Tumoral and Systemic Immune Correlates of Response to Concurrent Pembrolizumab and Chemoradiotherapy in Patients with Resected High-Risk Head and Neck Squamous Cell Carcinoma
Lazar Vujanovic, Pedro Torres-Saavedra, Fei Tu, Ravindra Uppaluri, Min Yao, Josephine Chen, Richard Jordan, Jessica L. Geiger, Srinivas Jujjavarapu, Arnab Chakravarti, Minh Phan, Farzan Siddiqui, Aditi Kulkarni, Pragati Upadhyay, Brian Robert. Isett, Gabriel L. Sica, Carly Reeder, Riyue Bao, Jie Chen, Marion Joy, Tanner Freeman, Jonathan Harris, Quynh-Thu Le, Julie E. Bauman, Robert L. FerrisAbstract
Purpose: Patients with pathologically high-risk, HPV-negative HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). As CRT can upregulate PD-1/L1 immune checkpoints, adding pembrolizumab may reverse treatment-induced immunosuppression. NRG-HN003 was a phase I trial assessing the safety and recommended phase II schedule of adjuvant pembrolizumab with CRT. Here, we report exploratory immune and genomic correlates of disease-free survival (DFS). Patients and Methods: Thirty-four patients received pembrolizumab with CRT. PD-L1 expression was quantified by combined positive score (CPS) and spatial localization of PD-L1+ cells was assessed by multispectral imaging of baseline tumors. Disruptive TP53 mutations were evaluated by whole-exome sequencing. Soluble serum biomarkers were evaluated by Luminex, and circulating immune subsets were profiled by spectral flow cytometry at baseline and post-treatment. Results: Patients with PD-L1 CPS≥20 showed numerically lower DFS than those with CPS<20; however, higher densities of PD-L1+ stromal cells were associated with more favorable outcomes. Disruptive TP53 mutations were not a significant negative prognostic factor. Among soluble markers at baseline, elevated serum arginase-1 was associated with inferior DFS, while higher levels of GM-CSF, IL-2 and nectin-2 were associated with more favorable outcomes. In circulating immune cells, higher baseline frequencies of CD8+ granzyme K+ T cells, as well as higher post-treatment frequencies of CD8+ CD39+ and regulatory CD4+ T cells, were associated with improved DFS. Increased effector and central memory T cell populations, especially post-treatment, also showed favorable associations with DFS. Conclusions: These findings highlight multiple potential immunologic correlates of pembrolizumab with CRT in high-risk HNSCC, supporting further evaluation and validation in larger, adequately powered trials.