Abstract

Currentlyapprovedimmunotherapieshaveshownefficacyinpatientswithimmunogenictumortypes, suchasmelanomaandnon-smallcelllungcancer.However,immunotherapiesarelesseffectivefortumors withlowlevelsofinfiltratinglymphocytesandalowmutationrate,limitingthenumberofprimedTcellswithin thetumormicroenvironment.OurlaboratoryhasdevelopedaDNAvaccineplatformusingsyntheticconsensus sequencestobreaktolerancetogermlineantigens.Thesevaccinescanbreaktolerancetonativeproteinsin mousemodelsandinduceanti-tumoractivity.However,DNAvaccinesarestilllimitedbytheimmune suppressivemicroenvironment,whichpreventsCD8Tcellinfiltrationandactivationwithinthetumor. Specifically,theextracellularmatrixglycosaminoglycanhigh-molecular-weight(hmw)hyaluronan(HA)is abundantinthetumormicroenvironmentandisknowntorestrictTcellactivationinother(non-tumor)contexts throughengagementofCD44.HyaluronidaseisanenzymethatconvertshmwHAtolow-molecular-weight (lmw)HA,whichisknowntoengagetheinnateimmunesystemthroughToll-likeRecptors(TLRs). Hyaluronidasetreatmentofpancreaticandprostatecancerswasalsoshowntoenhanceangiogenesisand improvechemotherapeuticdelivery.Wethereforehypothesizethathyaluronidasetreatmentinthetumor microenvironmentwillenhanceTcellinfiltrationandactivationintumorsresultinginimproved efficacywhencombinedwithDNAvaccineimmunotherapyinapancreaticcancermodel. Weshowinpreliminaryexperimentsthatcombinationtherapywithhyaluronidaseandvaccinationina prostatecancermodelinducedcompletetumorregressionsinoverhalfofthemice,whiletreatmentwitheither vaccinealoneorhyaluronidasealonedidnotinduceanycompleteregressions.
Our firstaimi stocharacterize changestothetumormicroenvironmentuponhyaluronidasetreatmentincombinationwithourDNAvaccines, andtodeterminethespecificcontributionsofhmwandlmwHAtothesephenotypes.
Our secondaimi sto determinethemechanismofactionofthiscombinationtherapyusingfunctionalcellulardepletionexperiments, andagonisticorblockingantibodiestoHAreceptors.

Public Health Relevance

Amajorlimitationtocurrentimmunebasedtherapiesisthedenseenvironmentaroundthetumor, whichsuppressesimmunecells.Specifically,themoleculehyaluronanisabundantinprostateandpancreatic carcinoma,andhasimmunesuppressiveproperties.Here,Iproposetoutilizehyaluronidase,anenzymethat degradeshyaluronan,inatreatmenttoimprovetheefficacyofDNAvaccineimmunotherapyforpancreatic cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA213795-02
Application #
9451929
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakowlew, Sonia B
Project Start
2017-04-01
Project End
2018-10-19
Budget Start
2018-04-01
Budget End
2018-10-19
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Duperret, Elizabeth K; Trautz, Aspen; Ammons, Dylan et al. (2018) Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice. Clin Cancer Res 24:1190-1201
Duperret, Elizabeth K; Trautz, Aspen; Stoltz, Regina et al. (2018) Synthetic DNA-Encoded Monoclonal Antibody Delivery of Anti-CTLA-4 Antibodies Induces Tumor Shrinkage In Vivo. Cancer Res 78:6363-6370
Duperret, Elizabeth K; Wise, Megan C; Trautz, Aspen et al. (2018) Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT. Mol Ther 26:435-445
Walters, Jewell N; Ferraro, Bernadette; Duperret, Elizabeth K et al. (2017) A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity. Mol Ther 25:976-988
Veglia, Filippo; Tyurin, Vladimir A; Mohammadyani, Dariush et al. (2017) Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Nat Commun 8:2122
Muthumani, Kar; Marnin, Liron; Kudchodkar, Sagar B et al. (2017) Novel prostate cancer immunotherapy with a DNA-encoded anti-prostate-specific membrane antigen monoclonal antibody. Cancer Immunol Immunother 66:1577-1588