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

Publication Title

J Immunother Cancer

Authors

Brendan D Curti, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Yoshinobu Koguchi, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Rom S Leidner, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Annah S Rolig, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Elizabeth R Sturgill, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Zhaoyu Sun, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Yaping Wu, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Venkatesh Rajamanickam, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Brady Bernard, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Ian Hilgart-Martiszus, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Christopher B Fountain, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
George Morris, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow
Noriko Iwamoto
Takashi Shimada
ShuChing Chang, Medical Data Research Center, Providence St Joseph Health, Portland, Oregon, USAFollow
Peter G Traber
Eliezer Zomer
J Rex Horton
Harold Shlevin
William L Redmond, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAFollow

Document Type

Article

Publication Date

4-1-2021

Keywords

oregon; portland; chiles

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.

Area of Special Interest

Cancer

Specialty/Research Institute

Earle A. Chiles Research Institute

Specialty/Research Institute

Oncology

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