贝拉普利单抗增强抗 PD-1 的临床和免疫效果，一种半乳糖凝集素-3 抑制剂。

Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor.

机构信息

Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.

Shimadzu Bioscience Research Partnership, Shimadzu Scientific Instruments, Bothell, Washington, USA.

出版信息

J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2021-002371.

BACKGROUND

PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC).

METHODS

We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0-2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted.

RESULTS

Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab.

CONCLUSIONS

Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.

背景

PD-1/PD-L1 结合和半乳糖凝集素-3（Gal-3）的过表达是肿瘤诱导免疫抑制的关键机制，导致免疫治疗耐药。我们假设 Gal-3 阻断剂 belapectin（GR-MD-02）联合抗 PD-1（pembrolizumab）将增强转移性黑色素瘤（MM）和头颈部鳞状细胞癌（HNSCC）患者的肿瘤反应。

方法

我们进行了一项 belapectin+pembrolizumab 治疗晚期 MM 或 HNSCC 患者的 I 期剂量递增研究（NCT02575404）。belapectin 在 pembrolizumab（200mg IV 每 3 周一次，共 5 个周期）给药前 60 分钟静脉内给予 2、4 或 8mg/kg。有反应的患者继续接受 pembrolizumab 单药治疗，最多 17 个周期。主要入选标准为功能东部合作肿瘤组（ECOG）状态 0-2、可测量或可评估的疾病，以及无活动性自身免疫性疾病。允许使用先前的 T 细胞检查点抗体治疗。

结果

MM（7/14）和 HNSCC（2/6）患者的客观缓解率分别为 50%和 33%。与 pembrolizumab 单药治疗相比，belapectin+pembrolizumab 相关的免疫介导不良事件较少。在所研究的剂量范围内，belapectin 无剂量限制毒性。与无反应者相比，反应者的效应记忆 T 细胞激活增加，单核细胞髓样来源的抑制细胞（M-MDSCs）减少。在反应者中，外周血 Gal-3+肿瘤细胞和 PD-1+CD8+T 细胞的基线表达增加与反应相关，而 pembrolizumab 的血清谷浓度升高也与反应相关。