Authors: Curti, Brendan D.; Koguchi, Yoshinobu; Leidner, Rom S.; Rolig, Annah S.; Sturgill, Elizabeth R.; Sun, Zhaoyu; Wu, Yaping; Rajamanickam, Venkatesh; Bernard, Brady; Hilgart-Martiszus, Ian; Fountain, Christopher B.; Morris, George; Iwamoto, Noriko; Shimada, Takashi; Chang, ShuChing; Traber, Peter G.; Zomer, Eliezer; Horton, J. Rex; Shlevin, Harold; Redmond, William L.
Online: https://jitc.bmj.com/content/9/4/e002371
Issue: J Immunother Cancer . 2021 Apr;9(4):e002371.
Abstract
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.
