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Principal Investigator: Efstathios Karathanasis
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $77,121
Funding agency: National Cancer Institute
PROJECT SUMMARY: Cancer immunotherapy is based on the premise of immune-recognition and targeted
killing of tumor cells, thus possesses the promising power to eradicate aggressive disease. Notably to date,
immunotherapy with immune checkpoint inhibitors significantly prolongs the survival of patients. Unfortunately,
recurrent and metastatic disease occurs to a significant portion of patients within 5 years largely due to
resistance to the immune checkpoint inhibitor. This largely stems from the local immunosuppressive tumor
microenvironment (TME), which is enriched with immunosuppressive myeloid cells. To reprogram the TME into
a “hot” environment enriched with functional myeloid cells, we designed a dual action immunostimulatory
nanoparticle (dual-NP) that triggers a highly potent activation of the dysfunctional tumor-resident myeloid cells.
The premise of our strategy is based on three key components: (1) Our previous studies showed that V domain
Immunoglobulin Suppressor of T cell Activation (VISTA) is a novel myeloid cell-intrinsic immune checkpoint
protein, which controls antitumor immunity. We showed VISTA is highly expressed on immunosuppressive
myeloid cells and blocking VISTA can synergize with TLR9 agonist to reprogram the immunosuppressive
myeloid cells to boost antitumor immunity. (2) The dual-NP is co-loaded with a VISTA siRNA and the TLR9
agonist CpG. Upon intratumoral administration, the dual-NP ensures the simultaneous uptake of its synergistic
cargoes by the same tumor-resident myeloid cells and proficient intracellular delivery of each cargo, thus
achieving optimal effects to activate these cells. Our recent studies show that simultaneous silencing of the
VISTA gene and stimulation of TLR9 leads to a synergistic T cell-mediated tumor clearance and curative
responses with protective immunological memory against tumor recurrence. (3) We developed a simple and
controllable method to generate ionizable lipid dual-NPs of different sizes (i.e., 30, 40 or 60 nm) with high
degree of uniformity and consistency. Our studies show that small dual-NPs achieve widespread distribution
and predominant uptake by myeloid cells throughout the tumor volume upon intratumoral administration.
Innovation: To our knowledge, this is the first effort to combine advanced nanoparticle design, simultaneous
delivery of siRNA and a TLR agonist, and silencing of a gene related to an immune checkpoint protein specific
to myeloid cells.
AIM 1: Optimize the design of the dual-NP and test the ex vivo and in vivo efficacy in reprograming
tumorassociated myeloid cells.
AIM 2: Evaluate the short and long-term safety profile of the dual-NP and characterize the mechanism of
antitumor immune responses associated with dosage and frequency of dual-NP administration.
AIM 3: Evaluate the therapeutic efficacy of the dual-NP as a monotherapy and in combination with standard
immune checkpoint inhibitors in murine models of advanced melanoma and metastatic breast cancer.
Terms: <Adverse Experience><Adverse event><Agonist><Cancers><Cell Body><Cells><Checkpoint inhibitor><Disease><Disorder><Disseminated Malignant Neoplasm><Ensure><Frequencies><Gene Activation><Genes><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immune memory><Immunes><Immunity><Immunoglobulin Domain><Immunoglobulin-Like Domain><Immunologic Memory><Immunological Memory><Immunologically Directed Therapy><Immunotherapy><Innate Immunity><Lipids><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Mediating><Melanoma><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Metastatic/Recurrent><Methods><Myeloid Cells><Myeloid-derived suppressor cells><Native Immunity><Natural Immunity><Neoplasm Metastasis><Non-Specific Immunity><Nonspecific Immunity><Operative Procedures><Operative Surgical Procedures><PD 1><PD-1><PD1><Patients><Proteins><Recurrent Neoplasm><Recurrent disease><Recurrent tumor><Relapsed Disease><Resistance><Safety><Secondary Neoplasm><Secondary Tumor><Short interfering RNA><Small Interfering RNA><Solid Neoplasm><Solid Tumor><Suppressor Cells><Suppressor-Effector T-Cells><Suppressor-Effector T-Lymphocytes><Surgical><Surgical Interventions><Surgical Procedure><T Suppressor Cell><T-Cell Activation><T-Cells><T-Lymphocyte><Testing><Therapeutic><Toxic effect><Toxicities><Treatment Efficacy><Tumor Cell><Tumor Immunity><Tumor Volume><activate T cells><anamnestic reaction><anti-cancer immunotherapy><anti-tumor immune response><anti-tumor immunity><anticancer immunotherapy><antitumor immunity><cancer immunity><cancer immunotherapy><cancer metastasis><cancer microenvironment><check point blockade><checkpoint blockade><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><design><designing><disease prevention><disorder prevention><dosage><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><immune check point><immune check point blockade><immune check point inhibitor><immune checkpoint><immune checkpoint blockade><immune microenvironment><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><in vivo><innovate><innovation><innovative><intervention efficacy><lymphocyte trafficking><malignancy><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm recurrence><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><recruit><recurrence prevention><resistance to therapy><resistant><resistant to therapy><response><secondary immune response><short interfering RNA delivery><siRNA><siRNA delivery><side effect><sle2><small interfering RNA delivery><stem><suppressive myeloid cells><suppressor T lymphocyte><surgery><synergism><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic resistance><therapy efficacy><therapy resistant><thymus derived lymphocyte><treatment resistance><tumor><tumor cell metastasis><tumor eradication><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><uptake>