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

Abstract

BackgroundPD-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).MethodsWe 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.ResultsObjective 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.ConclusionsBelapectin+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.

Trough levels of ipilimumab in serum as a potential biomarker of clinical outcomes for patients with advanced melanoma after treatment with ipilimumab

“…14-17 23 31 We have also observed the E-R relationship following pembrolizumab Open access treatment for patients with melanoma. 32 The presence of the E-R relationship seems to suggest that the adjustment of dosing may improve the therapeutic efficacy of ICB with the goal of increasing the trough level in some patients, although this has not been investigated. The E-R relationship for mAbs for inflammatory disease prompted the dose adjustment based on TDM, and TDM has been attempted to be incorporated into the clinical practice due to the successful dose adjustment despite practical challenges in its implementation.…”

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

“…Furthermore, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase the production of cytotoxic effector molecules [ 364 ]. In metastatic melanoma and head and neck cancers, anti-PD-1 treatments are improved by belapectin (GR-MD-02), a galectin-3 inhibitor [ 365 ]. This combinatory therapy significantly increases effector memory T cell activation and reduces monocytic myeloid-derived suppressor cells detected in blood [ 365 ].…”

“…In metastatic melanoma and head and neck cancers, anti-PD-1 treatments are improved by belapectin (GR-MD-02), a galectin-3 inhibitor [ 365 ]. This combinatory therapy significantly increases effector memory T cell activation and reduces monocytic myeloid-derived suppressor cells detected in blood [ 365 ]. In non-small cell lung carcinoma, high galectin-3 expression correlated with a poor response to PD-1 blockade in a small cohort of patients [ 366 ].…”

Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment

“…However, overall, all of these immune-related functions have provided the rationale for testing whether Gal-3 can potentiate the effect of ICIs. A recent study using belapectin, a polysaccharide polymer that contains galactose and other sugars, has reported that this drug can potentiate the effect of ICIs and anti-OX-40 agonists in preclinical studies of multiple cancer models [ 80 , 81 , 82 ]. Notably, a recent in silico analysis by Takashima and colleagues showed that the genes encoding Gal-3 and Gal-9 were among the top 20 immunotherapy-related genes whose expression was significantly modulated.…”

“…However, some of these inhibitors have been shown to potentiate the effect of ICIs. This is the case for GR-MD-02 (also called belapectin), which has shown promising results in a Phase I study with metastatic melanoma and head and neck squamous cell carcinoma [ 80 ]. Another inhibitor of Gal-3, the monosaccharide GB1107, has also been shown to increase the efficacy of anti-PD-L1 to inhibit tumor growth in a mouse xenograft model with the lung adenocarcinoma cell line (A549) [ 82 ].…”