Impact of acetaminophen on the efficacy of immunotherapy in cancer patients.

BACKGROUND: Acetaminophen (APAP) use has been associated with blunted vaccine immune responses. This study aimed to assess APAP impact on immunotherapy efficacy in patients with cancer. PATIENTS AND METHODS: Exposure to APAP was assessed by plasma analysis and was correlated with clinical outcome in three independent cohorts of patients with advanced cancer who were treated with immune checkpoint blockers (ICBs). The immunomodulatory effects of APAP were evaluated on a preclinical tumor model and on human peripheral blood mononuclear cells (PBMCs) from healthy donors. RESULTS: Detectable plasma APAP levels at treatment onset were associated with a significantly worse clinical outcome in ICB-treated cancer patients, independently of other prognostic factors. APAP significantly reduced ICB efficacy in the preclinical MC38 model, as well as the production of PD-1 blockade-related interferon-γ secretion by human PBMCs. Moreover, reduction of ICB efficacy in vivo was associated with significantly increased tumor infiltration by regulatory T cells (Tregs). Administration of APAP over 24 h induced a significant expansion of peripheral Tregs in healthy individuals. In addition, interleukin-10, a crucial mediator of Treg-induced immune suppression, was significantly up-regulated upon treatment with ICB in cancer patients taking APAP. CONCLUSIONS: This study provides strong preclinical and clinical evidence of the role of APAP as a potential suppressor of antitumor immunity. Hence, APAP should be used with caution in patients treated with ICB.

Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort.

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment.