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Principal Investigator: Debra Auguste
Organization: NORTHEASTERN UNIVERSITY
Fiscal Year: 2022
Award: $200,000
Funding agency: National Cancer Institute
PROJECT SUMMARY
The research objective is to engineer a nanoparticle platform to bind cell receptors and inhibit cell signaling more
effectively than an antibody. To date, antibodies are universally employed as antagonists due to their high binding
affinity for their target cell receptor. However, their large size may be less effective in blocking multiple cell
surface receptors that organize as homodimers or colocalize within lipid rafts. We propose that peptide-
conjugated liposomes (PCLs) - at an optimal peptide density - may be more effective than FDA-approved
antibodies due to their ability to bind and inhibit receptor homodimers via optimal interpeptide spacings and
receptor monomers due to cooperative binding. This proposal will evaluate the role of liposome peptide density
and cell receptor organization on PCL binding and inhibition in vitro and pharmacokinetics and
pharmacodynamics in vivo. In contrast to other liposomal delivery systems that encapsulate and release drugs,
the biological activity of PCLs is due to the peptide density and diffusivity of the lipid bilayer. We have previously
demonstrated that an optimized PCL bound and inhibited the CXCR4 homodimer, reducing triple negative breast
cancer (TNBC) primary tumor growth and metastasis. In this proposal, we will apply PCLs to TNBC
immunotherapy. Immune checkpoint inhibitor (ICI) therapy is predicated on strong binding between antibodies
and their target receptor, inducing anti-tumor activity. Atezolizumab is FDA approved for use in TNBC to activate
the anti-tumor response but only extends progression free survival from 5.5 months with chemotherapy to 7.2
months with chemotherapy and ICI therapy. Further research is needed to improve anti-tumor immune activity
in TNBC. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is present primarily as a homodimer on cell
surfaces whereas programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) are monomeric,
which suggests that different peptide spacings may be necessary to achieve maximal binding and inhibition.
Thus, we will synthesize and characterize a series of PCLs that target PD-1 (L-PD1), PD-L1 (L-PDL1), and
CTLA-4 (L-CTLA4) with increasing peptide density (9k/µm2, 24k/µm2, 39k/µm2, 53k/µm2, and 74k/µm2). TNBC
and activated T cells will be measured for PD-1, PD-L1 or CTLA-4 expression, PCL-cell binding, and inhibition.
We will compare PCL biodistribution in an immune competent TNBC tumor mice model and mice depleted of
lymphocytes, neutrophils, or macrophages to assess how immune cells affect PCL tumor accumulation. PCL
anti-tumor activity will be measured by cytokine expression (aim 1) and changes in tumor immune cell infiltration
(aim 2) relative to the FDA-approved, ICI therapy (anti-PD-1 (pembrolizumab), anti-PD-L1 (atezolizumab), anti-
CTLA-4 (ipilimumab)). Our team’s combined expertise in drug delivery, TNBC mouse models, and tumor
immunology is sufficient to successfully complete this research. The outcomes of the proposed research include
identifying PCL peptide densities to target receptor homodimers (CTLA-4) and monomers (PD-1, PD-L1) and
induce anti-tumor activity in vivo due to strong, cooperative binding and inhibition.
Terms: <Active Sites><Affect><Affinity><AmB><AmBisome><Amphocil><Amphotec><Amphotercin B><Amphotericin B><Antibodies><Antitumor Response><B7-H1><B7H1><Binding><Biodistribution><Biological><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Breast Cancer Cell><Breast Cancer Model><Breast tumor model><CD152><CD152 Antigen><CD152 Gene><CD274><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><CXC-R4><CXCR-4><CXCR4><CXCR4 gene><Caelyx><Cancers><Cell Body><Cell Communication and Signaling><Cell Membrane Lipid Rafts><Cell Signaling><Cell Surface Receptors><Cell surface><Cells><Checkpoint inhibitor><Chemoresistance><Co-Stimulator><Costimulator><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><D2S201E><DOX SL><DOXSL><Diffuse><Doxilen><Doxorubicin HCl Liposome><Doxorubicin Hydrochloride Liposome><Drug Delivery><Drug Delivery Systems><Drugs><EGF Receptor><EGFR><ERBB Protein><Encapsulated><Engineering><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epidermal Thymocyte Activating Factor><Estrogen Receptors><Evacet><Exhibits><FB22><FDA approved><Fungizone><Future><HER1><HM89><HSY3RR><Human><IL-2><IL2 Protein><Immune><Immune Cell Activation><Immune checkpoint inhibitor><Immune infiltrates><Immunes><Immunocompetent><In Vitro><Infiltration><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Keytruda><LAP3><LCR1><LESTR><Lipid Bilayers><LipoDox><Liposomal><Liposomal Doxorubicin Hydrochloride><Liposomes><Lymphatic cell><Lymphocyte><Lymphocyte Mitogenic Factor><Lymphocytic><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Measures><Medication><Membrane Microdomains><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Mitogenic Factor><Modern Man><Molecular Interaction><Murine><Mus><Myocet><Mysteclin-F><Mφ><NPY3R><NPYR><NPYRL><NPYY3R><Neoplasm Metastasis><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outcome><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><PK/PD><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Primary Neoplasm><Primary Tumor><Progesterone Receptors><Progestin Receptors><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Progression-Free Survivals><Receptor Cell><Receptor Inhibition><Receptor Protein><Recurrence><Recurrent><Research><Research Project Summaries><Role><Secondary Neoplasm><Secondary Tumor><Series><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><System><T cell growth factor><T cell infiltration><T cell tumor trafficking><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><TGF-alpha Receptor><TNBC><Therapeutic Studies><Therapy Research><Thymocyte Stimulating Factor><Transforming Growth Factor alpha Receptor><Tumor Immunity><Tumor-infiltrating immune cells><Urogastrone Receptor><Yervoy><aPD-1><aPD-L1><aPD1><aPDL1><antagonist><anti programmed cell death 1><anti programmed cell death ligand 1><anti programmed cell death protein ligand 1><anti-PD-(L)1><anti-PD-1><anti-PD-L1><anti-PD1><anti-PDL-1><anti-PDL1><anti-cancer immunotherapy><anti-programmed cell death protein 1><anti-tumor immunity><anti-tumor response><antiPD-1><antiPD-L1><antiPD1><antiPDL1><anticancer immunotherapy><antitumor immunity><base><biologic><biological signal transduction><breast tumor cell><c-erbB-1><c-erbB-1 Protein><cancer immunity><cancer immunology><cancer immunotherapy><cancer metastasis><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><cytokine><cytotoxic T-lymphocyte antigen 4><density><doxil><drug biological activity><drug/agent><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><immune activation><immune cell infiltrate><immune check point><immune check point inhibitor><immune check point therapy><immune checkpoint><immune checkpoint therapy><immune competent><immune infiltration><immune-based cancer therapies><immunecheckpoint><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><intratumoral immune cell><ipilimumab><lipid bilayer membrane><lipid raft><liposomal delivery><liposome delivery><lymph cell><macrophage><malignancy><mammary cancer model><mammary tumor model><monomer><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm immunology><neoplasm/cancer><neutrophil><pembrolizumab><pharmacokinetics and pharmacodynamics><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein expression><proto-oncogene protein c-erbB-1><receptor><receptor binding><receptor bound><response><sle2><social role><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor immune cell><tumor immunology><αPD-1><αPD-L1><αPD1><αPDL1>