signs of lung toxicity around 150 days post-RT, due to fibrotic changes in the lungs. Next, we performed a series of experiments in non- tumor-bearing mice: peripheral blood analysis, RNA- Seq and CyTOF immune cell characterization revealed enhanced CD8 T cell signatures in irradiated lungs from mice receiving the combination treatment. Despite these immunological changes, we observed no increase in lung toxicity based on histopathology or CT imaging across the different RT regimens and ICI combinations. These findings were consistent across both mouse strains. Depletion of CD8+ cells resulted in a slight reduction of early fibrotic alterations in irradiated animals, regardless of ICI combination. Conclusion: Our results did not reveal significantly enhanced lung injury after RT combined with ICI across a series of RT regimens and mouse models. Several immunobiological and molecular analyses showed enhanced CD8 T cell activation and lung infiltration after combination therapy. However, this was not causally linked to increased lung toxicity. These findings provide important insights into the safety and risk profile of combined RT and ICI therapy, helping to fill the current gap in the mechanistic understanding of risk profiles associated with RT-ICI combination treatments. References: 1 Naidoo J et al. Characterizing immune-mediated
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