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2564 Background: Although anti-programmed death-1 (PD-1) treatment has shown remarkable anti-tumor efficacy, immune-related adverse events (irAEs) develop with heterogeneous clinical manifestations. Immunological understanding of irAEs is currently limited. In the present study, we analyzed peripheral blood T cells obtained from cancer patients who received anti-PD-1 treatment to determine the immunological characteristics of severe irAEs. Methods: This study included 31 patients with refractorythymic epithelial tumor (TET) who were enrolled in a phase II trial of pembrolizumab (NCT02607631) and 60 patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab. T-cell profiling was performed by multi-color flow cytometry using peripheral blood obtained immediately before treatment and 7 days after the first dose of anti-PD-1 antibodies. Results: Severe irAEs (≥ grade 3) occurred in 7 TET patients (22.6%) and 6 NSCLC patients (10.0%). Patients with severe irAEs exhibited a significantly lower fold increase in the frequency of effector regulatory T (eTreg) cells after anti-PD-1 treatment, higher ratio of T helper-17 (Th17) and T helper-1 cells at baseline, and higher percentage of Ki-67+cells among PD-1+CD8+T cells post-treatment. In clustering analysis, patients with severe irAEs were grouped into four distinct subtypes: Th17-related, TNF-related,Treg-related, and CD8-related. Conclusions: Severe irAEs after anti-PD-1 treatment were clustered into four immunological subtypes, indicating that development of severe irAEs is not attributed to a single mechanism. Further investigations in larger cohorts are needed to validate our current findings.

e24115Background: A number of clinical trials have demonstrated the therapeutic efficacy of anti-PD-1 therapies against various human cancers. However, the clinical benefit is limited to a small pr...

e14118Background: Despite recent improved understanding of cancer, the 5-year survival rate for head and neck squamous cell carcinoma (HNSCC) remains relatively unchanged. It is critical to identify new therapeutic strategies for NHSCC. Deregulation of CDKN2A (p16) or CCND1 (cyclin D1) occurs commonly in HNSCC and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. In addition, HNSCC is characterized by persistent activation of the AKT/mTOR pathway that triggers a signaling cascade of cell proliferation and survival. Methods: HNSCC cell lines were tested for the CDK4/6 inhibitor LY2835219, alone and in combination with mTOR inhibitor, both in vitro and in vivo. Results: The selective CDK4/6 inhibitor, LY2835219 inhibited CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induced cell cycle arrest and growth inhibition. In an animal xenograft model of HNSCC, LY2835219 treatment led to reduced tumor growth. However, because single-agent treatment with LY2835219 showed a limited e...