Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial (NCT03307616) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

基于免疫检查点阻断 (ICB) 在晚期去分化脂肪肉瘤 (DDLPS) 和未分化多形性肉瘤 (UPS) 中已证实的临床活性，我们进行了一项新辅助纳武单抗或纳武单抗/伊匹单抗的随机、非比较 2 期试验 (NCT03307616)患有可切除腹膜后 DDLPS ( n  = 17) 和四肢/躯干 UPS 的患者（+同时纳武利尤单抗/放射治疗；n  = 10）。病理反应的主要终点（透明变性百分比）在 DDLPS 中为 8.8%，在 UPS 中为 89%。次要终点是免疫浸润、放射学反应、12 个月和 24 个月无复发生存率以及总生存率的变化。治疗前调节性 T 细胞密度较低与主要病理反应（玻璃样变 > 30%）相关。新辅助治疗后 B 细胞的肿瘤浸润增加，并且与 DDLPS 的总生存率相关。 B 细胞浸润与治疗前较高密度的调节性 T 细胞相关，而 ICB 治疗后调节性 T 细胞会丢失。我们的数据表明，新辅助 ICB 与 DDLPS 和 UPS 中肿瘤微环境内复杂的免疫变化相关，并且新辅助 ICB 联合同步放疗对 UPS 具有显着疗效。