Immune Biomarker Study for Salivary Gland Carcinoma

Overview

Salivary gland carcinomas (SGC) are rare tumors. The term SGC is not more than an umbrella for a variety of histogenetically, morphologically, and biologically distinct entities. Accordingly, SGCs have not been sufficiently investigated to date. Their rarity makes it challenging to recruit a high number of patients for individual entities in clinical studies, leading to the pooling of patients with different histological subtypes to achieve sufficient participants. The different histological subtypes of SGC exhibit significant differences in their clinicopathological features, including grading, occurrence, and outcome. SGCs usually are stratified into low-, intermediate-, or high-grade tumors. In most kinds of SGC, specific targetable molecular markers are lacking. The inclusion of immunotherapy (IT), however, might improve the outcome of patients suffering from high-grade SGCs. To integrate IT as a therapeutic option for SGC and to facilitate informed therapeutic decisions based on tumor (immune) biology, predictive and prognostic immunological biomarkers are indispensable. In this prospective study, 500 patients will be enrolled, distributed across three arms. The observational cohort includes patients with malignant salivary gland tumors, whereas patients with benign tumors of a salivary gland are grouped in the control group 1. In the control cohort, two patients do not have a salivary gland tumor but have a planned functional surgery of the nose or ear or a maxillofacial surgery. The local immune status of the tumor tissue and the microbiome will be sampled before treatment. In addition, the systemic immune status from peripheral blood will be analyzed before and after surgery and after the adjuvant and definitive chemoradiotherapy (CRT), if applicable. Clinical baseline characteristics and outcome parameters will additionally be collected. Data mining and modeling approaches will be applied to identify interactions between local and systemic immune parameters and to define predictive and prognostic immune signatures based on the evaluated immune markers.

Interventions

• Other Sampling
  Evaluation of immune characteristics by using patient's stool, saliva, blood, and tumour (not in control group 2) samples.

Primary outcome measures

• Progression-free survival (PFS) [Time frame: 2 years]

Secondary outcome measures (7)

• Locoregional recurrence rate (LRR) [Time frame: From baseline to the end of study period, up to 5 years]
• Occurrence of distant metastases [Time frame: From baseline to the end of study period, up to 5 years]
• Longitudinal immunophenotyping of the patients: Detection of about 30 distinct immune cell (sub)types together with their activation markers during study period [Time frame: Change of the immunophenotyping from baseline to the end of study period, up to 5 years]
• Immune status of the resected tumor [Time frame: 1 year]
• Transcriptional changes in immune cell gene expression [Time frame: Change of the immunophenotyping from baseline to the end of study period, up to 5 years]
• Analysis of patient's microbiomic state by examination of saliva, tumor and stool [Time frame: The analyses are conducted from baseline to the end of study period, up to 5 years]
• Analysis of cytokines and metabolites in peripheral blood and their change at certain points in the course of treatment [Time frame: Change of the cytokine expression from baseline to the end of study period, up to 5 years]

Eligibility criteria

Inclusion criteria

• Observational group

• Initial diagnosis of a primary salivary gland carcinoma in the head and neck region (no squamous cell carcinomas)
• Specimen collection from the center of the tumor when the primary tumor is sufficiently large without that the pathological assessment is impaired
• Control group 1

• Initial diagnosis of a benign salivary gland tumor in the head and neck region
• Specimen collection from the center of the tumor when the primary tumor is sufficiently large without that the pathological assessment is impaired
• Control group 2

• functional diseases of the nose or ear (patients with the indication for functional ear surgery and rhinoplasty)
• Specimen collection with sufficiently large resectate during a functional nose surgery

for all groups:

• Willingness of patients to collect blood, saliva and stool and consent to the preservation of all samples for study purposes.
• Age ≥ 18 years
• sufficient cognitive ability of the patients to understand the purpose of the study and to understand the purpose of the study and agree to it

Exclusion criteria

• Distant metastasis at the time of diagnosis and simultaneous second cancers, i.e. at study inclusion
• Malignancy in the last 5 years regardless of location (except basal cell carcinoma or cis of the uterine cervix)
• Carcinomas for which specimen collection is not possible or likely without compromising the compromise the pathological evaluation
• Persistent drug or medication abuse
• Patients who are unable or unwilling to comply with protocol and to be treated
• Patients who are represented by a legal guardian
• Patients who are not suitable for participation in the study due to a language barrier

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Germany · 2 centers

• Universitätsklinikum Erlangen, HNO — Erlangen
• Universitätsklinikum Erlangen, Strahlenklinik — Erlangen

Publications

• Donaubauer AJ, Ruhle PF, Becker I, Fietkau R, Gaipl US, Frey B. One-Tube Multicolor Flow Cytometry Assay (OTMA) for Comprehensive Immunophenotyping of Peripheral Blood. Methods Mol Biol. 2019;1904:189-212. doi: 10.1007/978-1-4939-8958-4_8. PMID 30539471
• Donaubauer AJ, Becker I, Ruhle PF, Fietkau R, Gaipl US, Frey B. Analysis of the immune status from peripheral whole blood with a single-tube multicolor flow cytometry assay. Methods Enzymol. 2020;632:389-415. doi: 10.1016/bs.mie.2019.03.003. Epub 2019 Apr 4. PMID 32000906
• 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-2020-001 PMID 33593828
• Hiss S, Eckstein M, Segschneider P, Mantsopoulos K, Iro H, Hartmann A, Agaimy A, Haller F, Mueller SK. Tumour-Infiltrating Lymphocytes (TILs) and PD-L1 Expression Correlate with Lymph Node Metastasis, High-Grade Transformation and Shorter Metastasis-Free Survival in Patients with Acinic Cell Carcinoma (AciCC) of the Salivary Glands. Cancers (Basel). 2021 Feb 25;13(5):965. doi: 10.3390/cancers13050 PMID 33669038
• Freitag V, Lettmaier S, Semrau S, Hecht M, Mantsopoulos K, Muller SK, Traxdorf M, Iro H, Agaimy A, Fietkau R, Haderlein M. High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases. Eur Arch Otorhinolaryngol. 2022 May;279(5):2553-2563. doi: 1 PMID 34436631
• Haderlein M, Scherl C, Semrau S, Lettmaier S, Uter W, Neukam FW, Iro H, Agaimy A, Fietkau R. High-grade histology as predictor of early distant metastases and decreased disease-free survival in salivary gland cancer irrespective of tumor subtype. Head Neck. 2016 Apr;38 Suppl 1:E2041-8. doi: 10.1002/hed.24375. Epub 2016 Feb 3. PMID 26841273
• Donaubauer AJ, Frey B, Agaimy A, Lange F, Mogge L, Fietkau R, Iro H, Munoz LE, Weber M, Kesting M, Gaipl US, Haderlein M, Muller S. Definition of predictive and prognostic immune biomarkers for salivary gland cancer from the intratumoural and systemic immune status: detailed protocol of the prospective, observatory ImmoGlandula study. BMJ Open. 2026 Jan 12;16(1):e100021. doi: 10.1136/bmjopen-2025- PMID 41526019

Identifiers

NCT: NCT06047236 · ImmoGlandula

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗