KEYNOTE 048 FREE

KEYNOTE 048 FREE

However, there were no significant improvement in the progression free survival for patients receiving pemrolizumab as a monotherapy or in combination with chemotherapy in both group of patients, with PD-L expression (CPS >1) and without it (CPS 20) in total population. KEYNOTE-048 study results became basis for changing standard of care in the 1 st line treatment of patients with recurrent / metastatic squamous cell cancer of the head and neck (SCCHN). Based on our data, we propose that CD155 and CD276 are promising novel targets for HNSCC, possibly in combination with the current standard of care or novel immunotherapies to come. Lastly, the co-presence of both (i) CD155 positive cells with intratumoral NK cells and (ii) PD-L1 expression with regulatory T cell infiltration may hold prognostic value for these cohorts. Our IHC analyses confirmed the relevance of CD155 and CD276 protein expression, and in addition PD-L1 expression, as independent negative prognostic factors, while HLA-E overexpression was associated with better outcomes.

Of these, CD73, CD276 and CD155 gene expression were negative prognostic factors, while CD40L, CEACAM1 and Gal-9 expression were associated with significantly better outcomes. HNSCC tumors in our TCGA cohort showed differential RNA over- and underexpression of 28 immune inhibitory and activating checkpoint ligands compared to healthy tissue. TCGA data showed prognostic relevance of dendritic cells, M2 macrophages and neutrophils, while IHC analysis associated T cells and natural killer cells with better/worse prognostic outcome. Our results indicated that HNSCC tumors are in close contact with both cytotoxic and immunosuppressive immune cells. The outcome of both analyses was correlated with clinicopathological parameters and patient overall survival. This initial investigation was followed by immunohistochemical (IHC) staining for a curated selection of immune cell types and checkpoint ligands markers in tissue samples of 50 advanced stage HNSCC patients. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. The results are encouraging and indicate that data obtained from patient‑specific tumors in a dish might be finally translated into personalized immuno‑oncology. Second, it will highlight the significance of current promising approaches to establish HNSCC 3D models for new immunotherapies. The present review will first summarize recent findings on immunotherapy, predictive biomarkers, the role of the TME and signaling cascades eliciting during CPI. Sophisticated 3D models are therefore urgently needed to be able to validate such basic science hypotheses and to test novel immuno‑oncologic treatment regimens in consideration of the individual biology of each tumor. Particularly in a heterogeneous disease such as HNSCC, thoroughly studying the interactions and crosstalking between tumor and TME cells is one of the biggest challenges. Accordingly, analyzing and modeling the complexity of the tumor microenvironment (TME) is key to i) stratify subgroups of patients most likely to respond to CPI and ii) to define new combinatorial treatment regimens. One potential factor is the expression of target molecules of the tumor allowing cancer cells to acquire therapy resistance mechanisms. Clinical response and, consecutively, treatment success remain unpredictable in most of the cases. Although checkpoint inhibition (CPI) has definitely enriched the treatment options for advanced stage HNSCC during the past decade, the percentage of patients responding to treatment is widely varying between 14‑32% in second‑line setting in recurrent or metastatic HNSCC with a sporadic durability. Immunotherapy has evolved into a powerful tool in the fight against a number of types of cancer, including head and neck squamous cell carcinomas (HNSCC).

Keynote 048