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Principal Investigator: Jianxin You
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $180,425
Funding agency: National Cancer Institute
Project Summary
Tumor immune suppression represents a major obstacle in achieving effective cancer
immunotherapy. The goal of this exploratory project is to develop a novel mRNA-lipid
nanoparticle (mRNA-LNP)-based immunotherapy to overcome this challenge in pancreatic
cancer, one of the deadliest malignancies. Currently, few effective treatments are available for
pancreatic cancer. The majority of pancreatic cancers are also resistant to immune checkpoint
blockade. Thus, novel therapeutic strategies are needed to target this lethal cancer. Most
pancreatic cancers display a highly immunosuppressive tumor microenvironment (TME).
Tumor-infiltrating effector CD8+ T cells are critical for improved patient survival, and yet they are
either absent or sparse in the majority of pancreatic cancers, indicating an intrinsic mechanism
that impedes T cell infiltration and activation. We recently discovered that Stimulator of
Interferon Genes (STING) is silenced in pancreatic and other cancers. Because STING function
is critical for stimulating antitumor T cell responses, our finding suggests that STING silencing
contributes to the immunologically “cold” TME. We found that reactivating STING upregulates
cytokines/chemokines that are crucial for promoting intratumoral T cell infiltration. More
importantly, reactivation of STING specifically kills STING-silenced cancer cells. Because tumor
antigens released by dying cancer cells in vivo could be engulfed by antigen-presenting cells to
generate systemic antitumor response and amplify tumoricidal effect, we hypothesize that
targeted reactivation of STING in pancreatic cancer could invigorate the immune-dampened
TME and improve tumor immunogenicity. In this project, we will develop mRNA-LNP to
specifically deliver permanently active STING mutants into pancreatic cancer to bolster T cell
antitumor cytotoxicity. This approach aims to overcome the limitations of traditional STING
agonists, which lack tumor specificity and do not work in STING-silenced cancers. To define
their efficacy in stimulating antitumor immunity, the STING mRNA-LNP will be tested in vitro and
in an orthotopic syngeneic murine pancreatic cancer model, which faithfully recapitulates the
immunobiologically “cold” TME of pancreatic cancer. We will also combine STING mRNA-LNP
with PD-1 blockade to circumvent pancreatic cancer resistance to the immune checkpoint
therapy and spur synergistic antitumoral activity. These preclinical studies have the potential for
developing a novel immunotherapy to overcome immune resistance and improve treatments for
a diverse array of STING-silenced cancers that are refractory to current therapies.
Terms: <2019-nCoV vaccine><Agonist><Antibody Therapy><Antigen-Presenting Cells><Antitumor Response><Assay><Bioassay><Biological Assay><Biological Response Modifiers><Biomodulators><Body Tissues><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 vaccine><Cancers><Checkpoint inhibitor><Chemoattractants><Chemotactic Cytokines><Chemotactic Factors><Chemotaxins><Clinical><Collaborations><DNA Therapy><Development><Diagnosis><Effectiveness><Engineering><Face><Gene Down-Regulation><Gene Inactivation><Gene Silencing><Gene Transfer Clinical><Genetic Intervention><Goals><Grant><Homologous Chemotactic Cytokines><Human><Hyperactivity><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Infiltration><Intercrines><Legal patent><Letters><Link><Lytotoxicity><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Messenger RNA><Methods><Mice><Mice Mammals><Modern Man><Murine><Mus><Non-Polyadenylated RNA><PD-1 antibody><PD-1 blockade><PD-1/PD-L1><PD-1/PDL1><PD1 antibody><PD1 blockade><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDA model><PDAC Model><PDAC cancer cell><PDAC cell><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Patents><Patients><Peptides><Production><Publishing><RNA><RNA Gene Products><Repression><Resistance><Ribonucleic Acid><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><SIS cytokines><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Stimulator of Interferon Genes><T cell infiltration><T cell response><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Transcription Repression><Transcriptional Repression><Translating><Treatment outcome><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor-Associated Antigen><Work><accessory cell><activate T cells><advanced pancreatic cancer><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 blockade><anti-PD-1 monoclonal antibodies><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 blockade><anti-PD1 monoclonal antibodies><anti-cancer><anti-cancer immunotherapy><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><anti-tumor immunity><anti-tumor response><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><anticancer immunotherapy><antitumor immunity><autoinflammatory diseases><autoinflammatory disorders><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer antigens><cancer cell><cancer immunity><cancer immunotherapy><cancer microenvironment><cell killing><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemoattractant cytokine><chemokine><complement chemotactic factor><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cyclic GMP-AMP synthase/STING><cytokine><cytotoxicity><developmental><effective therapy><effective treatment><engineered T cells><faces><facial><gene function><gene repair therapy><gene repression><gene therapy><gene-based therapy><genetic therapy><genetically engineered T-cells><genomic therapy><immune check point blockade><immune check point inhibitor><immune check point therapy><immune checkpoint blockade><immune checkpoint therapy><immune microenvironment><immune resistance><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-resistant><immuno therapy><immunogenicity><immunomodulatory biologics><immunoresistance><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><implantation><improved><in vitro testing><in vivo><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA Expression><malignancy><migration><multidisciplinary><mutant><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nanoparticle therapy><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pancreatic cancer model><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic tumor model><pre-clinical study><preclinical study><prevent><preventing><refractory cancer><resistant><resistant cancer><success><synergism><therapeutic nanoparticles><thymus derived lymphocyte><transcriptional silencing><transgenic T- cells><tumor><tumor DNA><tumor cell DNA><tumor immune microenvironment><tumor microenvironment><tumor specificity><tumor-immune system interactions><tumor-specific DNA><tumor-specific antigen><ultrasound><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID>