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Principal Investigator: Nicole Franziska Steinmetz
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $354,119
Funding agency: National Cancer Institute
Summary
This R01 renewal application is focused on triple negative breast cancer (TNBC), which is an aggressive life-
threatening disease with poor prognosis and increased likelihood of recurrence and distant metastasis.
Advances in cancer immunotherapy have demonstrated that modulation of the patient’s immune system can
result in dramatic antitumor activity. The most promising immunotherapy approaches are those that are
personalized and take advantage of the unique neoantigens within each patient’s tumor. Toward this goal, we
developed a plant virus nanoparticle immunotherapy approach that activates innate immune cells within
the tumor microenvironment (TME) to launch adaptive, systemic, and durable antitumor immunity.
Specifically, intratumorally injected cowpea mosaic virus (CPMV) demonstrates potent efficacy in multiple mouse
models, incl. TNBC. Trials in companion dogs with breast cancer also demonstrate potent antitumor efficacy.
During the previous funding cycle, we gained insights into the mechanism of action and demonstrated that
CPMV is recognized by pathogen-associated molecular pattern (PAMP) receptors that detect danger signals
and activate the innate immune system; specifically, CPMV is recognized by Toll-like receptors (TLR2, 4 and 7).
Further, we developed and tested combination and dual-pronged treatment approaches: we demonstrated
efficacy of CPMV as solo-treatment as well as in combination with radiation, chemotherapy, immunomodulatory
drugs, and checkpoint inhibitors, amongst others. This proposal builds on this strong portfolio of data. Our first
goal is to focus on dual-pronged CPMV that combines its immunomodulatory and antitumor immunity properties
with checkpoint therapy (Aim 1). Checkpoint blocking antibodies are effective at removing inhibitory signals but
as monotherapy have variable and limited efficacy. In situ vaccination with CPMV increases tumor antigen
specific effector T cells and our preliminary data indicate that CPMV treatment synergizes with immune
checkpoint therapy. Next, we seek to develop targeted approaches that effectively concentrate systemically
administered CPMV in tumors and provide further therapy options to treat metastatic disease (Aim 2). S100A9-
targeted CPMV will be studied: expression of S100A9 (also known as myeloid-related protein 14 [MRP-14]), is
linked to inflammation and carcinogenesis. Higher S100A9 expression in breast cancer correlates with a worse
prognosis. S100A9 expression is an early event in tumorigenesis, enhancing tumor aggressiveness and
metastasis. In the TME, S100A9 is secreted to the extracellular matrix, making it a highly suitable target for
nanomedicine. Recognizing the potential of S100A9 as a pharmacologic target, we developed S100A9-targeted
CPMV that efficiently concentrates at sites of metastasis enabling potent efficacy preventing outgrowth of
metastases. Here we set out to detail the mechanisms of action and understand the pharmacology of S100A9-
targeted CPMV. Finally, the preclinical development will be substantially extended with veterinary clinical trials
in companion dogs with mammary tumors (Aim 3).
Terms: <4T1><Assay><B7-H1><B7H1><Binding><Bioassay><Biodistribution><Biological Assay><Blocking Antibodies><Blood><Blood Reticuloendothelial System><Body Tissues><Breast Cancer><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><CAGB><CD274><CGCB><Cancer Induction><Cancers><Canine Species><Canis familiaris><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Extracellular Matrix><Cells><Checkpoint inhibitor><Clinical><Clinical Treatment Moab><Clinical Trials><Combined Modality Therapy><Cowpea Mosaic Viruses><Data><Development><Disease><Disorder><Disseminated Malignant Neoplasm><Distant Cancer><Distant Metastasis><Dogs><Dogs Mammals><Dose><Drug Delivery><Drug Delivery Systems><ECM><Engineering><Event><Extracellular Matrix><Female><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Future><Genomics><Goals><Human><IMiD><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immune modulatory therapeutic><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunotherapy><In Vitro><Inflammation><Innate Immune System><Intracellular Communication and Signaling><Intravenous><LIAG><Libraries><Life><Link><MAC387><MRP14><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modern Man><Molecular><Molecular Interaction><Monitor><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Myelogenous><Myeloid><Neoplasm Metastasis><Oncogenesis><PD-L1><PDL-1><PDL1><Patients><Pattern><Pattern recognition receptor><Peptides><Personalized medical approach><Pharmacology><Plant Viruses><Prognosis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Property><Proteins><Radiation><Receptor Protein><Recurrence><Recurrent><Research><Research Resources><Resources><S100A9><S100A9 gene><Safety><Schedule><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spain><Specificity><T-Cells><T-Lymphocyte><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><TM-MKR><TNBC><Teff cell><Testing><Time><Tissues><Toll-Like Receptor 2><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Toxic effect><Toxicities><Tumor Antigens><Tumor Immunity><Tumor Markers><Tumor-Associated Antigen><Virus-like particle><aPD-L1><aPDL1><anti programmed cell death ligand 1><anti programmed cell death protein ligand 1><anti-PD-(L)1><anti-PD-L1><anti-PDL-1><anti-PDL1><anti-cancer immunotherapy><anti-tumor immunity><antiPD-L1><antiPDL1><anticancer immunotherapy><antitumor immunity><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cancer antigens><cancer immunity><cancer immunotherapy><cancer metastasis><cancer microenvironment><candidate identification><candidate selection><canine><carcinogenesis><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemotherapy><combination therapy><combined modality treatment><combined treatment><companion animal><companion cat><companion dog><companion pet><cowpea virus><determine efficacy><developmental><domestic dog><effector T cell><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><flow cytophotometry><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulation><immune modulatory agents><immune modulatory drugs><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoregulation><immunoregulatory><immunotherapy for cancer><immunotherapy of cancer><in situ vaccination><in vivo><individualized approach><insight><mAbs><malignancy><malignant breast tumor><mammary tumor><monoclonal Abs><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano medicinal><nano medicine><nano particle><nano-sized particle><nanodrug><nanomedicinal><nanomedicine><nanoparticle><nanopharmaceutical><nanosized particle><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><pathogen><personalized approach><pharmacologic><pre-clinical development><precision approach><preclinical development><prevent><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><receptor><residence><residential building><residential site><response to therapy><response to treatment><safety assessment><synergism><tailored approach><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><thymus derived lymphocyte><treatment response><treatment responsiveness><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor biomarker><tumor cell metastasis><tumor growth><tumor microenvironment><tumor specific biomarker><tumor-specific antigen><tumorigenesis><virus-like nanoparticles><viruslike particle><αPD-L1><αPDL1>