Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor
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 respons...
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doaj-b74b3ece4a084cb7ac2ccf373351e2ec2021-09-27T05:00:04ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-04-019410.1136/jitc-2021-002371Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitorWilliam L Redmond0Yoshinobu Koguchi1Annah S Rolig2Noriko Iwamoto3Takashi Shimada4Elizabeth R Sturgill5Zhaoyu Sun6Venkatesh Rajamanickam7Brady Bernard8Peter G Traber9Eliezer Zomer10J Rex Horton11Harold Shlevin12Earle A. Chiles Research Institute, Portland, Oregon, USA1Providence Cancer Institute, Portland, OR, USAEarle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA2Shimadzu Scientific Instruments, Bothell, WA, USA2Shimadzu Scientific Instruments, Bothell, WA, USAEarle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAEarle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAEarle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAEarle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USAUniversity of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USAGalectin Therapeutics, Norcross, Georgia, USAGalectin Therapeutics, Norcross, Georgia, USAGalectin Therapeutics, Norcross, Georgia, USABackground 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.https://jitc.bmj.com/content/9/4/e002371.full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
William L Redmond Yoshinobu Koguchi Annah S Rolig Noriko Iwamoto Takashi Shimada Elizabeth R Sturgill Zhaoyu Sun Venkatesh Rajamanickam Brady Bernard Peter G Traber Eliezer Zomer J Rex Horton Harold Shlevin |
spellingShingle |
William L Redmond Yoshinobu Koguchi Annah S Rolig Noriko Iwamoto Takashi Shimada Elizabeth R Sturgill Zhaoyu Sun Venkatesh Rajamanickam Brady Bernard Peter G Traber Eliezer Zomer J Rex Horton Harold Shlevin Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor Journal for ImmunoTherapy of Cancer |
author_facet |
William L Redmond Yoshinobu Koguchi Annah S Rolig Noriko Iwamoto Takashi Shimada Elizabeth R Sturgill Zhaoyu Sun Venkatesh Rajamanickam Brady Bernard Peter G Traber Eliezer Zomer J Rex Horton Harold Shlevin |
author_sort |
William L Redmond |
title |
Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor |
title_short |
Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor |
title_full |
Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor |
title_fullStr |
Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor |
title_full_unstemmed |
Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor |
title_sort |
enhancing clinical and immunological effects of anti-pd-1 with belapectin, a galectin-3 inhibitor |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2021-04-01 |
description |
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. |
url |
https://jitc.bmj.com/content/9/4/e002371.full |
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