Phase 1 evaluation of APN401, an autologous CBL-B-silenced PBMC therapy, in advanced solid tumors

Intracellular immune checkpoints regulate activation thresholds in cytotoxic immune cells. Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is an E3 ubiquitin ligase that negatively regulates antigen receptor signaling and T cell activation. APN401 is an autologous peripheral blood mononuclear cell (PBMC) therapy incorporating transient small interfering RNA (siRNA)-mediated CBL-B silencing. Two phase 1 studies evaluated escalating doses of APN401 in patients with advanced treatment-refractory solid tumors. APN401 was manufactured from leukapheresis-derived PBMCs using the EPiC point-of-care platform. Seventeen patients received APN401 across three dose levels. APN401 demonstrated a favorable safety profile, with no dose-limiting toxicities, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or grade ≥3 treatment-related adverse events. Manufacturing was reproducible across sites. Although no objective responses were observed, disease stabilization occurred in 5 of 10 Response Evaluation Criteria in Solid Tumors (RECIST)-evaluable patients (50.0%), corresponding to 29.4% of all 17 treated patients. Exploratory analyses identified treatment-associated systemic immune changes, including enrichment of circulating CD8⁺ T cells, induction of cytotoxic mediators, and expansion of dominant T cell receptor β (TCRβ) clonotypes. These changes were most pronounced in patients with stable disease but remain exploratory and hypothesis-generating. These findings support further evaluation of APN401 in larger, controlled studies.