{
  "abstract": "Background Plinabulin is a first-in-class, clinical stage, differentiated tubulin binder that exerts anti-cancer activity primarily by activating GEF-H1-mediated pathways in dendritic cell (DC) maturation and subsequent T-cell activation. When given after radiation in ICB-relapsed/refractory cancers, plinabulin (30 mg/m 2) potentiates systemic immunity with standard-of-care checkpoint inhibitors1 with promising anti-cancer benefit of ORR 23% and DCR 54%. Using scRNA sequencing, our investigation herein focuses on GEF-H1-dependent immune signature at pre/post-treatment timepoints (C1D1/C1D4/C3D1) in monocytes/macrophages from peripheral blood mononuclear cell (PBMCs) and available tumor biopsies of non-irradiated target lesions.Methods In the phase I translational study ( NCT04902040), 12 patients of mixed cancers (7 PR+SD and 5 PD) were available for examination of GEF-H1 immune activation in PBMCs and 5 of them had pre/post-treatment tumor biopsies (2 NSCLC, 1 fibrolamellar HCC, 1 RCC, 1 SCCHN). For PBMCs, whole transcriptome scRNAseq was performed using Evercode kits (Parse Biosciences) and a DNBSEQ T7 genetic sequencer using Complete Genomics’ 100 bp paired end (PE100) high-throughput sequencing kit. For dissociated tumor biopsies, scRNA-seq was performed using 10X genomics and aligned using the hg38 human reference genome. Here, we examined a 47-gene GEF-H1 immune activation signature in peripheral CD14+ and CD16+ monocytes and tumor-infiltrating immune cells (TIICs) focusing on monocyte-derived macrophages (MoMac I-IV) in PR+SD and PD subjects at C1D1/baseline, C1D4 and/or C3D1 timepoints.Results At all timepoints in PBMCs, there were significant differences in GEF-H1 immune scores between PR+SD and PD patients in CD16+ and CD14+ monocytes. As treatment progressed, a notable increase in monocyte proportions corresponded to a decrease in the T-cell proportions in all patients, although such trends were not significant when examined individually. In patient-matched tumor biopsies, GEF-H1 immune scores in TIICs and total MoMac were significantly increased in the PR+SD group but decreased in the PD group (C3D1 vs. C1D1). There was no baseline difference in TIIC-associated GEF-H1 immune scores between PR+SD and PD groups, whereas total MoMac-associated GEF-H1 immune score was higher in PD group when compared to PR+SD group. Further subgroup analysis of MoMac I-IV suggests that AGR1+ MoMac-III may represent the dominating pro-tumor M2 phenotype and that plinabulin combined with RT+ICB drives differential monocyte-macrophage responses in responders.Conclusions In addition to maturation of DCs to generate a systemic immune response, plinabulin combined with radiation and ICB promotes proinflammatory monocytes and M1 polarization via a GEF-H1-dependent mechanism with the potential of overcoming acquired ICB resistance from pro-tumor macrophages.Reference Lin S, Subbiah V, Cohen E, et al. Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relapsed/refractory cancers. Med. 2025 (online first, June 27, 2025).Ethics Approval Among the 19 patients evaluable for safety, 1 male (Hispanic or Latino) patient entered ‘other’ ethnics and should be added to the 18 patients under ‘Racial Categories’.",
  "authors": [
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Steven H Lin"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Ziyi Li"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Yue Lyu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Evan Cohen"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Ye-Lin Son"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Hui Gao"
    },
    {
      "affiliations": [
        "BeyondSpring Pharmaceuticals, Inc., Florham Park, NJ, USA"
      ],
      "name": "James J Tonra"
    },
    {
      "affiliations": [
        "BeyondSpring Pharmaceuticals, Inc., Florham Park, NJ, USA"
      ],
      "name": "Yingjuan June Lu"
    },
    {
      "affiliations": [
        "BeyondSpring Pharmaceuticals, Inc., Florham Park, NJ, USA"
      ],
      "name": "Lan J Huang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Siqing Fu"
    }
  ],
  "title": "672 Immune activation with plinabulin promotes monocyte-macrophage responses combining radiation with immune checkpoint blockade (ICB) in ICB-relapsed/refractory tumors",
  "uid": "e28bfd42-4994-513e-91c9-2403ac702826"
}