Immunotherapy and senolytics in head and neck squamous cell carcinoma: phase 2 trial results

Recent advancements in cancer immunotherapy have improved patient outcomes, yet responses to immunotherapy remain moderate. Immunosenescence has been shown to contribute to the development and progression of various diseases; however, its specific role in solid tumors has not been fully delineated. Here we conducted a phase 2 clinical trial involving 51 patients with cancer undergoing neoadjuvant chemoimmunotherapy and applied single-cell RNA as well as TCR and BCR sequencing on tumor and blood samples to elucidate the immune cell perturbations. Our findings associate poor response with reduced levels of CCR7+ CD4+ naive T cells and CD27+ memory B cells, as well as higher expression of immunosenescence-related genes in T and B cell subsets. Using naturally aged mice and Ercc1-deficient mice (premature aging), we found that senolytics enhance the therapeutic efficacy of immunotherapy in multiple solid tumors by mitigating immunosenescence. Notably, we launched a phase 2 clinical trial (COIS-01) investigating the combination of senolytics with anti-PD-1 therapy. The results showed that the combination therapy achieved a 33.3% (95% confidence interval 16.6–54.7%) major pathological response rate with a low incidence of grade 3–4 adverse events (4.2%). These findings underscore the pivotal role of immunosenescence characteristics in influencing the effectiveness of immunotherapy and suggest a promising therapeutic efficacy along with a favorable safety for the combination of senolytics with anti-PD-1 therapy. ClinicalTrials.gov Identifier: OOC-001( NCT04718415 ) and COIS-01( NCT05724329 ). Two phase 2 trials, along with translational analysis of prospective cohorts and experimental analysis, indicate that immunosenescence as a mechanism of resistance to immunotherapy can be overcome with the senolytics dasatinib and quercetin in patients with head and neck squamous cell carcinoma.