Combinatorial cancer immunotherapy strategies with proapoptotic small-molecule IAP antagonists

Members of the inhibitor of apoptosis (IAP) family control several critical aspects of innate immunity, cell death, and tumorigenesis. Small molecule antagonists that target specific IAP oncoproteins, primarily cIAP1 and cIAP2, but potentially also XIAP and Livin, modulate distinct immune signal transduction pathways that can lead to an increased sensitivity of tumors cells to cytokine-mediated apoptosis. These antagonists are based on the structure of an endogenous cellular IAP inhibitor called Smac. Smac is normally sequestered within the mitochondria and is released into the cytoplasm upon cell death stimuli, thereby overcoming the anti-apoptotic action of the IAPs. The therapeutic usefulness of recombinant tumoricidal cytokines to treat cancer patients is principally limited due to their unacceptable adverse side effects. Therefore, investigators have sought to develop alternative regimens that do not rely on exogenously delivered death ligands. These approaches include the stimulation of the immune system with oncolytic virus-based agents or Toll-like receptor agonists in combination with Smac mimetics. Similarly, preclinical combination immunotherapy studies reveal that recombinant interferon synergizes with Smac mimetics to kill cancer. This strategy opens up new therapeutic avenues for anti-cancer therapy by modulating specific immune-mediated death pathways employing unique dual-pronged combinatorial approaches.