Pancreaticcancerisoneofthemostlethalcancersamongallsolidtumors,withanextremelypoorprognosis, andadismalfive-yearsurvivalrateof7%.Newinsightsintotheregulationofimmuneresponsesandthe malignantprocesshaveledtotheemergenceofnewimmunotherapeuticstrategiestotreatpancreaticcancer. Thechallengesinthedevelopmentoftumorvaccineslieintheidentificationoftumor-associatedantigens, inductionofantigen-specificcellmediatedimmuneresponses,overcomingimmunetolerance,andthe immunosuppressivetumorenvironment.InthisU01application,weproposetodevelopnovelmucin-containing nanovaccineplatformsandcombinethemwithcheckpointblockadeagentsthatcansimultaneouslyinduce long-livedcytotoxicTlymphocyteresponsesandactivateinnateimmunityandmaintaintheTcellresponse, thusovercomingtheimmunosuppresiveenvironment.Amongthemanystructuralandfunctional transformationsthatoccurduringoncogenesis,alteredexpressionofcellsurfaceglycoproteins,suchas mucins,presentsanopportunityforthedevelopmentofvaccinestrategies.WeproposetoutilizeMUC4mucin forimmunotherapeuticnano-formulationsbecausethisproteinisoverexpressedin>90%ofpancreatictumors andundetectableinnormalpancreas(unlikethemostexploredmucinvaccinecandidate,MUC1).Our proposednanoadjuvantplatformconsistsofamphiphilicpolyanhydrideand/orpolyesternanoparticles, containingCpG,andisideallysuitedforprotein-basedsubunitvaccines.Ourcentralhypothesis,basedon significantpeer-reviewedpreliminarydata,isthataleadnanovaccinethatinducesMUC4-specific,cytotoxic CD8+Tcellswilltherapeutically(i.e.,inthepresenceoftumor)provideanti-tumorbenefitsincombinationwith checkpointinhibitors.Wewillpositionthisnanovaccineforpreclinicalstudiesthatwilladvancethe developmentofpancreaticcancervaccinetechnologiesbyaccomplishingthefollowingSpecificAims,eachof whichisboundedbymilestonesandfallbackpositions:
Aim1 :Formulation,optimization,andimmunological characterizationofMUC4-specificimmuneresponseswithnano-adjuvants.
Aim2 :Evaluationoflead nanovaccine(s)andcheckpointblockadeagentsinasyngeneicmurinemodelofpancreaticcancer.
Aim3 : Evaluationofleadnanovaccineandcheckpointblockadeagentsintransgenicmousemodels.Attheendofthe projectperiod,wewilldeliveranovelnanovaccineasaneffectivetherapyforpancreaticcancerpatients. OveralltheproposedstudieswillestablishtheutilityofMUC4,whichisthemostdifferentiallyoverexpressed mucinasatargetforpancreaticcancerimmunotherapy,andthenanotechnologyandcellandanimalmodels generatedinthisprojectwillhavebroaderapplicabilityforevaluatingotherpancreaticcancervaccine approaches.
Pancreaticcancerisalethalmalignancyduetolackofearlydiagnosisandpoorresponsetotherapeutic modalities.Theobjectiveofthismulti-disciplinaryendeavoristoexploitthepowerofnanotechnologyand immunologytotransformthelandscapeofpancreaticcancerpatientcarebydevelopinganovelnanovaccine thatwillinduceantigen-specificcellmediatedimmuneresponses,andovercomeimmunetoleranceandthe immunosuppressivetumorenvironment.Attheendoftheprojectperiod,wewilldeliveranovelnanovaccine asaneffectivetherapyforpancreaticcancerpatients.
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| Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86 |
