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Background In head and neck squamous cell cancer (HNSCC) a valid predictive parameter for the efficacy of immune-checkpoint inhibitors is still missing especially in locally advanced stages. Methods In the phase II CheckRad-CD8 trial unselected patients with HNSCC stage III-IVB receive one cycle of induction chemo-immunotherapy with cisplatin (30mg/m² d1-3)/ docetaxel (75mg/m² d1) plus durvalumab (1500mg absolute d5)/ tremelimumab(75mg absolute d5). Intra- and peritumoral CD8+ cytotoxic T-cells are assessed before and after the induction chemo-immunotherapy. Patients with CD8+ T-cell increase after induction chemo-immunotherapy enter radio-immunotherapy, patients without CD8+ T-cell increase enter radio-chemotherapy. This interim analysis including immunophenotyping of whole blood was performed after 10 patients had completed the re-evaluation after induction chemo-immunotherapy. Results 6 patients with oropharyngeal, 2 patients with hypopharyngeal and 2 patients with supraglottic laryngeal cancer were included. The mean pre-treatment intratumoral CD8 density was 1094 CD8+ cells/mm². 8 of 10 patients had a pathological complete response of their primary tumor defined by complete absence of remaining tumor cells in re-biopsies after induction treatment. The other two patients showed an average intratumoral increase from 227 CD8+ cells/mm² to 1074 CD8+ cells/mm². According to RECIST 1.1 criteria 6 patients had a partial response (PR), 3 patients a stable disease (SD), 1 patient was not evaluable. Grade III-IV toxicity included one case of hepatitis and one infectious diarrhea. Detailed immunophenotyping revealed a trend of slight reduction of CD8+ T-cells in the peripheral blood of patients with initially lower numbers of intratumoral CD8+ T-cells. The early activation marker CD69 is increased on T-cells and PD-1 on T-helper cells after induction treatment. Conclusions These preliminary results suggest a promising response to single cycle induction treatment with cisplatin/ docetaxel plus durvalumab/ tremelimumab in unselected HNSCC patients. Furthermore, they show an induction of an immune response in both in the tumor tissue and the peripheral blood. Clinical trial identification NCT03426657. Legal entity responsible for the study The authors. Funding AstraZeneca. Disclosure M. Hecht: Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD. A. Gostian: Advisory / Consultancy: test. M. Eckstein: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Janssen-Cilag/JohnsonJ Honoraria (self): Astellas; Honoraria (self): Roche. M.G. Hautmann: Honoraria (self): AstraZeneca. S. Laban: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Merck Serono. A. Hartmann: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Cepheid; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): NanoString; Advisory / Consultancy, Research grant / Funding (institution): Illumina; Advisory / Consultancy: Quiagen; Advisory / Consultancy, Research grant / Funding (institution): Biontech; Advisory / Consultancy: 3D Histotech. U. Gaipl: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MSD. R. Fietkau: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novocure; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Brainlab; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Fresenius Kabi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD. All other authors have declared no conflicts of interest.