Τετάρτη 27 Ιουνίου 2018

IFN-{gamma}-induced chemokines are required for CXCR3-mediated T cell recruitment and anti-tumor efficacy of anti-HER2/CD3 bispecific antibody

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.



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