Clinical Response to Neoadjuvant Immunotherapy Combined with Targeted Therapy and Chemotherapy in Oral Squamous Cell Carcinoma: Experience in Three Patients.

Immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab have been approved for the treatment of head and neck squamous cell carcinoma (HNSCC) and used in neoadjuvant immunotherapy in clinical trials. However, combination of ICIs with targeted therapy and chemotherapy was rarely used in pre-surgical HNSCC patients. Herein, we encountered three cases of patients with oral squamous cell carcinoma (OSCC) who all had good responses to neoadjuvant immunotherapy (anti-PD-1 inhibitors) combined with nimotuzumab (anti-EGFR monoclonal antibody) plus paclitaxel. Both Case 1 and Case 2 underwent the same neoadjuvant therapeutic combination (nivolumab, nimotuzumab and paclitaxel) and exhibited a marked tumor shrinkage even complete disappearance by radiological evaluation. Moreover, pathological response was observed in post-surgical tissues of Case 1. Additionally, Case 3 with tongue squamous cell carcinoma also had satisfactory tumor regression (complete healing of his tongue ulcer upon treatment) after receiving similar neoadjuvant therapy with sintilimab (another PD-1 inhibitor), nimotuzumab and paclitaxel. We characterized their potential causes behind favorable treatment outcomes. While there were differences in driver mutations and tumor mutation burden (TMB) identified in pre-treatment tumor tissues among the three patients, numerous CD68+ (macrophages) infiltrates were common for all the cases. Of note, the majority (>80%) of the total macrophages were molecularly defined as PD-L1-positive macrophages. Given the high expression of PD-L1 in macrophages is associated with better immunotherapy outcomes, we propose that the high proportion of CD68+PD-L1+ cells in total macrophages alone could serve as a promising biomarker for neoadjuvant immunotherapy in combination with other therapies in HNSCC.