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Principal Investigator: Efstathios Karathanasis
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2023
Award: $578,041
Funding agency: National Cancer Institute
PROJECT SUMMARY
First-line chemotherapy is the standard of care for patients with triple-negative breast cancer (TNBC). While
short-term response is achievable, most patients succumb to recurrence due to metastasis. Micrometastasis
encompasses a small population of dormant disseminated tumor cells (dDTCs) that survive in
quiescent/senescent states prior to initiating their ‘explosive’ metastatic outgrowth. Standard chemotherapy is
completely ineffective against the slow-dividing dDTCs. In contrast, cancer immunotherapy is based on the
premise of immune-recognition and targeted killing of tumor cells, thus possess the promising power to control
dormant metastatic cancer cells. However, one major hurdle in immunotherapy is to overcome the profound
immunosuppression within the tumor microenvironment (TME). TME is associated with the accumulation of
dysfunctional antigen-presenting cells (APCs). An effective approach to alter TME is to reprogram these
inhibitory APCs into properly activated APCs that stimulate tumor antigen-specific T cells. We designed an
immuno-stimulatory nanoparticle that exploits the unique physiological features of metastatic TME, which
allows the systemic delivery of nanoparticles to achieve a robust immunostimulation within the TME. First, to
drive a sustainable antitumor immune response, we harness two synergistic innate immune pathways by co-
delivering two immune agonists. The immuno-NP is co-loaded with an agonist of the Stimulator of Interferon
Genes (STING) pathway and a Toll-like receptor 4 (TLR4) agonist, which synergize to produce high levels of
Type I interferon (IFN) β. The dual-agonist NP guarantees uptake of both agonists by the same APC, which
elicits functional synergy. Second, the immuno-NP facilitates proficient presentation of each agonist to the
appropriate intracellular location of APCs. Third, the immuno-NP is designed for systemic administration
targeting the APC-rich perivascular areas of metastasis, leading to uptake predominantly by APC cells. As a
result, high levels of IFNβ produced within the tumor site lead to the activation of APC and NK cells that
consequently drive the recruitment of additional immune cells as well as the activation of tumor-reactive
cytotoxic CD8+ T cells. Any immuno-NP-associated toxicity was minimal and reversible. Our central
hypothesis is that the dual-agonist cargo (STING and TLR4 agonists) of the immuno-NP targeted to the
perivascular regions of metastasis will produce a strong IFNβ-driven antitumor immune response.
Aim 1: Optimize an immuno-NP design that targets the metastatic TME with high efficiency and mediates co-
delivery of the dual-agonist cargo at the ratio of STING/TLR4 agonists for optimal functional synergy.
Aim 2: Evaluate the short and long-term safety profile of the immuno-NP and characterize the mechanism of
antitumor immune responses associated with dosage and frequency of immuno-NP administration.
Aim 3: Evaluate the therapeutic efficacy of the immuno-NP as a monotherapy and in combination with immune
checkpoint inhibitors in murine models of metastatic TNBC.
Terms: <Agonist><Antigen Targeting><Antigen-Presenting Cells><Area><Binding><Blood Vessels><Breast Metastasis><Breast cancer metastasis><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Biology><Cancers><Cell Body><Cell Survival><Cell Viability><Cell-Mediated Lympholytic Cells><Cells><Cellular Membrane><Checkpoint inhibitor><Clinical><Clinics and Hospitals><Clinics or Hospitals><Collaborations><Comprehensive Cancer Center><Cristobalite><Cyclicity><Cytolytic T-Cell><Cytosol><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic agent><Cytotoxic cell><Cytotoxic drug><Deposit><Deposition><Disease><Disorder><Disseminated Malignant Neoplasm><Endogenous Interferon Beta><Endosomes><Exhibits><Fibroblast Interferon><Frequencies><H+ element><Homolog of Drosophila TOLL><Hydrogen Ions><IFN-Beta><IFN-β><IFNb><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunologic Stimulation><Immunological Stimulation><Immunologically Directed Therapy><Immunomodulation><Immunomodulators><Immunooncology><Immunostimulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Interferon Type I><Interferon-beta><Interferon-β><Investigators><K lymphocyte><Lead><Lilium><Lily><Lipid A><Lipids><Location><MICMET><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Mediator><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Micrometastasis><Micromets><Molecular Interaction><NK Cells><Nanotechnology><Natural Interferon Beta><Natural Killer Cells><Natural human interferon beta><Neoplasm Metastasis><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Pb element><Periodicity><Physiologic><Physiological><Population><Porifera><Production><Protons><Publishing><Receptosomes><Recurrence><Recurrent><Research Personnel><Researchers><Rhythmicity><Route><Safety><Sand><Secondary Neoplasm><Secondary Tumor><Silica><Silicon Dioxide><Site><Sponges><Stimulator of Interferon Genes><Stimulus><Surface><T8 Cells><T8 Lymphocytes><TLR4><TLR4 gene><TNBC><Testing><Toll Homologue><Toxic effect><Toxicities><Treatment Efficacy><Tridymite><Tumor Antigens><Tumor Cell><Tumor-Associated Antigen><Universities><University Hospitals><accessory cell><anti-cancer immunotherapy><anti-cancer research><anti-tumor immune response><anti-tumor immune therapy><anti-tumor immunotherapy><anticancer immunotherapy><anticancer research><antigen-specific T cells><antitumor immune response><antitumor immune therapy><antitumor immunotherapy><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer cell><cancer immunology><cancer immunotherapy><cancer metastasis><cancer microenvironment><cancer research><chemotherapy><cyclic GMP-AMP synthase/STING><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><design><designing><dosage><endosome membrane><heavy metal Pb><heavy metal lead><immune check point inhibitor><immune modulation><immune modulators><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immune-oncology><immuno oncology><immuno therapy><immunologic reactivity control><immunology oncology><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><innate immune pathways><intervention efficacy><killer T cell><lipophilicity><malignancy><mouse model><murine model><nano particle><nano particle delivery><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotech><nanotechnological><neoplasm immunology><neoplasm immunotherapy><neoplasm/cancer><neoplastic cell><oncoimmunology><pathway><programs><recruit><response><senescence><senescent><standard of care><synergism><therapeutic efficacy><therapy efficacy><toll-like receptor 4><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor immune therapy><tumor immunology><tumor immunotherapy><tumor microenvironment><tumor-specific antigen><uptake><vascular>