Immune Biomarker Study for Head and Neck Cancer (ImmunBio-KHT)

The aim of this prospective non-interventional multi-center trial is to study the prognostic value of intratumoral and systemic immune biomarkers in newly diagnosed non-metastatic head and neck cancer. Furthermore, the local immunological processes in the tumor will be correlated with the systemic immune status determined in the peripheral blood to identify prognostic immune signatures. In addition, tumor organoids will be generated ex vivo for functional biological analyses. The main objective is to create a prognostic score determined by clusters based on tumor immunologic criteria.

Study Overview

• Status: Recruiting
• Conditions: Head and Neck Cancer; Laryngeal Cancer; Hypopharyngeal Cancer; Oropharyngeal Cancer; Oral Cavity Cancer
• Intervention / Treatment: Other: Sampling

Detailed Description

Except for human papillomavirus(HPV)-associated oropharyngeal cancer, immunological biomarkers do not influence treatment algorithms in locally advanced head and neck cancer. In the meantime, a prognostic significance of tumor infiltrating lymphocytes has been recognized. However, these biomarkers do not influence clinical decisions. This may be due to previous focus on the entire group of heterogeneous squamous cell carcinomas in the head and neck region, while the tumor localization has been neglected. In addition, the isolated observation of singular immune cell populations may not be sufficient with regard to the complex interactions of the tumor with the local and systemic immune system, e.g. the presence of regulatory T cells (FoxP3+) in immunologically highly active tumors ("inflamed" or "hot") improves the prognosis, whereas the prognosis is worsened in immunologically less active tumors ("immune desert").The immune checkpoint molecule programmed death-ligand 1 (PD-L1) is currently used as a single predictive marker for immunotherapy with PD(L)-1 inhibitors. Certainly, combined prospective analyses of immune cells and immune checkpoint molecules in large patient cohorts are scarce so far. Of note, the prognostic relevance of immune cells and immunologically active substances in the peripheral blood serving as makers for immunotherapies has already been described. Yet prognostic and predictive markers in the peripheral blood have rarely been studied or linked to the local tumor immune status. However, analyses of single biomarkers of local and systemic immune responses and different immune cell populations can be expected to gain prognostic precision through cluster formation and allow grouping of head and neck tumors according to immunobiological criteria rather than anatomic localization. Therefore, the investigators expect to be able to identify an immunobiological biomarker signature for head and neck tumors that will contribute to the development of future individualized treatment approaches leading to precision head and neck oncology.

• Study Type: Observational
• Enrollment (Anticipated): 1100

Contacts and Locations

• Study Contact: Name: Antoniu-Oreste Gostian, PD Dr. med.; Phone Number: +49 9131 85-33156; Email: antoniu-oreste.gostian@uk-erlangen.de

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • ENT - Head and Neck Surgery Department
      • Contact: Antoniu-Oreste Gostian, PD Dr. med.; Phone Number: +49 9131 85-33156; Email: antoniu-oreste.gostian@uk-erlangen.de
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • Maxillo-Facial-Surgery Department
      • Contact: Manuel Weber, PD Dr. med.
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • Radiation Oncology Department
      • Contact: Markus Hecht, PD Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients presenting for treatment at the participating study centers and meeting the inclusion criteria

Description

Inclusion Criteria:

• Initial diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, paranasal sinuses or larynx in stage UICC II-IVB (study group)
• Diseases other than malignant diseases (patients with the indication for surgery of the ear, nose nose or maxillofacial surgery) (control group)
• Absence of a currently existing or previous malignant disease regardless of the anatomical localization (control group)
• Agreement of the patients for sampling blood, saliva and stool as well as consent to the preservation of all samples for further study purposes
• Age ≥ 18 years
• Cognitive ability of the patients to understand the meaning and purpose of the study and agree to it

Exclusion Criteria:

• Distant metastases and / or simultaneous secondary carcinoma at the time of diagnosis (= inclusion date)
• Carcinomas in which it is (likely) impossible to take a sample without interfering with the further pathological assessment
• Present drug abuse
• Patients who are unable or unwilling to behave and receive treatment according to protocol
• Patients who are legally patronized
• Patients who are not eligible for participation in the study due to language barrier

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Study Cohort; The study cohort consist of patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, paranasal sinuses or larynx in stage UICC (Union internationale contre le cancer) II-IVB	Other: Sampling; This is an observational study. Consequently, study participation does not alter the therapy of the treated disease. Blood will be drawn from patients at several time points during and after radiotherapy (RT) and therapy with immune checkpoint inhibitor (ICI) for detailed immunomonitoring of the patients. In addition, faeces and sputum of the patients for microbiomic and metabolomic measures will be collected. Whenever possible, adequate tissue samples are taken from the center of the tumor and a biopsy is taken from the edge of the tumor including the adjacent mucosa in the nearby area without affecting the pathological assessment (study group). Blood, faeces and sputum will be taken from patients of the control group prior to surgery. After surgery, only blood will be taken.
Control Group; The control group consists of patients with no current diagnoses of cancer undergoing surgery at the participating medical center	Other: Sampling; This is an observational study. Consequently, study participation does not alter the therapy of the treated disease. Blood will be drawn from patients at several time points during and after radiotherapy (RT) and therapy with immune checkpoint inhibitor (ICI) for detailed immunomonitoring of the patients. In addition, faeces and sputum of the patients for microbiomic and metabolomic measures will be collected. Whenever possible, adequate tissue samples are taken from the center of the tumor and a biopsy is taken from the edge of the tumor including the adjacent mucosa in the nearby area without affecting the pathological assessment (study group). Blood, faeces and sputum will be taken from patients of the control group prior to surgery. After surgery, only blood will be taken.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Observation of changes in an established immune matrix (intratumoral and systemic) of responding/non-responding patients at certain points in time in the course of treatment	Based on the intrinsic immunological biology of the tumors, different immune cells and tumor cell markers will characterize immunological groups using cluster analysis. Immune matrix of patients assessed by LIPS (liquid immune profile-based signature) (acc. Zhou et al. JITC 2021) and Tumour Associated Lymphocytes (TAL).	Change of the immune matrix from baseline (before surgery; day0) and after surgery (day 7) and at the end of radiotherapy (day 60-70) and end of study period up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longitudinal immunophenotyping of the patients: Detection of about 30 distinct immune cell (sub)types together with their activation markers during study period	The distribution of immune cells and messenger substances in the blood will be examined by means of immunophenotyping in order to add the systemic immune cell composition. Flow cytometric assessment of the amount of circulating immune cell-distribution per milliliter whole blood according to the LIPS (liquid immune profile-based signature) technique (Zhou et al. JITC 2021).	The analyses are conducted at time points before (day 0) surgery and after surgery (day 7) as well as at the end of radiotherapy (day 70-80) or end of study period up to 5 years
Analysis of cytokines in peripheral blood and their change at certain points in the course of treatment	Electrochemiluminescent MULTI-ARRAY measurement of concentration (pg/ml whole blood) cytokines/chemoattractant cytokines in the serum/plasma of the patients according to the LIPS (liquid immune profile-based signature) technique (Zhou et al. JITC 2021).	The analyses are conducted at time points before (day 0) surgery and after surgery (day 7) as well as at the end of radiotherapy (day 70-80) or end of study period up to 5 years
Determination of transcription processes in the immune cells at certain points in the course of treatment to extend the prognostic immune signature	Genetic profiling (Whole exome sequencing, RNASeq, ddPCR, realtimePCR) of transcribed genes in blood lymphocytes.	The analyses are conducted at time points before (day 0) surgery and after Surgery (day 7) as well as at the end of radiotherapy (day 70-80) or end of study period up to 5 years
Analysis of patient's metabolic state	Massspectometric untargeted metabolomic of patients serum/plasma to assess the change of metabolites (pg/ml whole blood) from baseline to end of radiotherapy.	The analyses are conducted at time points before (day 0) surgery and after Surgery (day 7) as well as at the end of radiotherapy (day 70-80) or end of study period up to 5 years
Analysis of patient's microbiomic state by examination of saliva, tumor and stool	16S rRNA deep sequencing of microbiome in salvia, tumour and stool samples to assess the presence and relative distribution of microbiotes (Operational taxonomic units [OTUs]).	The analyses are conducted at time point before surgery (day 0)

Collaborators and Investigators

• Sponsor: University of Erlangen-Nürnberg Medical School
• Collaborators: University Hospital Erlangen; University Hospital Regensburg; University Hospital Augsburg
• Investigators: Study Director: Antoniu-Oreste Gostian, PD Dr. med., ENT - Head and Neck Surgery Department, University of Erlangen-Nurnberg; Study Director: Markus Hecht, PD Dr. med., Radiation Oncology, University of Erlangen-Nurnberg; Principal Investigator: Manuel Weber, PD Dr. med. Dr. med. dent., Maxillo-facial-surgery, University of Erlangen-Nurnberg; Principal Investigator: Udo Gaipl, Prof. Dr. rer. nat. habil., Translational Radiobiology, University of Erlangen-Nurnberg; Principal Investigator: Benjamin Frey, PD Dr.-Ing. Dr. habil. med., Translational Radiobiology, University of Erlangen-Nurnberg

Publications and helpful links

General Publications

• Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1. Erratum In: Lancet. 2020 Jan 25;395(10220):272. Lancet. 2020 Feb 22;395(10224):564. Lancet. 2021 Jun 12;397(10291):2252.
• Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, Lugli A, Zlobec I, Rau TT, Berger MD, Nagtegaal ID, Vink-Borger E, Hartmann A, Geppert C, Kolwelter J, Merkel S, Grutzmann R, Van den Eynde M, Jouret-Mourin A, Kartheuser A, Leonard D, Remue C, Wang JY, Bavi P, Roehrl MHA, Ohashi PS, Nguyen LT, Han S, MacGregor HL, Hafezi-Bakhtiari S, Wouters BG, Masucci GV, Andersson EK, Zavadova E, Vocka M, Spacek J, Petruzelka L, Konopasek B, Dundr P, Skalova H, Nemejcova K, Botti G, Tatangelo F, Delrio P, Ciliberto G, Maio M, Laghi L, Grizzi F, Fredriksen T, Buttard B, Angelova M, Vasaturo A, Maby P, Church SE, Angell HK, Lafontaine L, Bruni D, El Sissy C, Haicheur N, Kirilovsky A, Berger A, Lagorce C, Meyers JP, Paustian C, Feng Z, Ballesteros-Merino C, Dijkstra J, van de Water C, van Lent-van Vliet S, Knijn N, Musina AM, Scripcariu DV, Popivanova B, Xu M, Fujita T, Hazama S, Suzuki N, Nagano H, Okuno K, Torigoe T, Sato N, Furuhata T, Takemasa I, Itoh K, Patel PS, Vora HH, Shah B, Patel JB, Rajvik KN, Pandya SJ, Shukla SN, Wang Y, Zhang G, Kawakami Y, Marincola FM, Ascierto PA, Sargent DJ, Fox BA, Galon J. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018 May 26;391(10135):2128-2139. doi: 10.1016/S0140-6736(18)30789-X. Epub 2018 May 10.
• O'Sullivan B, Huang SH, Su J, Garden AS, Sturgis EM, Dahlstrom K, Lee N, Riaz N, Pei X, Koyfman SA, Adelstein D, Burkey BB, Friborg J, Kristensen CA, Gothelf AB, Hoebers F, Kremer B, Speel EJ, Bowles DW, Raben D, Karam SD, Yu E, Xu W. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016 Apr;17(4):440-451. doi: 10.1016/S1470-2045(15)00560-4. Epub 2016 Feb 27.
• de Ruiter EJ, Ooft ML, Devriese LA, Willems SM. The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Oncoimmunology. 2017 Aug 9;6(11):e1356148. doi: 10.1080/2162402X.2017.1356148. eCollection 2017.
• Hecht M, Gostian AO, Eckstein M, Rutzner S, von der Grun J, Illmer T, Hautmann MG, Klautke G, Laban S, Brunner T, Hinke A, Becker I, Frey B, Semrau S, Geppert CI, Hartmann A, Balermpas P, Budach W, Gaipl US, Iro H, Fietkau R. Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8. J Immunother Cancer. 2020 Oct;8(2):e001378. doi: 10.1136/jitc-2020-001378.
• Wondergem NE, Nauta IH, Muijlwijk T, Leemans CR, van de Ven R. The Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: on Subsets and Subsites. Curr Oncol Rep. 2020 Jun 29;22(8):81. doi: 10.1007/s11912-020-00938-3.
• Echarti A, Hecht M, Buttner-Herold M, Haderlein M, Hartmann A, Fietkau R, Distel L. CD8+ and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer. Cancers (Basel). 2019 Sep 19;11(9):1398. doi: 10.3390/cancers11091398.
• Rudolf J, Buttner-Herold M, Erlenbach-Wunsch K, Posselt R, Jessberger J, Haderlein M, Hecht M, Hartmann A, Fietkau R, Distel L. Regulatory T cells and cytotoxic T cells close to the epithelial-stromal interface are associated with a favorable prognosis. Oncoimmunology. 2020 Apr 14;9(1):1746149. doi: 10.1080/2162402X.2020.1746149. eCollection 2020.
• Posselt R, Erlenbach-Wunsch K, Haas M, Jessberger J, Buttner-Herold M, Haderlein M, Hecht M, Hartmann A, Fietkau R, Distel LV. Spatial distribution of FoxP3+ and CD8+ tumour infiltrating T cells reflects their functional activity. Oncotarget. 2016 Sep 13;7(37):60383-60394. doi: 10.18632/oncotarget.11039.
• Wimmer S, Deloch L, Hader M, Derer A, Grottker F, Weissmann T, Hecht M, Gostian AO, Fietkau R, Frey B, Gaipl US. Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells. Int J Mol Sci. 2021 Aug 24;22(17):9114. doi: 10.3390/ijms22179114.
• Zhou JG, Donaubauer AJ, Frey B, Becker I, Rutzner S, Eckstein M, Sun R, Ma H, Schubert P, Schweizer C, Fietkau R, Deutsch E, Gaipl U, Hecht M. Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors. J Immunother Cancer. 2021 Feb;9(2):e001845. doi: 10.1136/jitc-2020-001845.
• Driehuis E, Kolders S, Spelier S, Lohmussaar K, Willems SM, Devriese LA, de Bree R, de Ruiter EJ, Korving J, Begthel H, van Es JH, Geurts V, He GW, van Jaarsveld RH, Oka R, Muraro MJ, Vivie J, Zandvliet MMJM, Hendrickx APA, Iakobachvili N, Sridevi P, Kranenburg O, van Boxtel R, Kops GJPL, Tuveson DA, Peters PJ, van Oudenaarden A, Clevers H. Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy. Cancer Discov. 2019 Jul;9(7):852-871. doi: 10.1158/2159-8290.CD-18-1522. Epub 2019 May 3. Erratum In: Cancer Discov. 2020 Mar;10(3):476.
• Tanaka N, Osman AA, Takahashi Y, Lindemann A, Patel AA, Zhao M, Takahashi H, Myers JN. Head and neck cancer organoids established by modification of the CTOS method can be used to predict in vivo drug sensitivity. Oral Oncol. 2018 Dec;87:49-57. doi: 10.1016/j.oraloncology.2018.10.018. Epub 2018 Oct 23.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2022
• Primary Completion (Anticipated): March 31, 2026
• Study Completion (Anticipated): March 31, 2027

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: May 11, 2022
• First Posted (Actual): May 16, 2022

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 16, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Immunotherapy; Immunologic markers
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Neoplasms by Site; Respiratory Tract Neoplasms; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Mouth Diseases; Laryngeal Diseases; Head and Neck Neoplasms; Mouth Neoplasms; Oropharyngeal Neoplasms; Laryngeal Neoplasms; Hypopharyngeal Neoplasms
• Other Study ID Numbers: 12-384-B

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No