Research Article: Docetaxel enhances V?-directed T-cell activation and antitumor immunity mediated by a bifunctional TCR agonist in breast and prostate cancer models
Abstract:
STAR0602 is a selective bifunctional T cell agonist targeting V?6/V?10 T-cell receptors fused to interleukin-2, with emerging clinical activity in anti-PDL1–resistant tumors. Its murine surrogate, mSTAR1302, expands V?13 T cells and mediates antitumor activity. Docetaxel, beyond its cytotoxic effects, induces immunogenic modulation of tumor cells. We hypothesized that docetaxel-driven tumor sensitization would enhance susceptibility to immune-mediated killing, while mSTAR1302 would expand functional T cell subsets, resulting in coordinated antitumor responses.
The therapeutic efficacy and mechanism of action of docetaxel and mSTAR1302 combination therapy were evaluated in 4T1 triple-negative breast cancer and TRAMP-C2 prostate cancer models. Immune profiling, functional assays, and CRISPR-mediated gene knockdown were used to define mechanisms of response.
Combination therapy significantly reduced tumor burden and improved survival compared to monotherapies in both models. Docetaxel induced immunogenic modulation characterized by upregulation of MHCI, FAS, and TRAIL-R2, enhancing tumor susceptibility to immune-mediated lysis. Mechanistically, TRAIL-R2 expression contributed substantially to antitumor activity, as knockdown attenuated therapeutic efficacy. mSTAR1302 expanded V?13+ CD4+ and CD8+ tumor-infiltrating lymphocytes and promoted antigen-specific T cell responses. Depletion studies demonstrated that CD4+ T, CD8+ T, and NK cells collectively mediated the antitumor effects of combination therapy.
These findings identify a mechanistic axis in which docetaxel-induced tumor sensitization via TRAIL-R2 cooperates with V?-targeted T cell expansion to drive coordinated immune-mediated tumor regression. This work supports the clinical evaluation of STAR0602 in combination with chemotherapy and highlights TRAIL-R2–mediated tumor sensitization as a mechanistically defined strategy to enhance immunotherapy efficacy in immune-excluded tumors.
Introduction:
STAR0602 is a selective bifunctional T cell agonist targeting V?6/V?10 T-cell receptors fused to interleukin-2, with emerging clinical activity in anti-PDL1–resistant tumors. Its murine surrogate, mSTAR1302, expands V?13 T cells and mediates antitumor activity. Docetaxel, beyond its cytotoxic effects, induces immunogenic modulation of tumor cells. We hypothesized that docetaxel-driven tumor sensitization would enhance susceptibility to immune-mediated killing, while mSTAR1302 would expand functional T cell…
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