National Cancer Institute Alliance For Nanotechnology In Cancer 15 .

National Cancer Institute Alliance forNanotechnology in Cancer 15 years PerspectivePiotr GrodzinskiNational Cancer Institute2020 NSF Nanoscale Science and Engineering PortalNanotechnology Frontiers at 20 years of NNIProceedings, December 1, 2020, www.nseresearch.org/2020/

Physics and Engineering Innovationin Biology and MedicineYuri Lazebnik, Cancer Cell, Sept 2002The Back Page: The Impact of Physics on Biology andMedicine, By Harold VarmusFor at least several hundred years, physicists-and especiallytheir principles, methods and machines-have been illuminatingour views of the human body and of every other living thing.APS Centennial meeting inAtlanta on March 22, 19992

NNI Humble Beginnings3

National Nanotechnology Initiative (NNI)Spending by Agency NIH has been growing its nanotechnology funding after initial wave of investments from NSF,DOD, and DOE to benefit from maturing materials scienceNIH is currently responsible for largest portion of NNI investment4

NCI Alliance for Nanotechnology in CancerProgram ObjectivesNCI investment of almost 400M over15 years was strongly leveraged withadditional funds from philanthropy andindustryresearch discoverypre-clinicalChallenge areas: Early diagnosis using in vitro assays anddevices or in vivo imaging techniques Multifunctional nano-therapeutics and posttherapy monitoring tools Devices and techniques for cancerprevention and controlResearch and translational capabilities todevelop new cancer interventions based onnanotechnologyMost promising strategies discovered anddeveloped by grantees in academia are handedoff to for-profit partners for effective clinicaltranslation and commercial developmentclinicalFrom basic to translational research: Fundamental understanding ofdelivery mechanisms andcharacteristics of nano-devices Translation and commercialization ofmaturing technologies5

NCI Alliance for Nanotechnology in Cancer(since 2005)Sun-set in Summer 2020after 15 years of operationDevelops comprehensive solutions tosignificant problems in cancer biology and/oroncology and produces cancer careinterventions with clinical utilityTrains next generation workforceinmulti-disciplinary, multi-mentorenvironmentCenters for Cancer NanotechnologyExcellence (CCNE), RFA – U54Multi-disciplinary TrainingT32 Awards (Center for Cancer Tr.)Innovative Research in CancerNanotechnology (IRCN), PAR - U01/R01Nanotechnology CharacterizationLaboratoryDevelops fundamental understanding of theprocesses associated with the use ofnanotechnology in cancerPerforms pre-clinical characterization ofnanomaterials used in nano-therapeutics insupport of their clinical translation Close to 400M for all Alliance programs approved by the NCI Executive Committeeto-date; Scientific output 4000 publications over 15 years; Translating technologies through formation of start-up companies (over 130to-date); Over 20 clinical trials have been pursued by start-ups.6

Evolution of Program FocusCancers with lowsurvival rates:brain, lung,pancreas, ovarianPre-clinical,Translational,Technology DrivenCancer Types15 yearsResearch15 yearsSupported by basic/fundamental research Nanoparticle development; Development of invitro diagnosticdevices; Technology platformsapplicable to range ofsolid tumors.Encouraged to concentrateon cancers that have beencharacterized at themolecular genetics levelPre-clinical, Translational,Oncology/Cancer BiologyDriven Continuing to build anunderstanding ofdeliverymechanisms; Nano-constructs tailoredto a specific cancerapplication; Approaches to supportprecision medicine andpatient stratification.7

Forward StrategiesSeeking community input to formulate 5-year strategic developmentplans for cancer 8

Breakdown Among Different Cancer Interventionsin 3 Phases of the Alliance GrantsHartshorn CM, Russell LM, Grodzinski P. National Cancer Institute Alliance for nanotechnology in cancerCatalyzing research and translation toward novel cancer diagnostics and therapeutics. Wiley Interdiscip RevNanomed Nanobiotechnol. 2019 Nov;11(6):e15709

Trends in Publishing Investigators representing physics, chemistry, engineering gradually shifted focus of their publications fromnon-medical nanotechnology (indicated as “Nanotech” in red) to medical applications (“Biomedical” in blue); Investigators, who traditionally researched cancer and medicine, began to involve more nanotechnologies intheir work as demonstrated by growing “Nanotech” (red) portion of their publicationportfolio.10

Commercial OutcomesSeveral companies were formed based on licensing technologies from the Alliance investigators’laboratories11

Leveraged Fundsequity 160M NCI support for 4 CCNEs funded in all 3 Phases (Stanford, Caltech/UCLA,Northwestern, UNC) resulted in significant additional funding from the government, philanthropy,and venture capital and enabled performing additional research and clinical translation12

Ending CCNEs after 15 yearsReactions in the PressPiotr Grodzinski, National Cancer Inst.Kinam Park, Purdue UniversityVictor C. YangCollege of Pharmacy, University of Michigan13

Nano- R01 Applications at NCI11nano R01 Applications70010600950087400630052004100032008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018nano R01s as % of All NCI R01 Applications128002Year Number of nanotechnology R01 applications to NCI has been growing rapidly;Alliance Nanotechnology program acted as a seed and enabler to expanding NCI nanotechnologyportfolio14

Current NCI Nanotechnology FOA PortfolioThe Innovation Emphasis vs. Translational EmphasisDiscoveryParent R01 applicationsMechanistic studiesFurther understandingIRCN PAR-20-284‘Innovative Research inCancerNanotechnology’TranslationTTNCI PAR-20-116:‘Toward Translation ofNanotechnology CancerInterventions’15

Nanotechnology CharacterizationLaboratory (NCL)Dendritic cellsNK nMolecular weightSurface ntRBC proteinMast cellsGranulocytesMacrophageIn Vitro:PharmacologyBlood contactpropertiesImmune cell http://ncl.cancer.gov/assay cascade.aspIn Vivo:ADMESafetyEfficacy16

Nanotechnology CharacterizationLaboratory (NCL)17

Nanoparticles in MedicinePubmed Entries Per YearPublications involving nanoparticlesYear Research in nanomedicine has been growing at a very rapid pace Is clinical translation lagging behind?18

Approved Cancer Drug TherapiesBased on NanotechnologyApproval date2019 ticle materialDrugIndicationLocally-advanced soft tissuesarcoma (STS)Hafnium ute myeloid leukemiaMerrimack PharmaLiposomeIrinotecanPancreatic cancerTalonLiposomeVincristineAcute lymphoid bo2010 (EU)NanoTherm2009 (EU)MepactTakeda2007 (South Sigma-tau2005AbraxaneAbraxis/Celgene2000 (EU)Myocet1999PharmaMagforceNanotechnologiesIron oxide nanoparticleMifamurtide MTP-PEOsteosarcomaPaclitaxelBreast cancer, Lung cancer,Ovarian minPaclitaxelBreast cancer, Pancreatic cancer,Non-small-cell lung cancerCephalonLiposomeDoxorubicinBreast CancerDepoCytPaciraLiposomeCytarabineNeoplastic meningitis1998 (Taiwan)Lipo-DoxTaiwan LiposomeLiposomeDoxorubicinKaposi’s sarcoma, Breast cancer,Ovarian meDoxorubicin1995199920032007 lastomaPEG-PLA polymericmicellePolymer proteinconjugateKaposi’s sarcomaKaposi’s sarcoma,Ovarian cancer,Breast cancer,Multiple myeloma19

Where does Nanomedicine Stand? Several nanomedicines have been approved by FDA to-date, but majorityof them rely on liposomal delivery of known (previously FDA-approved)active pharmaceutical ingredients (APIs); These nanomedicines resulted in significant reduction of side effects, butdemonstrated only modest improvement in survival; Quest for new nanoparticle designs and delivery of wider range oftherapeutic molecules is on-going.20

Expanding Scope of Nano-therapies “Smart” delivery of established drugs: toxicity reduction and tumor accumulation“Making new tricks with old drugs” Protecting, stabilizing, and enabling delivery of new classes of agents (e.g., nucleicacids) Co-encapsulated, multi-drug formulations for synergistic effects with nonoverlapping toxicities Theranostics for real time imaging, prediction of response, and advise patientselection Targeting and recruiting the immune system for improved immunotherapy andvaccination and addressing immune-resistance Combination with physical therapies (Radiotherapy, Hyperthermia, PDT )Focus efforts on enhancing efficacy andimproving survival as compared to existinginterventionsfrom Alberto Gabizon,Hebrew University21

Expanding Scope of Nano-therapiesvan der Meel R, Sulheim E, Shi Y, Kiessling F, Mulder WJM, Lammers T.Smart cancer nanomedicine. Nat Nanotechnol. 2019 Nov;14(11):1007-1017.22

Correlating Nanomaterial Designwith Suitable Cancer Applications Nanoparticles can be used as carriers of drugsmoleculesTheir material characteristics can also achievetherapeutic effect23

Assuring Success ofNanomedicine Trials Nanomedicines are moving through the translational pipeline; four approvals were issued inlast 5 years: Onivyde (liposomal irinotecan) for pancreatic cancer from Merrimack Pharma; Vyxeos (liposomal cytarabine/daunorubicin) for AML from Celator/Jazz Pharma; Onpattro (RNAi) for polyneuropathy in hereditary amyloidosis from Alnylam; Hensify (hafnium oxide nanoparticle) from Nanobiotix; Effectiveness of nano-formulations and success rates of trials will be enhanced by: New therapeutic loads; More rigorous design of clinical trials.Hare JI, Lammers T, Ashford MB, Puri S, Storm G, Barry ST. Challenges and strategies in anti-cancernanomedicine development: An industry perspective. Adv Drug Deliv Rev. 2017Jan 1;108:25-38.24

Future Priorities and Directions forNanomedicine Expand the range of delivery molecules; Build on immunotherapy opportunity; Leverage combination therapies; Use patient stratification as means to enhance nanodrug efficacy; Use imaging to provide further insight into heterogeneity of EnhancedPermeability and Retention (EPR) effect; Explore further in vitro diagnostic opportunities; Consider ‘evolutionary’ vs ‘revolutionary’, when identifying applications; Remember basic research!! Continue nanomaterials innovation; Continue building the community by engaging more oncologists anddeveloping training and degree programs; Rely on the industry experience for effective translation.25

Acknowledgements:Nanodelivery Systems and Devices BranchChristina Liu, PhD, PEProgram DirectorChris Hartshorn, PhDProgram Directorhttp://www.cancer.gov/sites/nano26

Nanotechnology in Cancer 15 years Perspective 2020 NSF Nanoscale Science and Engineering Portal Piotr Grodzinski . Number of nanotechnology R01 applications to NCI has been growing rapidly; Alliance Nanotechnology program acted as a seed and enabler to expanding NCI nanotechnology