期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 9, 期 4, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-002371
关键词
programmed cell death 1 receptor; T-lymphocytes; immunohistochemistry; clinical trials as topic; myeloid-derived suppressor cells
资金
- NIH/NCI [R21CA190790]
- Galectin Therapeutics
- Providence Portland Medical Foundation
Combination therapy of belapectin and pembrolizumab shows promising activity in patients with metastatic melanoma and head and neck squamous cell carcinoma, with increased activation of effector memory T cells and decreased levels of monocytic myeloid-derived suppressor cells observed in responders. Additionally, increased expression of Gal-3, PD-1+CD8+ T cells, and higher serum trough levels of pembrolizumab are correlated with treatment response, indicating potential biomarkers for clinical outcomes.
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.
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