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Background STAR0602 is a novel bi-functional T-cell engager comprised of an antibody targeted to Vβ6/Vβ10 T-cell receptors conjugated to interleukin-2 that is currently being evaluated in clinical trials. The murine surrogate of STAR0602, mSTAR1302, targets Vβ13 in mice and shows antitumor monotherapy activity against several in vivo preclinical cancer models. Docetaxel, a commonly prescribed chemotherapeutic for the treatment of breast, prostate, and lung cancers, is known for its cytotoxic effects in addition to its ability to induce immunogenic modulation, i.e., the phenotypic changes that make tumor cells more targetable by immunotherapies. We hypothesized that combining mSTAR1302 with docetaxel will lead to an increase in anti-tumor activity in in vivo models.Methods To investigate docetaxel-induced immunogenic modulation and cell lysis, 4T1 (triple-negative breast cancer) and TRAMP-C2 (castration resistant prostate cancer) murine cell lines were treated with 250nM of docetaxel for 48 hours. To test the antitumor efficacy of combining docetaxel and mSTAR1302 in vivo, female Balb/c mice and male C57bl/6 mice were inoculated subcutaneously with 4T1 cells in the mammary fat pad and TRAMP-C2 cells on the flank, respectively. mSTAR1302 (1mg/kg) was administered once per week for 3 weeks, and docetaxel (500µg) in 3 doses, every other day, for 1 week. Tumors, spleens and lungs were harvested, processed and used for flow cytometry, ELISPOT, Immunofluorescence staining, RNA analysis, or cell culture.Results Docetaxel pre-treatment in 4T1 and TRAMP-C2 led to a functional increase in FAS and TRAIL-R2 death receptors as well as NK mediated cell lysis. Combination therapy significantly decreased tumor volumes and increased the survival of 4T1 and TRAMP-C2 tumor-bearing mice. Development of 4T1 lung metastases were inhibited most significantly with mSTAR1302 and docetaxel co-treatment. In addition, the combination therapy increased tumor-infiltrating lymphocytes (TILS) in the 4T1 primary lesions, specifically VB13+CD8+ T-cells. Anti-tumor activity was strongly dependent on CD8, CD4, and NK cell and was completely abrogated upon concurrent depletions. Furthermore, the expression of TRAIL-R2 and FAS, as well as TRAIL and FAS ligands, were upregulated in 4T1 tumor-bearing mice receiving mSTAR1302 and docetaxel co-treatment. Lastly, combination treatment led to a significant increase in AH1 antigen-specific T-cells in the 4T1 model.Conclusions Here, we show that combining mSTAR1302 with docetaxel resulted in enhanced anti-tumor activity compared to either single agent alone showing an increased efficacy in cold tumor models such as 4T1 and TRAMP-C2. This data provides groundwork for the clinical development of docetaxel and STAR0602 as a combination therapy.