CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains an aggressive disease with limited response to systemic therapies despite androgen deprivation. Immune-excluded prostate tumors are typically resistant to immunotherapy. STAR0602 is a selective bifunctional T-cell agonist composed of an antibody targeting Vβ6 and Vβ10 T-cell receptor chains fused to human interleukin-2 that selectively expands Vβ6 + CD8 + memory T cells and has demonstrated clinical activity as a monotherapy in anti-programmed death-ligand 1-resistant tumors (NCT05592626). We hypothesized that combining poly ADP-ribose polymerase (PARP) inhibition with Vβ-directed T-cell activation would enhance antitumor immunity and promote polyclonal T-cell responses in immune-excluded prostate cancer. METHODS: The antitumor activity of the PARP inhibitor olaparib combined with mSTAR1302, the murine surrogate of STAR0602, was evaluated in TRAMP-C2 and RM-1 prostate tumor models. Tumor growth, survival, and immune responses were assessed by flow cytometry and functional depletion studies. The role of tumor-intrinsic TRAIL-R2 signaling was evaluated using a TRAIL-R2 knockout TRAMP-C2 model, and clinical relevance was explored by assessing TRAIL-R2 expression in tumor samples from patients treated with olaparib in a Phase 2 clinical trial (NCT02484404). RESULTS: Combination therapy with olaparib and mSTAR1302 induced significant tumor regression and improved survival compared with either agent alone. Treatment increased tumor-infiltrating lymphocytes, expanded activated Vβ13 + CD4 + and Vβ13 + CD8 + T cells, reduced immunosuppressive populations, and enriched stem-like progenitor exhausted CD8 + T cells. Depletion studies demonstrated that Vβ13 + CD4 + T cells, Vβ13 + CD8 + T cells, natural killer cells, and interferon-γ were required for therapeutic efficacy. TRAIL-R2 knockout experiments demonstrated that tumor-intrinsic TRAIL-R2 signaling contributes to the antitumor activity of the combination. Mechanistically, these findings support a model in which PARP inhibition sensitizes tumors while mSTAR1302-mediated Vβ13 + T-cell expansion initiates a broader polyclonal antitumor immune response associated with antigen spreading and recognition of multiple tumor antigens and neoepitopes. CONCLUSIONS: These findings suggest that combining tumor-sensitizing therapies with selective T-cell activation may represent a broader strategy to overcome immune exclusion in solid tumors. Together, these results provide mechanistic rationale for clinical evaluation of olaparib in combination with STAR0602 in patients with mCRPC who have progressed on androgen deprivation therapy.