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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.

Background In Germany, approximately 30-50% of Oropharyngeal squamous-cell carcinoma (OPSCC) are related to human papillomaviruses (HPV), of which 90% are caused by HPV-16. The analysis of cancer-associated antigens is needed to develop antigen-specific immunotherapy and to determine the level of personalization required for therapeutic cancer vaccines. Methods Human leucocyte antigen (HLA) ligands from fresh frozen OPSCC biopsies were analyzed. HLA molecules were extracted from tumor tissue using immunoaffinity chromatography. HLA-bound peptides were subjected to high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Tumor-exclusive antigens in OPSCC were identified by comparative profiling against an in-house benign and malignant database. Additionally, whole exome sequencing of RNA and DNA isolated from the respective cancer biopsies was performed to complement the database. Results To date, HLA ligandomes from 28 OPSCC (15 HPV+; 13 HPV-) patients were analyzed. Compared to the benign samples database, 148 source proteins were tumor-exclusive for HLA class I and 200 source proteins for HLA class II. The mean number of tumor-exclusive proteins per sample was 6.0 (0-14) for HLA class I and 7.7 for HLA class II (0-41) respectively. Among the tumor exclusive proteins for HLA class I, 23 had not been detected in other malignant tumor ligandomes (n = 703 samples) and 75 for HLA class II (n = 433 samples). A principal component analysis of the HLA-ligandomes from HPV+ and HPV- revealed significant differences between the two groups. For HLA-class I, 85 tumor-exclusive proteins were only found in HPV+ and 55 in HPV-, whereas 8 proteins were found in both groups. Among the 200 HLA class II tumor-exclusive proteins, 96 were only found in HPV+ and 95 in HPV- respectively, whereas 9 were shared by HPV+ and HPV-. Conclusions The analysis of HLA-ligandomes from OPSCC revealed tumor-exclusive and newly discovered antigens. We found clear differences between the HLA ligandomes of HPV+ and HPV- patients. These differences need to be taken into account for therapeutic vaccination strategies. The level of personalization needed for such vaccines remains to be determined. Legal entity responsible for the study The authors. Funding University of Ulm, Clinician Scientist Programme. Disclosure S. Laban: Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme (MSD); Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (institution): Merck Serono. P.J. Schuler: Advisory / Consultancy: Bristol-Myers Squibb. T.K. Hoffmann: Honoraria (institution), Advisory / Consultancy: Merck Sharp & Dohme (MSD); Honoraria (institution): Bristol-Myers Squibb; Honoraria (institution): Merck Serono. H. Rammensee: Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Immatics; Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: CureVac; Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Synimmune. All other authors have declared no conflicts of interest.