CD3 bispecific antibody (CD3 bsAb) therapy is clinically approved for refractory hematological malignancies, but responses in solid tumors have been limited so far. One of the main hurdles in solid tumors is the lack of sufficient T-cell infiltrate. Here, we show that pre-treatment vaccinations, even when they comprised tumor-unrelated antigens, induced CXCR3-mediated T-cell influx in immunologically ‘cold’ mouse tumor models. In the absence of CD3 bsAb, the infiltrate was mainly confined to the tumor invasive margin, however subsequent CD3 bsAb administration induced profound infiltration of activated effector CD8 T cells into the tumor cell nests. This combination therapy installed a broadly inflamed Th1-type tumor microenvironment, resulting in effective tumor eradication. Interestingly, multiple vaccination strategies, including synthetic long peptides, viruses and COVID-19 mRNA, empowered CD3 bsAb therapy. Our results imply that eliciting tumor infiltration with vaccine-induced tumor non-specific T cells can greatly improve the efficacy of CD3 bsAbs in solid tumors.
