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

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

doi:10.1016/j.medj.2025.100752

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

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

Authors

Steven H Lin¹, Vivek Subbiah², Evan N Cohen³, Ziyi Li⁴, Yingjuan June Lu⁵, Ye Lin Son⁶, Yue Lyu⁴, Hui Gao³, Gitanjali Jayachandran³, Shinya Neri⁶, Amrish Sharma⁶, Penny Fang⁶, Daniel Karp², David Hong², Jordi Rodon², Hao Yu², Jing Peng², G Kenneth Lloyd⁵, James R Tonra⁵, James M Reuben³, Lan Huang⁷, Siqing Fu⁸

Affiliations

¹ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: shlin@mdanderson.org.
² Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
³ Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁴ Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁵ BeyondSpring Pharmaceuticals, Inc., 100 Campus Drive, Florham Park, NJ 07932, USA.
⁶ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁷ BeyondSpring Pharmaceuticals, Inc., 100 Campus Drive, Florham Park, NJ 07932, USA. Electronic address: lhuang@beyondspringpharma.com.
⁸ Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: siqingfu@mdanderson.org.

PMID: 40580957
DOI: 10.1016/j.medj.2025.100752

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.