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Educational Web Seminar
Accelerating Your Cell Therapy: A PACT Program UpdateMonday, 11 February 2019
12:00 noon – 1:00 PM ET
Lis Welniak, PhDDirector
PACT ProgramNational Heart, Lung, and Blood Institute, NIH
Robert Lindblad, MDPrincipal Investigator and Chief Medical Officer
PACT Program Coordinating CenterThe Emmes Corporation
Ann M. Leen, PhDAssociate Professor
Department of PediatricsBaylor College of Medicine
David H. McKenna, Jr., MDDirector
Molecular and Cellular Therapeutics FacilityUniversity of Minnesota
Collaboration with NHLBI/NIH programs
PACT program updates- clinical scope, regulatory services, and information on application process
Examples of 2 previous PACT clinical projects
Q&A
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Educational Web Seminar
Accelerating Your Cell Therapy: A PACT Program UpdateMonday, 11 February 2019
12:00 noon – 1:00 PM ET
11 February 2019
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PACT - Collaboration
Lis Welniak, PhD
Program Director, PACT
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
PACT - Collaboration
• NIH Regenerative Medicine Innovation Project (RMIP)
• NHLBI Cure Sickle Cell Initiative
• And with other NIH and NHLBI Programs
Collaboration
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• 21st Century Cares Act passed in December 2016
• Support for clinical research on adult stem cells
• NIH released 4 funding opportunities, applications were due October 19, 2018
• PACT to offer RMIP awardees:
• technical and administrative services to assist with FDA regulatory requirements
• Phase-appropriate manufacturing assistance for the development of their clinical-grade product
NIH Regenerative Medicine Innovation Project (RMIP)
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• Launched in September 2018
• To accelerate the development of genetic therapies to cure sickle cell disease
• PACT will support the Cure Sickle Cell Initiative by enabling increased capacity to safely manufacture cellular therapy products through cell processing facilities capable of producing cGMP-grade genetically modified cells
• PACT currently providing regulatory support services to investigators
• Pre-IND meeting package preparation
• Pre-IND meeting support
Cure Sickle Cell Initiative
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• PACT mission• to support the production and testing of novel cell therapies, particularly in
relation to the strategic goals, objectives and research priorities of NHLBI https://www.nhlbi.nih.gov/about/strategic-vision
Collaboration
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Production Assistance for CellularTherapies (PACT) Program
NHLBI
Robert Lindblad, MDChief Medical Officer
The Emmes CorporationPI PACT Coordinating Center
Production Assistance for CellularTherapies (PACT) Program
NHLBI
Objectives
• What is PACT?
• Why contact PACT?
• How do I contact PACT?
Email: [email protected]
Website: www.pactgroup.net
• PACT PROGRAM• Program, cell types, application for manufacturing
assistance
• Education
• Technical projects
• REGULATORY SUPPORT• Gap analysis
• FDA meeting support
Outline
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NHLBI‐funded initiative
• PACT 1: Began in September 2003‐2009 (1 year no cost extension)
▫ 3 facilities/1 Coordinating Center. Scope ‐ clinical product support
• PACT 2: Renewed in January 2010‐2015
▫ 5 facilities/1 Coordinating Center. Scope ‐ clinical/translational
• 1 ½ year hiatus
• PACT 3: Re‐awarded in July 2016
▫ 5 facilities/1 Coordinating Center. Scope ‐ preclinical/translational
Current MissionProvide assistance with cellular therapy translational research and the manufacture of cellular therapy products
PACT Program
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PACT Organizational Structure
Steering Committee
National Heart, Lung, and Blood Institute
Expert Evaluation Panel
5 Cell Processing Facilities Coordinating Center (The EMMES Corporation)
Baylor Collegeof Medicine
CAGT
Universityof Minnesota
MCT
Universityof Miami ISCI
Moffitt Cancer Center
Center for Biomedicine and
GeneticsCity of Hope
Scope
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• Products and services of programmatic interest to theNational Heart, lung and Blood Institute
• Products that aid in the repair and regeneration ofdamaged/diseased tissues, organs, and biologicsystems
• Cell therapy manufacturing for preclinical studiesincluding basic and translational work
• Cell therapy manufacturing for phase 1/2 clinical trials
• Regulatory support
• Proposals possessing procedural advancements tofurther foster and standardize cell therapies
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PACT’s Role in Supporting Preclinical Work and Early Phase Clinical Trials
• Dose escalation;• Safety/toxicity studies;• Small trial size
IND Filing
Pre-clinical
Dose ranging;safety and efficacy studies; increasetrial size
Efficacy and safety studies; full product characterization; potency; scale up;full GMP
Discovery; Proof of concept; cell product potential; therapeutic mechanism and pathway; cell and disease interaction
Phase I, early Phase 2Phase IIBasic Research Phase III
*Manufacturing• Scale up• Validation• Release Criteria• CMC*Animal Studies• GLP/GMP product• Efficacy• Toxicity
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Educational Resources
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• SOPs▫ 309 individual requests totaling >1275 individual SOP
distributions▫ 113 US Institutions/sites and 22 international countries
Most requested
Regulatory Support
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Phase1, early Phase2 Clinical cell
manufacturing Dose escalation Safety/Toxicity
studies
GLP/GTP/GCP Manufacturing Scale-up Validation Release criteria CMC
Pre-clinical Studies Cell manufacturing
for animal studies Assay development
PACT-supported Translational Services
PACT-supported Clinical Manufacturing Services
Cell Manufacturing for IND-enabling and Early Phase Clinical Studies
Phase1, early Phase2 Clinical cell
manufacturing Dose escalation Safety/Toxicity
studies
GLP/GTP/GCP Manufacturing Scale-up Validation Release criteria CMC
Pre-clinical Studies Cell manufacturing
for animal studies Assay development
PACT-supported Translational Services
IND Filing
PACT-supported Clinical Manufacturing Services
PACT-supported Regulatory Services
Cell Manufacturing for IND-enabling and Early Phase Clinical Studies
• GAP Analysis• INTERACT/Pre-IND
meeting preparation• CMC development• IND Filing
• Provides insight into what additional work may beneeded to support an IND application
• Geared toward an understanding of how the datagenerated from Proof of Concept, non-clinical and CMCdevelopment map to the requirements of an INDapplication
• Recommendations for facilitating a successful a PACTRequest for Service Application (RSA)
GAP Analysis
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FDA Meeting support
FDA communication and assistance:• INTERACT and pre-IND meeting scheduling and planning• Developed questions to ask the agency
• Content• Format
• Quality of the CMC information• Status of the Pre-clinical information• Status of the general investigational plan and proposed
clinical indication• Adequate phase 1 synopsis, defined activity evaluation and
protocol
FDA Meeting Support
• Serious or life threatening disease
• Disease or condition associated with morbidity thathas substantial impact on day-to-day functioning
• Unmet medical need
• A condition whose treatment or diagnosis is notaddressed adequately by available therapy
Definitions for Acceleration of Review
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• Orphan Designation
• Special Protocol Assessment
• Accelerating Development• Fast Track
• Breakthrough Designation
• Priority Review
• Accelerated Approval
• Regenerative Medicine Provisions
• Electronic submissions
Other Regulatory Considerations
Contact Information
Lani Ibenana or Ashraf El Fiky
Phone: 301-251-1161
Email: [email protected]
Website: www.pactgroup.net
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T cell therapy for viruses
Ann Leen
Viral infections post-transplant
• 40% deaths after alternative donortransplant due to viral infections
• Antiviral drugs–Costly–Significant side effects–Often ineffective
• Alternative - Adoptive T cell transfer
InfusionCell
expansion
Virus-specific T cellsSC
T r
ecip
ient
Antigen Specificity
Adoptive T cell
transfer
Blood draw
Donor lymphocytes
SC
T d
onor
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Immunotherapy for viral infections
• Virus-specific T cells as prophylaxisand treatment–EBV–Adv/EBV (bivirus)–Adv/EBV/CMV (trivirus)
Generation of trivirus-specific T cell lines using Ad5f35 vectors
6 wk
PBMCs EBV LCL
B95-8 EBV virus Ad5f35pp65 vector
Ad5f35pp65transduced EBV LCLs
PBMCs
Ad5f35pp65 vector
Restimulation
6 wk
+IL2
• In vitro expanded donor-derived virus-specific T cells targeting Adv, EBV, CMV
–Safe–Reconstituted antiviral immunity for
EBV, CMV and Adv–Effective in clearing disease–Considerable expansion in vivo
Clinical Outcome Summary –Donor-specific setting
Leen et al, Nat Med. 2006Leen et al, Blood. 2009
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InfusionCell
expansion
Virus specific T-cellsSC
T r
ecip
ient
Antigen Specificity
Adoptive T-cell
transfer
Blood draw
Donor lymphocytes
SC
T d
onor
Limitations
- Cost
- Complexity
- Limited viral range
Cost
6 wk
PBMCs EBV LCL
B95-8 EBV virus Ad5f35pp65 vector
Ad5f35pp65transduced EBV LCLs
PBMCs
Ad5f35pp65 vector
Restimulation
6 wk
+IL2
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EBV LCL
Ad5f35pp65
15mer pepmixes
Target antigens- EBV- EBNA1, LMP2, BZLF1- CMV- IE1, pp65- Adv- Hexon, Penton
Reduce cost:Replace virus/vector with peptides
1
10
100
1000
10000
HEXON PENTON IE1 PP65 EBNA1 LMP2 BZLF1 NO PEP
AdV CMV EBV
Specificity
SF
C/2
x10
5
Reduce cost – peptides
Complexityday 0 – VST initiation 2.4 x 107
day 12 – IL2 feed
day 20 – split + IL2 feed
Day 30 - harvest/freeze
day 27 – split + IL2 feed
3.6 x 108
day 9 - restim 2 x 107centrifuge
day 16-harvest and reseed 6 x 107
centrifuge
day 23 – harvest and reseed 1.2 x 108
centrifuge
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Reduce complexity:Simplifying Production using G-Rex devices
• Gas permeable membrane allows CO2/O2 exchange• Supports cell growth with large volumes of media• Reduces feeding frequency and manipulation• No rocking or stirring
G-Rex 10
CO2
O2
Manufacturing limitations
Reduce cost – peptides
Reduce complexity – G-Rex
Extend target viruses - HHV6+ BKGerdemann et al, Blood, 2013
Gerdemann et al, Mol Ther, 2012
Vera et al, JIT, 2010
Clinical trial – PACT application
AdV– Hexon, PentonEBV– EBNA1, LMP2, BZLF1CMV– IE1, pp65BKV– LT, VP1HHV6– U11, U14, U90
ARMS - Rapidly generated T cell lines targeting 5 viruses
Papadopoulou et al, Sci Trans Med, 2014
mVSTs(multivirus VSTs)
+IL4/7
T cell stimulation/ expansion
10 days
PACT - 0053
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• 11 pts infused on study: 4 pts: 5x106/m2 (DL1) 4 pts: 1x107/m2 (DL2) 3 pts: 2x107/m2 (DL3)
• No dose limiting toxicity• 1 Grade II skin GvHD (improved with topical steroids)
• 3 infused prophylactically• All remained infection-free for at least 3 months
• 8 pts had active infections
Patients infused
Patient with AdV CMV EBV BKV HHV6
1 virusx
x
2 viruses
x x
x x
x x
3 virusesx x x
x x x
4 viruses x x x x
8 pts treated for infections
0
50
100
150
200
250
1
10
100
1000
10000
100000
1000000
wk-3 wk-2 wk-1 Infusion wk1 wk2 wk3 wk4 wk6 wk8 wk12
SF
C/5
x105
Adv
cop
ies/
ml
Viral load AdV T cells
Clinical response - Pt with AdV
mVSTs
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0
100
200
300
400
500
600
1
10
100
1000
10000
100000
1000000
wk-2 wk-1 Infusion wk1 wk2 wk3 wk4 wk6 wk8 wk12
SF
C/5
x105
EBV T cells
Clinical response - Pt with EBV-PTLD
mVSTs
Viral load
Pre mVSTs Post mVSTs
EB
V c
opi
es/μ
g D
NA
0
200
400
600
800
0
10
20
30
40
50
60
Pre wk3 wk5 wk6 wk8 wk12
CMV T cells
Viral load
Clinical response - Pt with CMV
mVSTs
Ant
igen
emia
(C
MV
)
SF
C/5
x105
0
20
40
60
80
1
10
100
1000
10000
wk-3 wk-2 wk-1 Infusion wk1 wk2 wk3 wk4 wk6 wk8 wk10 wk12
1.E+00
1.E+02
1.E+04
1.E+06
1.E+08
1.E+10
wk-3 wk-2 wk-1 Infusion wk1 wk2 wk3 wk4 wk6 wk8 wk10 wk12
BKV T cells
Clinical response - Pt with BKV
Viral load
Viral load
SF
C/5
x105
BK
V c
opie
s/m
lB
KV
cop
ies/
ml
Blood
Urine
mVSTs
mVSTs
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0
5
10
15
20
25
1
10
100
1000
10000
Infusion wk1 wk2 wk3 wk4 wk6 w8 w12
Viral load
HHV6 T cells
Clinical response - Pt with HHV6
mVSTs
HH
V6
copi
es/m
l
SF
C/5
x105
Outcomes
• Complete response: (√)
viral load to the normal range
resolution of clinical signs/symptoms
• Partial response: (PR)
>50% reduction in viral load
Patient with AdV CMV EBV BKV HHV6
1 virusx
2 viruses
PR
3 viruses
x 4 viruses PR
8 pts treated for infections
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Conventional Rapid
SpecificityAdV, EBV, CMV AdV, EBV, CMV,
BK, HHV6
Blood vol. 60ml 20ml
Cells LCL, VSTs VSTs
Time 56-84 days 10 days
Cell # 200x106 390x106
Old vs New
Papadopoulou et al, Sci Trans Med, 2014
Summary• Feasible to generate broad spectrum
VST products
• Manufacturing simple and robust
• VST therapy safe
• VST therapy effective
Thanks
CAGTLisa RollinsShanna Fulton
CAGT PIsJuan VeraHelen HeslopCliona RooneyMalcolm Brenner
Leen-Vera LaboratoryAyumi WatanabeManik KuvalekarPremal LullaShivani MukhiSpyridoula VasileiouTsung-Yen ChangNorihiro WatanabePradip BajgainSujita SukumaranAndrew JacksonAlejandro TorresYovana VelazquezElizabeth Laval
Ulrike GerdemannAnastasia PapadopoulouIfigeneia Tzannou
Clinical ResearchBambi GrilleyAmy Reyna
QA/QC Laboratory
Adrian GeeSara RichmanNatasha LaptevaMygiao LeDebbie LyonApril DurettCrystal Silva-Lentz
Clinical PIsBilal OmerRobert KranceCarlos RamosPremal LullaSwati NaikStephen Gottschalk
GMP LaboratoryHuimin ZhangBirju MehtaGouqing GeSilvana PercontiJuntima Sritabal-Ramirez
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PACTA resource for both pre‐clinical and clinical support
PACT Webinar
11FEB2019
David McKenna, MD
University of Minnesota
Disclosures
• No conflicts of interest
• Cell manufacturing support throughProduction Assistance for Cellular Therapies(PACT)/NIH
Objective
• Describe an example of NIH/PACTmanufacturing in support of pre‐clinical, IND‐enabling studies and ultimately clinicalmanufacturing for phase I and phase II studies
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The beginning…
Dr. Michael Matthay, M.D.Professor of MedicinePulmonary, Critical CareUC‐San Francisco
• Initial request was for mesenchymal stromal cells (MSC) manufacturing support for a phase I clinical trial in acute lung injury (ALI)
• Research team had worked for years on MSCs in ALI
• Now wanting to move into clinical trials• First step was a pre‐IND call with FDA
Molecular & Cellular Therapeutics
Pathogenesis of Acute Lung Injury
MSC & ALI ‐ Rationale
‐ Anti‐inflammatory properties
‐ Restore endothelial & epithelial barrier integrity
‐ Enhance alveolar & lung edema fluid clearance
‐ Anti‐microbial properties
‐ Anti‐apoptotic effects
‐ Cell contact dependent & independent effects
Ware & Matthay,NEJM, 2000
?
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Brief Summary of Proof‐of‐Principle and Pre‐Clinical Studies
Gupta N, et al. The Journal of Immunology, 2007
Survival:
80% vs. 42% at 48 hr 64% vs. 18% at 72 hr
In vivo
Ex vivo
Frank J et al. AJP:Lung , 2007Lee JW et al, PNAS, 2009
FDA requests large animal studies…
MSCs for ALIIn preparation for Ph I Trial
Clinical‐Grade (UM‐made) MSC in theEx Vivo Perfused Human Lung Model of ALI
Michael Matthay, M.D.
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MSC Manufacturing
• Trilineage assays• KGF assay
• 3rd party MSCs• Limit donors • 3-5 billion cells/lot• Ph II:
• 1 billion cells/pt• 40 patients (cells)• 8-13 lots needed• Packaging
Research/pre-clinical: NIH MSC Repository (Tulane/Texas Tech, Prockop) Pre-clinical/pre-IND: NIH PACT Group (U of MN)
In vivo (large)
Ex vivo
In vivo (small)
In vitro
Human clinical trials
Roadmap for Translation of Human Mesenchymal Stem Cells to a Clinical Trial for Acute Lung Injury
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Mouse Experiments
Ex Vivo Perfused Human Lung Experiments
Rat Studies
Sheep Studies
Pre‐IND Consultation, Submission, &
Approval
NHLBI U01
Phase 1 Trial
Phase 2 Trial
*
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More details on trials…
Acknowledgements
CT Lab:Diane KadidloDarin SumstadLisa VanOrsowNancy BostromSheryl AdamsNancy ColeyCindy StanawayLien LeMolly CarlsonAnh DoStacy LinnKristen ReynaJulie LaTourLeyla Hassan
MCT QA:Fran RabeAlison JakubekMaria Opitz&
Materials Management/Administrative & Support Staff
MCT
UCSF/ClinicalMichael MatthayJae Woo LeeNaveen GuptaKathleen D. LiuCarolyn S. CalfeeDanny McAuleyAnna KrasnodembskayaEJ ReadLiz LeiningerLizette CaballeroAndrew LeavittU of TX, U Pitt, MGH, Stanford, OSU
Thank you!
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Accelerating Your Cell Therapy: A PACT Program Update
Contact UsPACT Coordinating [email protected]
Robert [email protected]
David [email protected]
We are listening!
• How helpful was today’s web seminar?• What other cell therapy topics are you
interested in learning about?
Complete this 5-minute survey to let us know:https://www.surveymonkey.com/r/11Feb2019PACTwebinar
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On-demand Web Seminars
Today’s web seminar (presentation slides, audio/video recording) and previous web
seminars are available publicly at www.pactgroup.net
Select Education PACT Web Seminars
Thank you for attending!
To register for updates on upcoming web seminars visit us on the web at:
www.pactgroup.net
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