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Treatment with poxvirus-based active immunotherapies shows evidence of robust immune responses against a variety of tumor-associated antigens in preclinical and clinical studies. Poxvirus-based immunotherapies in development include PSA-targeted PROSTVAC, now in Phase 3 clinical development; CV-301 (targeting CEA and MUC-1); as well as MVA-BN-HER2 and MVA-BN-Brachyury (targeting HER-2 and the transcription factor Brachyury, respectively). Evidence of robust and productive anti-tumor efficacy in preclinical models was accompanied by treatment-emergent infiltration of tumors by activated cytotoxic CD8 T cells producing high amounts of IFNγ. Treatment with immune checkpoint inhibitors such as anti-PD-1 antibodies is showing significant clinical benefit by re-activating dormant tumor-specific T cells. Furthermore, preclinical studies have shown further synergistic efficacy by combining PD-1 blockade with inhibition of LAG-3, which acts independently of PD-1 to modulate T cell function. We hypothesized that poxvirus-based active immunotherapy may provide even greater improvements to patient outcome when used in combination with immune checkpoint blockade, by inducing new productive tumor-specific responses. This may be especially important in patients lacking an endogenous T cell response against their tumors. In therapeutic CT26-HER2 solid and metastatic tumor models, mice were administered MVA-BN-HER2 immunotherapy alone or in combination with anti-PD-1 and/or anti-LAG-3 antibodies. Synergistic benefit for anti-tumor efficacy was observed when combining MVA-BN-HER2 immunotherapy with anti-PD-1 alone, while combination with anti-LAG-3 alone had little effect. Notably, a further enhancement occurred when MVA-BN-HER2 immunotherapy was combined with PD-1 and LAG-3 blockade as shown by complete tumor regression in 20/20 mice. Subsequent rejection of HER-2 negative tumors 6 months after the original challenge revealed that immune responses were durable and included antigen spread to additional tumor antigens. Flow cytometric analysis demonstrated that tumor infiltrating lymphocytes (TILs) in untreated tumors were PD-1hi and LAG-3+, a more exhausted phenotype. Poxvirus-based immunotherapy led to the induction of activated TILs characterized by low to mid-levels of PD-1 expression. While PD-1 blockade prevented binding to PD-L1 it also caused an increase in LAG-3 expression on T cells. Together these data provide further rationale for why combination therapy of poxvirus-based immunotherapy with inhibition of PD-1 plus LAG-3 resulted in synergistic efficacy in preclinical tumor models. Overall these data demonstrate that combining complementary immune-based therapies such as poxvirus-based active immunotherapy and PD-1 plus LAG-3 immune checkpoint blockade result in synergistic anti-tumor efficacy. Citation Format: Barbara Sennino, Susan P. Foy, Ryan B. Rountree, Tracy dela Cruz, Evan J. Gordon, Veronica Xavier, Felicia Kemp, Alex Franzusoff, James Breitmeyer, Stefanie J. Mandl. Poxvirus-based active immunotherapy synergizes with PD-1 plus LAG-3 immune checkpoint inhibition to enhance antitumor efficacy in preclinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-234. doi:10.1158/1538-7445.AM2015-LB-234