Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor
| Autor: | Yaping Wu, Brendan D. Curti, Zhaoyu Sun, William L. Redmond, Brady Bernard, Christopher B. Fountain, Peter G. Traber, Takashi Shimada, Yoshinobu Koguchi, Rom Leidner, Eliezer Zomer, Elizabeth Sturgill, George Morris, Venkatesh Rajamanickam, Noriko Iwamoto, Annah S Rolig, Ian Hilgart-Martiszus, J. Rex Horton, Shu Ching Chang, Harold Shlevin |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Time Factors medicine.medical_treatment Programmed Cell Death 1 Receptor Pembrolizumab 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Immunology and Allergy Immune Checkpoint Inhibitors T-lymphocytes RC254-282 Clinical/Translational Cancer Immunotherapy clinical trials as topic Neoplasms. Tumors. Oncology. Including cancer and carcinogens Blood Proteins Middle Aged Treatment Outcome Head and Neck Neoplasms 030220 oncology & carcinogenesis immunohistochemistry Molecular Medicine Pectins Female Multiple Myeloma Adult medicine.medical_specialty Galectins Immunology Antibodies Monoclonal Humanized 03 medical and health sciences Memory T Cells Immune system Internal medicine medicine Humans Aged Pharmacology Autoimmune disease business.industry Squamous Cell Carcinoma of Head and Neck Myeloid-Derived Suppressor Cells Immunotherapy medicine.disease Head and neck squamous-cell carcinoma Blockade 030104 developmental biology Myeloid-derived Suppressor Cell business CD8 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 4 (2021) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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