Using mice with HER2-overexpressing tumors, Li et al. demonstrate that an anti-HER2/CD3 bispecific antibody converts the tumor phenotype from poorly infiltrated to inflamed by inducing intratumoral CD8+ T cell proliferation and recruiting CD8+ T cells to the tumor, with the latter being the dominant mechanism and required for antitumor effect. The treatment led to rapid upregulation of IFNγ, which in turn triggered expression of CXCR3 on T cells and production of CXCR3 ligands (CXCL-9, -10, -11) by undetermined cells within the tumor, thereby increasing intratumoral T cell infiltration.
PURPOSE: The response to cancer immune therapy is dependent on endogenous tumor reactive T cells. To bypass this requirement, CD3-bispecific antibodies have been developed to induce a polyclonal T cell response against the tumor. Anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody is highly efficacious in the treatment of HER2 over-expressing tumors in mice. Efficacy and immunological effects of anti-HER2/CD3 TDB were investigated in a mammary tumor model with very few T cells prior treatment. We further describe the mechanism for TDB-induced T cell recruitment to tumors. EXPERIMENTAL DESIGN: Immunological effects and mechanism of CD3-bispecific antibody-induced T cell recruitment into spontaneous HER2 over-expressing mammary tumors was studied using human HER2 transgenic, immune-competent mouse models. RESULTS: Anti-HER2/CD3 TDB treatment induced an inflammatory response in tumors converting them from poorly infiltrated to an inflamed, T cell abundant, phenotype. Multiple mechanisms accounted for the TDB-induced increase in T cells within tumors. TDB treatment induced CD8(+) T cell proliferation. T cells were also actively recruited post-TDB treatment by IFN-g-dependent T cell chemokines mediated via CXCR3. This active T cell recruitment by TDB-induced chemokine signaling was the dominant mechanism and necessary for the therapeutic activity of anti-HER2/CD3 TDB. CONCLUSIONS: In summary, we demonstrate that the activity of anti-HER2/CD3 TDB was not dependent on high level baseline T cell infiltration. Our results suggest that anti-HER2/CD3 TDB may be efficacious in patients and indications that respond poorly to checkpoint inhibitors. An active T cell recruitment mediated by TDB-induced chemokine signaling was the major mechanism for T cell recruitment.