Naturally Targeted Exosomal TLR7/8 Agonist for Immunotherapy of Medulloblastoma
Naturally Targeted Exosomal TLR7/8 Agonist for Immunotherapy of Medulloblastoma
批准号:
10790660
负责人:
ALEXANDER V KABANOV
金额:
$42.76万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-20 至 2025-08-31
关键词:
AdjuvantAffectAgonistAnimalsBiological AvailabilityBlood - brain barrier anatomyBlood CirculationBrainBrain InjuriesBrain NeoplasmsCancer PatientCell SurvivalChemotherapy and/or radiationChildChildhood Malignant Brain TumorClinicalClinical TreatmentCognitive deficitsCombined Modality TherapyDataDendritic CellsDevelopmentDiagnosisDrug CarriersDrug Delivery SystemsDrug ExposureDrug KineticsEffector CellEncapsulatedEncephalitisFDA approvedFormulationFoundationsGene Expression ProfileGenerationsGenetically Engineered MouseGliomaGoalsImmune systemImmunologic StimulationImmunosuppressionImmunotherapeutic agentImmunotherapyInfiltrationInflammatoryLeftMacrophageMalignant NeoplasmsMalignant neoplasm of urinary bladderMicellesModalityModelingMusMutationMyeloid CellsOperative Surgical ProceduresOutcomeParentsPatientsPeripheralPharmaceutical PreparationsPhenotypePhysiologicalPositron-Emission TomographyProdrugsPropertyRadiation therapyRecurrent diseaseRetinoblastoma ProteinSHH geneSolubilityStructureSurvivorsSystemTLR7 geneTestingTherapeuticToll-like receptorsTumor-associated macrophagesVaccinesblood-brain tumor barriercancer clinical trialcancer immunotherapycarboxylesterasecerebral capillarychemotherapyclinically relevantdesigndrug distributionexosomeextracellular vesiclesimmune activationimmune cell infiltrateimprovedinterestmedulloblastomamelanomamonocytemotor deficitmouse modelnanomicellesnanopolymerneoplastic cellnovelnovel strategiesnovel therapeuticspediatric patientsprogramsresiquimodside effecttreatment effecttumortumor growthtumor microenvironmenttumor-immune system interactions
中文摘要
自然靶向外泌体TLR7/8激动剂用于髓母细胞瘤免疫治疗
英文摘要
Naturally Targeted Exosomal TLR7/8 Agonist for Immunotherapy of Medulloblastoma
Despite aggressive and highly toxic treatment, nearly half of the children diagnosed with medulloblastoma will
die from recurrent disease. Survivors are often left with disabling treatment-associated brain injury. More
effective and less toxic therapies are needed to improve clinical outcomes for children affected by
medulloblastoma. Sonic Hedgehog (SHH) medulloblastoma is enriched in tumor associated macrophages
(TAMs) which express Toll-like receptor (TLR) 7 and 8. Reprogramming these TAMs could result in the loss of
immunosuppressive signatures and acquisition of tumoricidal and proinflammatory signatures. We have shown
that TLR7/8 agonist, resiquimod, encapsulated in polymeric nano-micelles significantly prolonged survival in G-
Smo mice - genetically engineered mouse model (GEMM) of SHH medulloblastoma with intact blood brain barrier
(BBB) and tumor microenvironment (TME). The free drug was not active in G-Smo mice medulloblastoma model.
While micelles increase solubility and bioavailability of this agent to the brain capillaries, they do not target the
BBB. Moreover, micelles are dynamic structures and release most of their cargo peripherally before reaching
the brain, which can decrease therapeutic potential and increase side effects of this format. Hence, we propose
a different formulation using monocyte/macrophage derived exosomes as natural targeted carriers of resiquimod
for medulloblastoma. We discovered that exosomes secreted from macrophages are transported to the inflamed
brain and carry therapeutic molecules across the intact BBB. Our preliminary data suggest that macrophage-
derived exosomes accumulate in the brain of the G-Smo mice. Inspired by these discoveries we seek to develop
exosome delivered resiquimod as a novel approach to medulloblastoma. Toward this goal we developed the
exosome incorporated form of resiquimod (exo-Res) that was shown to polarize myeloid cells toward pro-
inflammatory M1-like phenotype. We will test the hypotheses that (a) exo-Res exosomes in a G-Smo mouse
model of medulloblastoma will effectively deliver the resiquimod to the tumor, (b) the delivered resiquimod will
repolarize TAMs in medulloblastoma, (c) this novel targeted exo-Res therapeutic modality will inhibit the tumor
growth and improve the clinically relevant outcomes compared to untargeted first generation nano-micelles, POx-
Res PMs. Our Specific Aims will be: 1) Determine if exosomes improve the tumor distribution of resiquimod
administered to medulloblastoma-bearing mice. SA2) Determine if exo-Res enhances the anti-tumor efficacy of
resiquimod in medulloblastoma-bearing mice. If successful, this will lead to novel therapy that has potential to
improve medulloblastoma treatment by replacing the current radiation and chemotherapy with the one that is
less toxic and more effective.
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