Acute Myeloid Leukemia (AML)
Acute Myeloid Leukemia (AML)
Initial Clinical Target
Treating Acute Myeloid Leukemia (AML) and other hematologic malignancies using novel peptide antagonists to VIP
Promising results generated from the laboratory of the founders demonstrated that VIP antagonistic peptides possess anti-tumor activity against hematopoietic malignancies like AML and acute T lymphoblastic leukemia (ALL). In a series of published studies, Waller and his team have demonstrated that daily administration of one of the previously characterized VIP antagonist peptide known as VIPhyb significantly enhanced survival of leukemia-bearing transplant recipients via a CD8+ T cell dependent GvL (graft versus leukemia) effect without increased GvHD in a mouse models of allogeneic bone marrow transplantation (Allo-BMT). Thus, blocking of VIP signal by its antagonist peptide represents a new type of pharmacologic agents that are able to differentiate between GvL from GvHD and enhance adaptive T cell response against leukemia-associated antigens following allo-BMT.
The ability of VIP antagonist peptide, VIPHyb to elicit a potent anti-tumor specific immune response in mice opened the possibility of testing some of the other inhibitory peptides against VIP that were designed and synthesized in the founders’ laboratory. One of the lead peptides VIP-ANT008, which has demonstrated strong anti-tumor immunity in combination with anti-PD1 antibody in pancreatic tumor, was tested in a syngeneic leukemia model in mice. To determine if VIP-ANT008, when used as a monotherapy, is able to trigger a strong anti-tumor specific immunity in syngeneic animals, we used C1498 cell injected AML tumor model developed in B6 mice. In the first study, subcutaneous administration of VIP-Hyb for a period of seven consecutive days resulted in a significantly increased survival in comparison to vehicle treated group of mice. These data highlight the fact that blocking of VIP pathway by peptide antagonist can be novel way to treat hematological malignancies like AML. The adoptive transfer of T cells from VIP-Hyb treated surviving mice to naïve animals induced protection against C1498 challenge confirm that VIP-Hyb treatment alone could trigger a robust anti-tumor immune response in mice. To further develop the POC studies against AML the founders decided to conduct experiments to determine the anti-tumor immunity potential of VIP-ANT008 peptide in C1498 tumor–bearing mice. Repeated administration of VIP-ANT008 alone clearly extended the survival time significantly compared to the control animals, and extent of the protection was similar to that of VIPHyb peptide.
Additional experiments are currently underway to measure the magnitude of anti-tumor immunity offered by the newly synthesized VIP-ANT008 peptide. The discovery program is in the process of selecting the best VIP-antagonist (VIP-ANT) peptide sequences that can be used alone or in combination with other chemotherapy and immunotherapy approaches to treat both solid (e.g., pancreatic cancer) and “liquid tumors” or blood cancer (e.g., AML).