PDF(Pubmed)
Abstract：
We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 - 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 - 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.
摘要：
我们对通过微流体挤压（CellSqueeze®技术）加载HPV16E6和E7抗原（SQZ-PBMC-HPV）的自体PBMC进行了剂量递增1期研究，HLA-A*02+晚期/转移性HPV16+癌症患者。在小鼠模型的临床前研究表明，这些细胞导致抗原特异性CD8+细胞的刺激和增殖，并证明了抗肿瘤活性。每3周给予SQZ-PBMC-HPV。注册遵循修改后的3+3设计，主要目标是定义安全性，耐受性,和推荐的2期剂量。次要和探索性目标是抗肿瘤活性，制造可行性，和免疫反应的药效学评价。18名患者以0.5×106至5.0×106活细胞/kg的剂量登记。制造证明是可行的，并且在1-2周的整体静脉到静脉时间内需要<24小时;在最高剂量下，中位给药剂量为4次.没有观察到DLT。大多数相关TEAE为1-2级，并报告了1例2级细胞因子释放综合征SAE。3例患者的肿瘤活检显示CD8+组织浸润淋巴细胞增加2至8倍，包括表现出MHC-I+和PD-L1+细胞密度增加和HPV+细胞数量减少的病例。记录了后一种情况的临床益处。SQZ-PBMC-HPV具有良好的耐受性;选择具有双重引发的5.0×106活细胞/kg作为推荐的2期剂量。多个参与者表现出与免疫反应一致的药效学变化，支持SQZ-PBMC-HPV的拟议作用机制，包括以前对检查点抑制剂难以治疗的患者。
