Immunoactivating Peptide AXT201 in Combination with Anti-PD-1 Antibody for Triple-Negative Breast Cancer

Immunoactivating Peptide AXTin Combination with Anti PDAntibody for Triple Negative Breast CancerNiranjan BPandeyPh DPIJordan JGreen Ph DCo I Aleksander SPopelPh DPI of subcontract Project SummaryImmunotherapies are showing remarkable promise for treating various cancersAlthough many patients with different kinds of cancers are benefiting from these treatmentsthey appear to have hit a ceiling of benefit offor some cancers and even lower ceilings for othersStrategies for increasing the efficacy of these very promising therapies are thus badly neededTumors have devised many ways to limit the immune system s ability to destroy themVEGFRactivation and Tiesuppression are two key mechanisms that tumors use for this purposeThese two pathways provide the tumors with a high vascular density but with vessels that are tortuous and leakyAs a result killer T cellschemotherapiesand immunotherapies do not perfuse deep into the tumorThese two pathways also directly increase suppression of the immune system so that by inhibiting dendritic cell maturationT cell proliferationand increasing the number of regulatory T cellsWe have identified the remarkable peptide AXTthat simultaneously inhibits VEGFRsignaling and activates Tiesignaling thus inhibiting angiogenesis and promoting anti tumor immunityAXTcould thus substantially increase the ceiling of efficacy of immunotherapiesHere we propose to determine the time required for AXTto normalize the vasculature and activate the immune system in syngeneic tumor models in mice after initiation of treatmentOnce we establish the optimal window in which these effects occurwe will test combinations of AXTwith anti PDantibodies in syngeneic models of triple negative breast cancerIf the studies proposed here are successfulwe will test combinations of AXTwith other checkpoint inhibitors in these same tumor modelsVascular normalization and activation of anti tumor immunity are general mechanisms that should result in enhancement of efficacy of many different types of checkpoint inhibitorsAlso as these general mechanisms are relevant to multiple tumor types because all tumors promote angiogenesis and suppress the immune systema combination of AXTand immunotherapies could be used to treat many different cancer types Project NarrativeTumors are versatile and one of the ways they survive is by suppressing the immune systemAlso immune cells and drugs do not penetrate deep into the tumor because of the abnormalleaky tumor vasculatureImmunotherapies are promising for treating triple negative breast cancer but they only help a minority of patientsIn this project we propose to test our promising anti angiogenicimmunoactivatingmultifunctional therapeutic peptide AXTto determine the time frame in which it normalizes the vasculature and activates the immune system in mice with a breast tumorFollowing that we will test a combination of an immunotherapy with our peptide to determine if our peptide enhances the efficacy of the immunotherapy