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Principal Investigator: Andre Elias Nel
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $479,283
Funding agency: National Cancer Institute
The use of nano-enabled chemotherapy to trigger an immune response to pancreatic ductal adenocarcinoma
(PDAC) introduces a novel approach for overcoming robust barriers to immunotherapy, including poor
immunogenicity, low neoantigen burden, stromal interference (“T-cell exclusion”), overexpression of
indoleamine 2,3-dioxygenase (IDO-1), and the immune privileged environment of the liver favoring metastatic
spread. Our preliminary data show that lipid-bilayer coated mesoporous silica nanoparticles (silicasomes)
provide an effective platform for inducing immunogenic cell death (ICD) by delivering prescreened
chemotherapeutic agents to the PDAC site. ICD promotes the presentation of endogenous tumor antigens
cells, raising the hypothesis that ICD offers a promising endogenous vaccination approach to generate a “hot”
tumor microenvironment (TME) that can be propagated by co-delivery of drugs interfering in regionally
overexpressed immunosuppressive pathways. These pathways can be targeted by inhibitors of IDO-1, CXCR4
(T-cell exclusion) and glycogen synthase kinase 3 (which controls PD-1 expression). We also propose that
metastatic spread can be reduced by ICD-induced memory T-cells and delivery of “stimulator of interferon
genes” (STING) agonists to tolerogenic antigen presenting cells in the liver. The long-term goal of our
interdisciplinary efforts is to develop a chemo-immunotherapy platform for delivery of ICD stimuli by the
silicasome contemporaneous with inhibitors of immune checkpoint and T-cell exclusion pathways (CXCR4).
The objectives include the use of innovative drug loading and cholesterol-conjugated prodrugs to synthesize
silicasomes that can be used to obtain the best synergy between ICD stimuli and inhibitors of
immunosuppressive pathways in orthotopic and genetic engineered PDAC models. This requires research
discovery into the mechanistic basis of synergy between ICD and regional immune escape pathways. We will
use an integrin-targeting, tumor-penetrating iRGD peptide to enhance drug delivery by a transcytosis pathway.
We will also construct polymeric nanocarriers to deliver STING agonists for preventing metastatic spread to the
liver. The rationale is that the use of an ICD approach to generate a “hot” tumor environment will facilitate
combination immunotherapy with improvement of PDAC mortality. We plan to test our hypothesis by pursuing
the following specific aims: Aim 1: To develop a nano-enabled chemo-immunotherapy platform for PDAC that
utilizes an endogenous (ICD-mediated) treatment approach plus interference in regionally overexpressed
immune checkpoint pathways to generate a “hot” tumor environment. Aim 2: To enhance the immunotherapy
impact of the ICD platform by using integrin-targeting, tumor-penetrating iRGD peptides and developing a
silicasome that interferes in T-cell exclusion in the stroma through the delivery of CXCR4 inhibitors. Aim #3: To
reprogram the immune suppressive effects of liver APC by STING nanoparticles that promote eradication of
PDAC metastases by the memory T-cells generated by ICD-inducing silicasomes.
Terms: <1-OHP><A5 Antigen><Adjuvant><Adoptive Transfer><Agonist><Antibodies><Antigen-Presenting Cells><Blocking Antibodies><C-terminal><CXC-R4><CXCL12><CXCL12 gene><CXCL12 protein><CXCR-4><CXCR4><CXCR4 gene><Campto><Cancers><Cell Body><Cell Death Induction><Cell-Mediated Lympholytic Cells><Cells><Checkpoint inhibitor><Chemokine (C-X-C Motif) Ligand 12><Cholesterol><Combination immunotherapy><Cristobalite><Custom><Cyclicity><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><D2S201E><Data><Dendritic Cells><Desmoplastic><Desmoplastic Reaction><Development><Dinucleoside Phosphates><Drug Combinations><Drug Delivery><Drug Delivery Systems><Drug Precursors><Drugs><Duct><Duct (organ) structure><Encapsulated><Environment><Exclusion><FB22><Failure><GSK-3><Gene Delivery><Gene Transcription><Generations><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Transcription><Glycogen Synthase Kinase 3><Glycolates><Goals><HM89><HSY3RR><Hepatic Neoplasm Secondary><Hepatic metastasis><IDOase><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immunes><Immuno-Chemotherapy><Immunochemical Immunologic><Immunochemotherapy><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Indoleamine 2,3-Dioxygenase><Innate Immune System><Integrin aVBeta3><Integrin alpha-v beta-3><Integrin alphaVbeta3><Integrin αVβ3><Integrins><Integrins Extracellular Matrix><Intervention><Intervention Strategies><LAP3><LCR1><LESTR><Lipid Bilayers><Lipids><Liver><Liver secondaries><Liver secondary cancer><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Medication><Memory><Metabolic Pathway><Metastasis><Metastasize><Metastatic Adenocarcinoma><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Liver><Metastatic Tumor><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Myeloid Cells><Myeloid-derived suppressor cells><NPY3R><NPYR><NPYRL><NPYY3R><NRP1 Protein><Neoplasm Metastasis><Neuropilin-1><Npn-1 Protein><Organ><Outcome Study><PBSF><PD 1><PD-1><PD-1 checkpoint pathway><PD-1 pathway><PD-1 signaling pathway><PD-1/PD-L1><PD-1/PDL1><PD-L1 pathway><PD1><PD1 checkpoint pathway><PD1 pathway><PD1 signaling pathway><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDA model><PDAC Model><PDL1 pathway><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Penetration><Peptides><Periodicity><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Pre-B Cell Growth Stimulating Factor><Primary Neoplasm><Primary Tumor><Pro-Drugs><Prodrugs><RNA Expression><Receptor Protein><Recombinant DNA Technology><Research><Resistance><Rhythmicity><Role><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><Sand><Science><Sdf1 protein><Secondary Neoplasm><Secondary Tumor><Sema III Receptor><Semaphorin III Receptor><Series><Silica><Silicon Dioxide><Site><Solid><Stimulator of Interferon Genes><Stimulus><Stromal Cell-Derived Factor 1><T cell response><T memory cell><T-Cells><T-Lymphocyte><TLSF-A><TLSF-B><TPAR1><Techniques><Testing><Therapeutic><Time><Transcription><Tridymite><Tryptophan 2,3 Dioxygenase><Tumor Antigens><Tumor-Associated Antigen><Tumor-associated macrophages><Vaccination><Vascular Endothelial Cell Growth Factor 165 Receptor><Veiled Cells><aVBeta3><accessory cell><alpha-v beta-3 Integrin Receptors><alternative treatment><anti programmed cell death protein 1 checkpoint pathway><anti programmed cell death protein 1 pathway><anti programmed cell death protein 1 signaling pathway><anti-cancer immunotherapy><anticancer immunotherapy><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><camptosar><cancer antigens><cancer cell><cancer immunotherapy><cancer location><cancer metastasis><cancer microenvironment><cancer site><check point receptors><checkpoint receptors><chemo-immuno therapy><chemoimmunotherapy><chemotherapeutic agent><chemotherapy><combinatorial immunotherapy><customs><cyclic GMP-AMP synthase/STING><design><designing><developmental><dinucleotide><drug/agent><dual immunotherapy><experiment><experimental research><experimental study><experiments><genetically engineered><glycolic acid><gsk-3 Gene Product><hIRH><hepatic body system><hepatic organ system><host response><immune check point><immune check point inhibitor><immune checkpoint><immune suppression><immune suppressive activity><immune suppressive function><immune system response><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><immunogenic apoptosis><immunogenic cell death><immunogenicity><immunological status><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive myeloid cells><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><improved><inhibitor><innovate><innovation><innovative><interventional strategy><irinotecan><killer T cell><lipid bilayer membrane><liver metastases><malignancy><malignant liver neoplasm, specified as secondary><memory T lymphocyte><metastasis in the liver><metastasis prevention><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic liver><metastatic liver neoplasm><migration><mortality><myeloid suppressor cells><myeloid-derived suppressive cells><nano><nano particle><nano particle delivery><nano polymer><nano-sized particle><nanocarrier><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanopolymer><nanosized particle><nanovessel><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><overexpress><overexpression><oxaliplatin><oxaliplatine><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pathway><pharmaceutical><prevent><preventing><programmed cell death 1><programmed cell death ligand 1 pathway><programmed cell death protein 1><programmed cell death protein ligand 1 pathway><programmed death 1><programs><receptor><recruit><resistant><response><secondary liver malignancy><secondary malignant liver neoplasm><side effect><site targeted delivery><sle2><small molecular inhibitor><small molecule inhibitor><social role><stromal cell-derived factor-1alpha><success><suppressive myeloid cells><synergism><systemic lupus erythematosus susceptibility 2><targeted delivery><thymus derived lymphocyte><transcytosis><treatment strategy><tryptamine 2,3 dioxygenase><tumor><tumor cell metastasis><tumor microenvironment><tumor-specific antigen><uptake>