Unfortunately, as they form, cancers evolve means to hide from and locally dampen the immune system allowing them to thrive when they would otherwise be eliminated. A critical mechanism of cancer immune suppression is engagement of “immune checkpoint” receptors on T cells, the killer cells of the immune system necessary to eliminate cancer, by checkpoint ligands expressed by the tumor or its stroma. Antibodies which block these immune checkpoint receptors in the clinic can induce tumor regressions and even durable cures by denying tumors the capacity to inactivate the immune system. Blockade of one of these “immune checkpoint receptors”, PD-1, or its best-described ligand, PD-L1, has show...
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Unfortunately, as they form, cancers evolve means to hide from and locally dampen the immune system allowing them to thrive when they would otherwise be eliminated. A critical mechanism of cancer immune suppression is engagement of “immune checkpoint” receptors on T cells, the killer cells of the immune system necessary to eliminate cancer, by checkpoint ligands expressed by the tumor or its stroma. Antibodies which block these immune checkpoint receptors in the clinic can induce tumor regressions and even durable cures by denying tumors the capacity to inactivate the immune system. Blockade of one of these “immune checkpoint receptors”, PD-1, or its best-described ligand, PD-L1, has shown promise in treating dozens of types of cancer and led to numerous FDA approvals. We and others have recently discovered a previously unappreciated importance of the other PD-1 ligand, PD-L2, in supporting the growth of many types of human cancer including some which respond poorly to existing therapies. Efforts to develop therapeutic antibodies targeting PD-L2, however, have been stymied by a lack of biologic understanding of its expression and function in both human cancer and pre-clinical models. This proposal will address critical questions in PD-L2 immunobiology including whether it functions only as a T cell co-inhibitory/checkpoint ligand or can also function as an activating co-stimulatory molecule. Also, we will pursue our novel preliminary data showing not only that PD-L1 and PD-L2 induce functionally disparate downstream signaling in T cells via PD-1 receptor binding, but that they can also heterodimerize. Finally, we have generated novel, fully human antibodies which bind to mouse, cyno and human PD-L2 and block it’s binding to PD-1. Using models of solid and hematologic tumors, we will determine the therapeutic potential and underlying mechanism of these PD-L2 antibodies with and without cytotoxic effector function.
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