Immune Re-sensitization in Checkpoint Inhibitor Refractory and Relapsed Cancers with Plinabulin, Radiation and Immune Checkpoint Blockade

Plinabulin exerts immunomodulatory activity through guanine-nucleotide-exchange-factor (GEF)-H1 activation, particularly in antigen-presenting cells. Here we demonstrate that radiation (RT) potentiates plinabulin-induced dendritic cell (DC) maturation, and when combined with immune-checkpoint-inhibitors (ICI), triggers an abscopal antitumor response via increased tumor-infiltrating CD86+ DCs and CD8+ T-cells. Nonclinical findings were translated in a phase 1 basket study (ClinicalTrial.org: NCT04902040) in patients with ICI-relapsed/refractory cancers. Plinabulin treatment after RT initiation plus ICI was safe and achieved an encouraging disease-control-rate (DCR) of 54% (3/13 partial response [PR] and 4/13 stable disease [SD]) in out-of-field unirradiated lesions; Enduring and 2/2 PR responses were seen in Hodgkin's lymphoma patients who had progressed after 12- or 16-prior lines of therapy. Responding PR+SD subjects had significant increases in peripheral blood proinflammatory monocytes, and activated DCs, and GEF-H1 induction in immune cells, T-cell clonal expansion, and intratumoral immune activation and GEF-H1 induction in DC subsetsactivation . These promising preliminary results provide the rationale for using this triple combination approach (RT/plinabulin/ICIdefine therapies?) in post-ICI-failure settings in future confirmatory trials.