PARP Inhibition Combined with Targeted T-Cell Activation Drives Polyclonal Antitumor Immunity in mCRPC

A novel therapeutic strategy combining PARP inhibition with selective T-cell receptor β chain activation is showing promising potential to overcome immune resistance in metastatic castration-resistant prostate cancer (mCRPC).This approach pairs olaparib, a well-established PARP inhibitor, with a bifunctional T-cell agonist (STAR0602) designed to selectively expand specific T-cell subsets through targeted delivery of interleukin-2.

Prostate tumors are typically immune-excluded, meaning that even when tumor antigens are present, immune cells fail to effectively infiltrate or respond. This has limited the success of conventional immunotherapies such as checkpoint inhibitors. The combination described in this study addresses this limitation by simultaneously increasing tumor immunogenicity and actively driving T-cell expansion.

PARP inhibition induces DNA damage within tumor cells, leading to the accumulation of neoantigens and increased susceptibility to immune-mediated killing. However, this alone is often insufficient to trigger a strong immune response. STAR0602 complements this effect by selectively expanding T cells expressing specific TCR Vβ chains, particularly memory CD8+ populations, while avoiding the systemic toxicity typically associated with IL-2 therapies.

Preclinical models demonstrated that the combination induces significant tumor regression and improves survival compared to either treatment alone. This effect is driven by increased infiltration of activated T cells into the tumor microenvironment, alongside a reduction in immunosuppressive cell populations. Importantly, the response is not limited to a single antigen-specific clone. Instead, the therapy promotes antigen spreading, resulting in a polyclonal T-cell response capable of recognizing multiple tumor-associated antigens and neoepitopes (i.e. more targets).

Mechanistically, the antitumor effect depends on coordinated activity between CD8+ cytotoxic T cells, CD4+ helper T cells, natural killer cells, and interferon-γ signaling. Additionally, tumor-intrinsic TRAIL-R2 signaling plays a critical role, suggesting that the therapy enhances susceptibility to apoptosis via death receptor pathways. This finding introduces a potential biomarker for patient stratification and response prediction.

The expansion of stem-like progenitor exhausted CD8+ T cells further supports the durability of the immune response, as these cells are known to sustain long-term antitumor activity and respond to subsequent immunotherapies. This raises the possibility that such a combination could not only generate initial tumor control but also prime patients for additional treatments such as checkpoint blockade.

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