hesc-derived cell therapies: safety in translation...2017/10/08 · the state stem cell agency...
TRANSCRIPT
The state stem cell agency
Tuesday, February 10, 2009 1
HESC-DERIVED CELL THERAPIES: SAFETY in TRANSLATION
Marie Csete MD, PhDChief Scientific Officer
California Institute for Regenerative Medicine
June 26 & 27, 2008 2
2
TIME TO COLLECTIVELY CATCH OUR BREATH
-FDA HEARING APRIL 2008
-SAFETY OF HESC DERIVATIVES:MAJOR CONCERNS
-CIRM IS INITIATINGDISEASE TEAMS 2009WITH IND APPLICATIONAS 4 YEAR MILESTONE
-EARLY TRANSLATION:BOTTLENECKS
June 26 & 27, 2008 3
3
SAFETY is #1
Historical precedent: Gene therapy• Acute procedure (surgical) risks
– Pain should be more of a consideration• Transmitted disease from donor• Xenogeneic contamination• Rejection• Survival (non-immune mediated death)• Tumorigenicity• Unintended consequences
– Fusion, transdifferentiation poorly understood
June 26 & 27, 2008 4
4
Transmitted disease from donor:Should be controllable
INFECTIONEnormous precedents from FDA:
Blood banking and solid organ transplantationStandardized assays available
(HIV, CMV, HTLV, hepatitis, etc.)Plus…added time to analyze master banks
XENOGENEIC VIRUSES: Also established guidelines
ADDITIONAL TESTING—Cancer risk? Donor re-contact?
June 26 & 27, 2008 5
5
Xenogeneic contaminants
• Routine for hESC growth & differentiation• All companies presenting at April FDA meeting
used non-human reagents in their product mfr• Scale-up with human excipients: $$$• Safety can be addressed: Individualized assays
June 26 & 27, 2008 6
6
Allogeneic immune response
• Every cell type different• Differentiation-dependent immunogenicity• Pre-clinical studies should cover all stages of
differentiation• Rodent models (even primate models) not
predictive of human reaction• Immune privilege (CNS) is relative
– Long-term: Autologous survival in brain is superior• Monitoring by biopsy
June 26 & 27, 2008 7
7
What is reasonable for an immunosuppression plan?
-- Pre-clinical exposure of cultured cells to drug--Conservative withdrawal of immunosuppression
-monitored (how?)-Phase I: Is the graft still there?
-- Transplant immunologist involvement-- Extensive data collection
-major and minor histocompatibility-allogeneic vs. autoreactive T cells-non-invasive assays from solid organ tx
--How can we capture the power of UNOS?
June 26 & 27, 2008 8
8
Targeted research
OPTIMAL IMMUNOSUPPRESSANT DRUG?Unusual effects of drugs on undifferentiated cells
ALLOGENEIC REACTIONS TO CELL RX: UNPREDICTABLE– Differentiation state– Single cell vs. clusters– Heterogeneity of transplanted population/angiogenic properties– iPS cells don’t guarantee immune tolerance
TOLEROGENIC STRATEGIESFeb 4-5 CIRM Immunology Workshop
NON-INVASIVE MONITORING ASSAYS
June 26 & 27, 2008 9
9
Tumorigenesis
• Major concern at April FDA hearing: Teratoma• Other proliferating cells as tumor sources?
– Placental/amniotic SC: Pluripotent but senesce (not 100%)
• Subtle chromosomal abnormalities• Particularly a problem for CNS applications• How long should animals be monitored?• Undifferentiated ESC à teratomas
– Reliance on differentiation protocol• Suicide genes? (Driven off Oct-4)• In theory: iPS have same issues
June 26 & 27, 2008 10
Right now: No guarantees
-Sorting techniques vs.-Differentiation protocols-(In)Sensitive imaging-Other non-invasive assays to monitor early tumor
formation-Cancer ßà stem cells
Basic science: Self-renewal, environment
June 26 & 27, 2008 11
11
Other technical hurdles
• MIGRATION: All stem cells are migratoryHome to hypoxic sites
• SCALE-UP under GMP CONDITIONS– November 3 at CIRM
• POOR ANIMAL MODELS- Underestimate human disease heterogeneity, complexity- Incomplete vs. complete SC injury - No large animal model for traumatic injury?
• DRUG-CELL INTERACTIONS- Specific to target disease- P450 expression in undifferentiated stem cells
June 26 & 27, 2008 12
Trial design: Phase I/II
• Efficacy end-points ideally incorporated into Phase I• Becomes indirect monitor of graft survival• Can speed translation by years, if Phase I is well-
designed• Almost all applications require objective pain monitoring
– Our results showing decreased pain with mixed marrow tx vs. fusion with peripheral nerve and increased pain
– GABA, endothelins, ?channels• Quantitative end-points by trained domain experts
– Important quantitative end-points not monitored well in animals– Quantitative pain testing requires real expertise
June 26 & 27, 2008 13
What is the best first application for hESC-derived rx?
June 26 & 27, 2008 14
DISEASE TEAM PLANNING AWARDS(and other conversations)
Muscular dystrophiesALSSMAMSCancers (Brain, many others)Type I DiabetesAlzheimer’s diseaseESLDInherited metabolic disordersARDSMITraumatic injuries (spinal cord, craniofacial, burn)Senescence of various organ systems
June 26 & 27, 2008 15
Spectrum of opinion
• HYPERACUTE
• LIFE-SPAN LIMITED
• CHRONIC, INTOLERABLE
• ANTICIPATED COMPLICATIONS
RISKSAFETY
SAFETYRISK
June 26 & 27, 2008 16
16
• Hyperacute disease– Unless new, compelling animal models emerge, not
easy to justify now. (What will we learn?)• Shortened life-span (ALS, DMD, SMA)
– Excellent historical controls (ALS)– Immunosuppression preferable to death– Patients don’t tolerate placebo-controlled trials
• Chronic, debilitating diseases– Higher safety standard– Dependent on current rx options
Each has distinct risk: benefit
June 26 & 27, 2008 17
17
June 26 & 27, 2008 18
18
Learn from failure: DMD
• Human myoblasts won’t migrate any faster than mouse• How to target huge volume of muscle mass?
-Dog model studies essential• Anatomic vs. functional cure (strength) models well-
established, highly quantitative• Relative myogenicity of different myoblast progenitors
well-studied: New cell tools are available– HESC-derived– Mesangioblast– Satellite subpopulations
• Revisit failed clinical trials• Potential for palliation (and cure?)
– HOW TO TARGET RESPIRATORY MUSCLES?
June 26 & 27, 2008 19
ACTIVE PUSH TOWARD TRANSLATION
BASIC MECHANISMS OF CHROMOSOMAL STABILITY IN CULTUREBASIC MECHANISMS OF MIGRATIONNEW IMAGING TECHNOLOGIESBASIC IMMUNOLOGY RESEARCHNOVEL TOOLS FOR SORTING
NEW ANIMAL MODELS/HUMANIZED MODELS
SCALE-UP
SENSITIVE ASSAYS FOR TERATOMA FORMATIONSENSITIVE ASSAYS FOR REJECTION/STATE OF IMMUNE SYSTEMDEFINITION OF DISEASE MICROENVIRONMENTS
Plus…DISEASE TEAM EFFORT
June 26 & 27, 2008 20
20
HurdlesàOpportunity
• Identify the real problems– Fund their solution
• Identify non-problems– Work with regulatory agencies (using all our allies) to
prevent focus on trivial issues• Leadership
– Our vantage point is broad enough that we can see the big picture landscape
– Partnering increases the view: Canada, Australia, JDRF, UK; others in negotiation
– Open discourse with regulatory agencies on risk vs. benefit
June 26 & 27, 2008 21
21
• Terminal differentiation from hESC is harder than anticipated– Rely on in vivo differentiation in a hostile environment?– Inability to define the ‘final’ cell product
• Despite large resources we can’t go it alone
• hESC-derived therapies necessary for some diseases
• Patients are impatient for progress and have distinct ideas about safety
• The ‘country’ of stem cell researchers is divided– APRIL FDA RULING IS A SIGNAL THAT HESC-DERIVED
THERAPIES ARE FAR AWAY vs. UNPRECENDENTED INSIGHT INTO COMMON PROBLEMS THAT DESERVE RESEARCH FOCUS
– Glass is half-full
MAJOR INSIGHTS
June 26 & 27, 2008 22
June 26 & 27, 2008 23
23
Adult stem cells vs. ESC
MSCs being globally applied– Already reaching the clinic for bone defects– Cardiac applications: No Phase III yet– GVHD IV: Usually fatal– Transient responses in all cases when given into
circulation (re-dosing required)– Immunologic implications of re-dosing– Not strictly regenerative therapies
2/10/2009 24
Pipeline encompasses all the hurdles(with some targeted RFAs)
Approved IND
Disease Team
Tools & Technol
Training Grants
SEED
Comprehensive
New Faculty I, II
New Cell Lines
Bridges to Stem Cell Research
Innovation Awards
Development Candidate
Translational Research I
Preclinical hurdles Clinical Research
Laying theFoundation
Scheduled RFAsUpcoming RFAs
Basic biology