Research Project
9777195
Immunoactivating Peptide AXT201 in Combination with Anti-PD-1 Antibody for Triple-Negative Breast Cancer Niranjan B. Pandey, Ph.D. ? PI Jordan J. Green Ph.D. ? Co-I Aleksander S. Popel, Ph.D. ? PI of subcontract Project Summary: Immunotherapies are showing remarkable promise for treating various cancers. Although many patients with different kinds of cancers are benefiting from these treatments, they appear to have hit a ceiling of benefit of 30-40% for some cancers and even lower ceilings for others. Strategies for increasing the efficacy of these very promising therapies are thus badly needed. Tumors have devised many ways to limit the immune system?s ability to destroy them. VEGFR2 activation and Tie2 suppression are two key mechanisms that tumors use for this purpose. These two pathways provide the tumors with a high vascular density but with vessels that are tortuous and leaky. As a result killer T cells, chemotherapies, and immunotherapies do not perfuse deep into the tumor. These two pathways also directly increase suppression of the immune system so that by inhibiting dendritic cell maturation, T-cell proliferation, and increasing the number of regulatory T cells. We have identified the remarkable peptide AXT201 that simultaneously inhibits VEGFR2 signaling and activates Tie2 signaling thus inhibiting angiogenesis and promoting anti-tumor immunity. AXT201 could thus substantially increase the ceiling of efficacy of immunotherapies. Here we propose to determine the time required for AXT201 to normalize the vasculature and activate the immune system in syngeneic tumor models in mice after initiation of treatment. Once we establish the optimal window in which these effects occur, we will test combinations of AXT201 with anti-PD-1 antibodies in syngeneic models of triple negative breast cancer. If the studies proposed here are successful, we will test combinations of AXT201 with other checkpoint inhibitors in these same tumor models. Vascular normalization and activation of anti-tumor immunity are general mechanisms that should result in enhancement of efficacy of many different types of checkpoint inhibitors. Also as these general mechanisms are relevant to multiple tumor types because all tumors promote angiogenesis and suppress the immune system, a combination of AXT201 and immunotherapies could be used to treat many different cancer types.
