SBIR-STTR Award

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.

Public Health Relevance Statement:


Project narrative:
Tumors are versatile and one of the ways they survive is by suppressing the immune system. Also immune cells and drugs do not penetrate deep into the tumor because of the abnormal, leaky tumor vasculature. Immunotherapies are promising for treating triple-negative breast cancer but they only help a minority of patients. In this project we propose to test our promising anti-angiogenic, immunoactivating, multifunctional therapeutic peptide AXT201 to determine the time frame in which it normalizes the vasculature and activates the immune system in mice with a breast tumor. Following that we will test a combination of an immunotherapy with our peptide to determine if our peptide enhances the efficacy of the immunotherapy.

Project Terms:
4T1; Aftercare; angiogenesis; Angiopoietin-2; anti-PD-1; anti-PD-L1; anti-PD1 antibodies; Antibodies; Antigen Presentation; Biological; Biomimetics; Blood Vessels; cancer cell; cancer immunotherapy; Cancer Patient; cancer therapy; cancer type; Case Study; cell killing; Cell Maturation; Cells; chemotherapy; Clinical Trials; Combination immunotherapy; Cytotoxic T-Lymphocytes; Dendritic Cells; density; design; Doctor of Philosophy; Drug Targeting; Endothelial Cells; Environment; Extravasation; FDA approved; Growth; IGF1R gene; Immune; immune activation; Immune checkpoint inhibitor; Immune system; Immunooncology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Intercellular Junctions; Jordan; KDR gene; Lymphangiogenesis; malignant breast neoplasm; Malignant Neoplasms; Mammary Neoplasms; melanoma; Minority; Modeling; Molecular Target; mouse model; Mus; Nivolumab; Non-Small-Cell Lung Carcinoma; orthotopic breast cancer; pancreatic cancer patients; Pathway interactions; Patients; PDCD1LG1 gene; PDGFRB gene; Penetration; peptide drug; Peptides; Perfusion; Pharmaceutical Preparations; prevent; receptor; Receptor Protein-Tyrosine Kinases; Regulatory T-Lymphocyte; response; Signal Transduction; SLEB2 gene; System; T-Cell Proliferation; T-Lymphocyte; Testing; TIE-2 Receptor; Time; triple-negative invasive breast carcinoma; tumor; Tumor Immunity; tumorigenic; Vascular Endothelial Growth