Vasoactive Intestinal Peptide (VIP)

Vasoactive Intestinal Peptide (VIP)

Vasoactive Intestinal Peptide (VIP) is a 28 amino acid neuropeptide secreted by the gastrointestinal tract, neural terminals, as well as by a variety of immune cells of both myeloid and lymphoid lineages. VIP bound to VPAC1 and VPAC2 receptors on white blood cells induces immunosuppression. The founder’s laboratory has successfully demonstrated that inhibition of VIP signalling by competitive binding of VIP antagonist peptides to the VIP receptor leads to immune activation. In fact, several hundred VIP signal inhibitory peptides have been screened, some of which potently disrupt VIP signalling and activate T cell proliferation. These nonclinical data support the development of small molecule drugs targeting the VIP receptor that generate robust T cell responses to treat a variety of cancers that are not responsive to current immune therapies.

Cambium Oncology has generated a substantial amount of data showing that VIP is overexpressed in many human cancers including pancreatic cancer, colon cancer, pheochromocytoma, and glioma, with, pancreatic cancer having the highest level of expression. Several publications with robust proof-of-concept results from multiple mouse tumor models including melanoma, myeloid leukemia, lymphoma, and pancreatic cancer, demonstrated that once-daily treatment of tumor-bearing animals with VIP antagonist peptide(s) induce a T-cell-dependent, long-lasting anti-cancer response in vivo. In more recent studies, Waller’s group have taken a combinatorial approach of treating pancreatic cancer bearing animals with VIP antagonist peptides along with anti-PD1 antibodies. Production of VIP in the vicinity of pancreatic tumor generate an immunosuppressive microenvironment, thus preventing the migration and activation of T cells that are needed for anti-tumor immunity. Treating mice with pre-established pancreatic tumors with the VIP antagonist drug leads to increased T cell infiltration into the tumor and is synergistic in controlling tumor growth when combined with anti-PD1 antibodies. In addition, the animals undergoing combinatorial immunotherapy exhibited maximum tumor shrinkage and increased survival time compared to any other treatment group. Toxicity of one of the VIP antagonistic peptide, VIP-hyb that stimulated potent T cell activation in vitro and anti-tumor immunity in vivo, was evaluated in normal mice. Blood tests of hematopoietic, renal and hepatic function and histopathological studies of all major organs following a single high dose of the peptide showed no clinical or anatomic pathology and no evidence for auto-immunity in any of the tested animals, supporting the safety of functionally active VIP antagonistic peptide.