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. 2025 Jun 25:100752.
doi: 10.1016/j.medj.2025.100752. Online ahead of print.

Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relapsed/refractory cancers

Steven H Lin  1 , Vivek Subbiah  2 , Evan N Cohen  3 , Ziyi Li  4 , Yingjuan June Lu  5 , Ye Lin Son  6 , Yue Lyu  4 , Hui Gao  3 , Gitanjali Jayachandran  3 , Shinya Neri  6 , Amrish Sharma  6 , Penny Fang  6 , Daniel Karp  2 , David Hong  2 , Jordi Rodon  2 , Hao Yu  2 , Jing Peng  2 , G Kenneth Lloyd  5 , James R Tonra  5 , James M Reuben  3 , Lan Huang  7 , Siqing Fu  8
Affiliations

Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relapsed/refractory cancers

Steven H Lin et al. Med. .

Abstract

Background: Plinabulin exerts immunomodulatory activity through guanine nucleotide exchange factor (GEF)-H1 release from depolymerizing tubulin in the cytoskeleton, leading to dendritic cell (DC) activation. Preclinical studies demonstrated that irradiation potentiates plinabulin-induced DC maturation and, when combined with immune checkpoint inhibitors (ICIs), triggers an abscopal antitumor response via increased tumor-infiltrating DCs and T cells.

Methods: A phase 1 translational study (NCT04902040) of plinabulin plus ICIs after radiation therapy (RT) initiation was conducted in ICI-relapsed/refractory cancers with primary (safety, tolerability, and objective tumor response rate) and secondary (disease control rate [DCR]) endpoints.

Findings: This triple regimen was safe and achieved a DCR of 54% (3/13 partial response [PR] and 4/13 stable disease [SD]) in mostly heavily pretreated patients. Responding tumors included non-small cell lung cancer (2/2 PR + SD), head-and-neck squamous cell carcinoma (2/3 PR + SD), and Hodgkin's lymphoma (2/2 PR in patients after 12 or 16 prior lines of therapy). PR + SD patients had significantly higher GEF-H1 immune-activation scores in peripheral blood and intratumorally at pretreatment/baseline and DC activation/T cell clonal expansion post-treatment compared with progressive disease patients.

Conclusions: These preliminary results provide a rationale for testing RT/plinabulin/ICI combination in future post-ICI-failure confirmatory trials.

Funding: This study was funded by BeyondSpring Pharmaceuticals, Inc.

Keywords: GEF-H1; ICI-relapsed cancer; PD-1; PD-L1; Translation to patients; biomarkers; cancer immunity; dendritic cell; immune checkpoint inhibitors; plinabulin; radiation therapy.

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Conflict of interest statement

Declaration of interests Full-time employment at The University of Texas MD Anderson Cancer Center: S.H.L., V.S., E.N.C., Z.L., Y.L.S., Y.L., H.G., G.J., S.N., A.S., P.F., D.K., D.H., J.R., H.Y., J.P., J.M.R., and S.F. Full-time employment and equity ownership at BeyondSpring Pharmaceuticals: Y.J.L., G.K.L., J.R.T., and L.H. S.H.L. receives research grants from BeyondSpring Pharmaceuticals, STCube Pharmaceuticals, and Nektar Therapeutics; serves on the advisory boards of AstraZeneca and Creatv Microtech; is a consultant for XRAD Therapeutics; and is a co-founder/stockholder/scientific advisor for Seek Diagnostics. S.H.L. is also a paid lecturer at The Osler Institute, a full member of the thoracic committee of NRG Oncology, and the chair of the Radiation Therapy Developmental Therapeutics committee. L.H. is a board member and stock shareholder of BeyondSpring Pharmaceuticals and Seed Therapeutics. S.F. receives clinical trial research support/grant funding through the institution from the following sources: NIH/NCI P30CA016672 – Core Grant (CCSG Shared Resources); Abbisko; Antengene; BeiGene; BeyondSpring Pharmaceuticals, Inc.; BioAtla, LLC; Boehringer Ingelheim; CUE Biopharma, Inc.; DEKA Biosciences; Eli Lilly & Co.; Exelixis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics Co., Ltd.; Jazz Pharmaceuticals; K-Group Beta; Lantern Pharma, Inc.; Lyvgen Biopharm Co., Ltd.; MacroGenics; MediLink Therapeutics Co., Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS; Parexel International, LLC; PharmaMar USA, Inc.; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Qurgen, Inc.; Shanghai Huaota Biopharmaceutical Co., Ltd.; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; and Virogin Biotech, Ltd. S.F. is also a committee member of the Southwest Cancer Chemotherapy Study Group (SWOG). J.R. reports non-financial support and reasonable reimbursement for travel from the European Society for Medical Oncology and Loxo Oncology. J.R. receives consulting and travel fees from Ellipses Pharma, Molecular Partners, IONCTURA, Sardona, Mekanistic, Amgen, Merus, MonteRosa, Aadi, and Bridgebio (including serving on the scientific advisory board). J.R. receives consulting fees from Vall d'Hebron Institute of Oncology/Ministerio De Empleo Y Seguridad Social; Chinese University of Hong Kong; Boxer Capital, LLC; Tang Advisors, LLC; and Guidepoint. J.R. receives research funding from Blueprint Medicines, Merck Sharp & Dohme, Hummingbird, AstraZeneca, Yingli, and Vall d'Hebron Institute of Oncology/Cancer Core Europe. J.R. serves as an investigator in clinical trials with Cancer Core Europe, Symphogen, BioAlta, Pfizer, Kelun-Biotech, GlaxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bicycle Therapeutics, Merus, Aadi Bioscience, ForeBio, Loxo Oncology, Hutchinson MediPharma, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, MonteRosa, Kinnate, Yingli, Debio, BioTheryX, Storm Therapeutics, Beigene, MapKure, Relay, Novartis, FusionPharma, C4 Therapeutics, Scorpion Therapeutics, Incyte, Fog Pharmaceuticals, Tyra, and Nuvectis Pharma. There is a patent application pending related to this work.

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