Establishment of Immunotherapy as the Fourth Pillar of Cancer Treatment

Major advances have been made in the immune-based therapy of cancer by antibody blockade of immune inhibitory pathways such as CTLA-4 and PD-1. Anti-PD-1 antibodies have produced objective responses in one third to one half of patients with advanced, chemotherapy refractory melanoma and renal cancer and one quarter of patients with non-small cell lung cancer. These responses are highly durable, the majority lasting significantly greater than one year and beyond cessation of therapy. Further, expression by tumor cells of ligands for PD-1 is associated with higher response to anti-PD-1 therapy. In exploring the basis for up-regulation of the major PD-1 ligand, PD-L1, on tumor cells, we found that its expression is not constitutive, but rather, is highly associated with lymphocytic infiltration. We identified IFN-g as an immune signal sensed by the tumor cell that induces PD-L1 expression. In addition to IFN-g, genes associated with Th1 responses, CTL responses and other inhibitory molecules, such as LAG-3, are up-regulated in lymphocytic infiltrates associated with PD-L1+ tumor cells. These findings indicate that multiple counterbalancing immune effector and inhibitory pathways are operative in the immune microenvironment. They led us to hypothesize a new mechanism of PD-L1 expression in tumors, termed adaptive resistance, distinct from a constitutive mechanism of PD-L1 expression in tumors. The adaptive resistance mechanism implies that other therapies such as vaccines may induce antitumor responses that in turn induce up-regulation of PD-L1. In such a circumstance, vaccination and PD-L1 blockade might produce synergistic anti-tumor activity. Using a novel vaccine formulation termed STINGVAX, we indeed demonstrate IFN-g dependent induction of PD-L1 on tumors and synergistic activity such that the vaccine/anti-PD-1 combination.