Ma et al. demonstrate that combining a GM-CSF-secreting, whole tumor cell vaccine with anti-PD-1 and agonistic CD40 antibody (agCD40) led to complete tumor control with effective memory in a PANC2 tumor and moderate control in a tolerant HER-2/neu tumor model. The vaccine was critical to T cell infiltration. Mechanistically, both models depended on CD8+ T cells, but CD4+ T cells were more important in the PANC2 model, and triple therapy promoted a less exhausted phenotype. AgCD40 upregulated T cell activation, promoted increases in CD11c+CD103+ DCs and M1 macrophage polarization, and reduced granulocytic MDSCs.

In cancers with tumor infiltrating lymphocytes (TIL), monoclonal antibodies (mAbs) that block immune checkpoints such as CTLA-4 and PD-1/PD-L1 promote antitumor T cell immunity. Unfortunately most cancers fail to respond to single agent immunotherapies. T regulatory cells, myeloid derived suppressor cells (MDSCs), and extensive stromal networks within the tumor microenvironment (TME) dampen antitumor immune responses by preventing T-cell infiltration and/or activation. Few studies have explored combinations of immune checkpoint antibodies that target multiple suppressive cell populations within the TME, and fewer have studied the combinations of both agonist and antagonist mAbs on changes within the TME. Here we test the hypothesis that combining a T cell-inducing vaccine with both a PD-1 antagonist and CD40 agonist mAbs (triple therapy) will induce T cell priming and TIL activation in mouse models of non-immunogenic solid malignancies. In an orthotopic breast cancer model and both subcutaneous and metastatic pancreatic cancer mouse models, only triple therapy was able to eradicate most tumors. The survival benefit was accompanied by significant tumor infiltration of IFNgamma-, Granzyme B-, and TNFalpha-secreting effector T cells. Further characterization of immune populations was carried out by high dimensional flow cytometric clustering analysis and visualized by t-distributed stochastic neighbor embedding (t-SNE). Triple therapy also resulted in increased infiltration of dendritic cells, maturation of antigen presenting cells, and a significant decrease in granulocytic MDSCs. These studies reveal that combination CD40 agonist and PD-1 antagonist mAbs reprogram immune resistant tumors in favor of antitumor immunity.

Author Info: (1) Oncology, Johns Hopkins University. (2) Johns Hopkins University. (3) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. (4) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney

Author Info: (1) Oncology, Johns Hopkins University. (2) Johns Hopkins University. (3) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. (4) Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. (5) Oncology, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. (6) Oncology, Johns Hopkins University. (7) Oncology, Johns Hopkins University. (8) Oncology, Johns Hopkins University. (9) Oncology, Johns Hopkins University. (10) Translational Research, Benaroya Research Institute at Virginia Mason. (11) Department of Oncology, Division of Gastrointestinal Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. (12) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University ejaffee@jhmi.edu.

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