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Consistent with this hypothesis, comprehensive and durable tumor regression was observed in 100% of mice treated with this triple combination therapy . Strikingly, tumors were observed to grow in size following initiation of the combination therapy, yet regressed completely upon the second administration two weeks after the first dose . The complete efficacy of triple combination therapy was greater than anti-PD-1 and anti-LAG-3 immune checkpoint blockade or MVA-BN-HER2 immunotherapy plus anti-PD-1 or MVA-BN-HER2 immunotherapy plus LAG-3 blockade . Mice that rejected their tumor after any treatment remained tumor-free more than 5 months after the initial tumor challenge .

Indeed, strong therapeutic synergy was still seen at doses where PD-1 blockade alone showed no effect on tumor growth. This suggests, that at low doses PD-1 blockade is acting to further enhance a functional immune response driven by the poxvirus-based immunotherapy. In contrast, PD-1 blockade alone had little therapeutic benefit with decreasing doses. This could be due to the lack of an endogenous immune response as demonstrated by overall lower numbers of CD8 T cell in the tumor. In mice treated with any combination of immune checkpoint inhibitors (anti-PD-1, anti-LAG-3, or anti-PD-1 and anti-LAG-3) but not MVA-BN-HER2, 64% (9/14) grew palpable tumors and 79% (11/14) rejected the re-challenge.

These findings agree with previous work showing that vaccination with vaccinia virus elevates intracellular LAG-3 expression in CD8 T cells . Furthermore, they highlight the need to address multiple compensatory immune responses for immunotherapy with immune checkpoint inhibitors, since full therapeutic benefit occurred only when poxvirus-based immunotherapy was combined with dual PD-1 and LAG-3 blockade. CD8 T cells that express LAG-3 can still produce effector cytokines, and cells that co-express mid-levels kryptovaluta of PD-1 and high levels of LAG-3 are more functional and produce more IFNγ, TNFα, and CD107 than cells that are PD-1hi or cells that co-express PD-1low and LAG-3 . However, though functional, the proliferative capacity of LAG-3+ T cells may be limited, as LAG-3 negatively regulates cell cycle progression of CD8 T cells . Thus, one role of LAG-3 blockade may be to increase proliferation of the antigen-specific CD8 TILs, while PD-1 blockade prevents T cell death or anergy through tumor cell PD-L1 ligation.

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There appear to be two mechanisms for PD-L1 up-regulation in tumors—innate and adaptive resistance. Innate resistance is driven by aberrant oncogenic signaling pathways and results in tumor cells that constitutively express PD-L1 . In contrast, adaptive resistance occurs in response to IFNγ produced by tumor-infiltrating T cells provoking PD-L1 upregulation on cells in the tumor microenvironment . PD-1 axis blockade confers significant clinical benefit, especially for patients with a pre-existing T cell-inflamed tumor microenvironment characterized by CD8+ and PD-1/PD-L1+ cells .

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Synergistic benefit of anti-tumor therapy was observed when MVA-BN-HER2 immunotherapy was combined with PD-1 immune checkpoint blockade. Interestingly, PD-1 blockade stimulated a second immune checkpoint molecule, LAG-3, to be expressed on T cells. Combining MVA-BN-HER2 immunotherapy with dual PD-1 plus LAG-3 blockade resulted in comprehensive tumor regression in all mice treated with the triple combination therapy.

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A triple therapy consisting of MVA-BN-HER2 poxvirus therapy, plus anti-PD-1 and anti-LAG-3 dual checkpoint inhibition was explored for optimizing therapeutic efficacy and to assess the durability of responses in mouse models. Beyond the PD-1/PD-L1 axis of immune suppression pathways, LAG-3 expression has also been shown to impact T cell mediated anti-tumor immune responses. Analysis of intratumoral LAG-3 expression by immunofluorescent microscopy demonstrated that LAG-3 expression co-localized with both CD8+ CD4+ T cells . Furthermore, the LAG-3 expression profile and the degree of T cell infiltration in tumors was influenced by the treatment regimen . LAG-3 expression was slightly but significantly increased by MVA-BN-HER2 immunotherapy as compared to control treated tumors. Importantly, the infiltrating CD8 T cells were detected throughout the tumor with MVA-BN-HER2 treatment .