[Immunotherapy for head and neck tumors : Updates from the 2024 ASCO Annual Meeting].

Immunotherapeutic approaches are now established in the treatment of various tumor entities, including head and neck squamous cell carcinoma (HNSCC). PD‑1 antibodies are currently approved for HNSCC with palliative intent but are increasingly being investigated in studies with curative objectives, e.g., as neoadjuvant therapy. At ASCO 2024, particular focus was placed on combinations of immunotherapy with therapeutic vaccines for human papillomavirus (HPV)-induced tumors. Moreover, the question of which patients benefit most from immunotherapy remains unresolved. The growing significance of PD-L1 expression, measured by the combined positive score (CPS), is becoming increasingly evident. This article summarizes the latest relevant findings from the largest international cancer congress, the American Society of Clinical Oncology (ASCO) 2024 Annual Meeting.

von Witzleben A ，Doescher J ，Hoffmann TK ，Laban S ... -  《-》

[Update on HPV-associated head and neck cancers-highlights of the 2024 ASCO Annual Meeting].

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is becoming increasingly important in head and neck oncology. At this year's conference of the American Society of Clinical Oncology (ASCO), a large number of papers were presented on the topic of HPV-associated HNSCC, particularly with regard to neoadjuvant treatment approaches, radiation de-escalation strategies, therapeutic vaccines, and treatment monitoring. In this context, study results on the treatment of HPV-related recurrent respiratory papillomatosis (RRP) were also presented. Based on contributions to the 2024 ASCO Annual Meeting, an insight into the latest developments in HPV-associated diseases of the head and neck is provided. The papers were reviewed for clinical relevance and contextualized based on current therapeutic concepts. A large number of studies on liquid biopsies (LB) were presented. It was shown that although the methods for analyzing LBs for HPV-positive patients are well developed and can be used for diagnostics, risk classification, treatment management, or tumor follow-up, the methods vary considerably, and their clinical application has not yet been sufficiently validated. With regard to therapeutic HPV vaccination, three large studies were presented for the treatment of recurrent/metastatic HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The only randomized study was on the vaccine ISA101b (peltopepimut-S) and did not reach its primary endpoint; however, the vaccine seemed to be highly effective in patients with a combined positive score (CPS) ≥ 20. Furthermore, data from a phase I study on PRGN2012, an adenovirus-based immunotherapy used therapeutically for the treatment of recurrent respiratory papillomatosis (RRP), were presented. PRGN2012 led to a reduction in surgical interventions for RRP, and the US Food and Drug Administration (FDA) designated PRGN2012 as a breakthrough therapy and orphan drug. However, the vaccine is not yet approved for the treatment of RRP.

Sharma SJ ，Klussmann JP ，Döscher J ，Hoffmann TK ，Laban S ... -  《-》

[Systemic therapy for head and neck cancer-highlights of the 2024 ASCO Annual Meeting].

Systemic therapy of head and neck squamous cell carcinoma (HNSCC), in contrast to local therapy, is a very general term for the use of drugs that affect the entire organism. Immunotherapy is a subtype of systemic therapy, although the boundaries are hard to define, since the immune system is likely to play an essential role in all treatments. This article focuses on systemic therapy. All abstracts and presentations on systemic therapy of HNSCC from the American Society of Clinical Oncology (ASCO) 2024 annual congress were assessed for relevance. The main contributions were reviewed and summarized. For the first time, a randomized trial demonstrated a survival advantage for systemic therapy in patients with a poor performance status over best supportive care (BSC). Clinical studies using antibody-drug conjugates (ADCs) show a promising response. In addition, the neoadjuvant approach was resumed through various study approaches. Even in patients with a reduced general condition, systemic therapy can lead to a substantial improvement in overall survival. The systemic therapy approach remains exciting for HNSCC, with new substances and areas of application not only in the palliative situation.

Blaurock M ，Brunner C ，Busch CJ 《-》

Integrating immune multi-omics and machine learning to improve prognosis, immune landscape, and sensitivity to first- and second-line treatments for head and neck squamous cell carcinoma.

In recent years, immune checkpoint inhibitors (ICIs) has emerged as a fundamental component of the standard treatment regimen for patients with head and neck squamous cell carcinoma (HNSCC). However, accurately predicting the treatment effectiveness of ICIs for patients at the same TNM stage remains a challenge. In this study, we first combined multi-omics data (mRNA, lncRNA, miRNA, DNA methylation, and somatic mutations) and 10 clustering algorithms, successfully identifying two distinct cancer subtypes (CSs) (CS1 and CS2). Subsequently, immune-regulated genes (IRGs) and machine learning algorithms were utilized to construct a consensus machine learning-driven prediction immunotherapy signature (CMPIS). Further, the prognostic model was validated and compared across multiple datasets, including clinical characteristics, external datasets, and previously published models. Ultimately, the response of different CMPIS patients to immunotherapy, targeted therapy, radiotherapy and chemotherapy was also explored. First, Two distinct molecular subtypes were successfully identified by integrating immunomics data with machine learning techniques, and it was discovered that the CS1 subtype tended to be classified as "cold tumors" or "immunosuppressive tumors", whereas the CS2 subtype was more likely to represent "hot tumors" or "immune-activated tumors". Second, 303 different algorithms were employed to construct prognostic models and the average C-index value for each model was calculated across various cohorts. Ultimately, the StepCox [forward] + Ridge algorithm, which had the highest average C-index value of 0.666, was selected and this algorithm was used to construct the CMPIS predictive model comprising 16 key genes. Third, this predictive model was compared with patients' clinical features, such as age, gender, TNM stage, and grade stage. The findings indicated that this prognostic model exhibited the best performance in terms of C-index and AUC values. Additionally, it was compared with previously published models and it was found that the C-index of CMPIS ranked in the top 5 among 94 models across the TCGA, GSE27020, GSE41613, GSE42743, GSE65858, and META datasets. Lastly, the study revealed that patients with lower CMPIS were more sensitive to immunotherapy and chemotherapy, while those with higher CMPIS were more responsive to radiation therapy and EGFR-targeted treatments. In summary, our study identified two CSs (CS1 and CS2) of HNSCC using multi-omics data and predicted patient prognosis and treatment response by constructing the CMPIS model with IRGs and 303 machine learning algorithms, which underscores the importance of immunotherapy biomarkers in providing more targeted, precise, and personalized immunotherapy plans for HNSCC patients, significantly contributing to the optimization of clinical treatment outcomes.

Yin J ，Xu L ，Wang S ，Zhang L ，Zhang Y ，Zhai Z ，Zeng P ，Grzegorzek M ，Jiang T ... -  《Scientific Reports》

Characterization of the adaptive immune response in a mouse model for HPV-positive head and neck squamous cell carcinoma with implications to human disease.

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a poor prognosis for survival. Risk factors include alcohol and tobacco abuse and infection with human papilloma virus (HPV). To enhance anti-tumor immune responses immunotherapeutic approaches are approved for recurrent metastatic disease but only approx. 20% of patients respond to checkpoint blockade of the PD-1/PD-L1 axis. Therefore, preclinical research is needed to better understand molecular and cellular processes and to identify new therapeutic targets. Immunocompetent mouse models can serve these purposes but only few are currently available for HPV-positive HNSCC. Here, we established a mouse cell line overexpressing the oncogenes E6/E7 of the HPV16 genome as well as a constitutively active form of H-Ras and studied the anti-tumor immune response upon orthotopic tumor growth at the floor of the mouth. Moreover, we analyzed the same immunoregulatory pathways in samples of HPV-positive cancer patients. T cells in the tumor of mice and humans exhibited high expression of CD39 and CD73, two ectoenzymes involved in the production of immunosuppressive adenosine from ATP, along with increased expression of PD-1, LAG-3 and GITR. Additionally, B cell responses were elevated in tumor-bearing mice, seen as an increase of germinal center, immunoregulatory marginal zone and follicular B cell subtypes. Taken together, this study suggests that the generated mouse model shares characteristics with human disease and can thus be used as a platform to study anti-tumor responses in HPV-positive HNSCC which will help to identify novel therapeutic targets.

Oliveri F ，Neher L ，Pscheid R ，Sewald I ，Gowdavally S ，Betzler AC ，Hallitsch J ，Greve J ，Laban S ，Schmid S ，Hoffmann TK ，Schuler PJ ，Brunner C ... -  《-》