Cutting-Edge Health Technologies: Opportunities and Challenges Landscape ... · 2019. 11. 5. ·...
Transcript of Cutting-Edge Health Technologies: Opportunities and Challenges Landscape ... · 2019. 11. 5. ·...
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Cutting-Edge Health Technologies: Opportunities and ChallengesLandscape & Perspectives for Health Outcomes.
How CAR-T is likely to impactpublic health ... the “Spanish model”?
Manel Juan. MD, PhD Immunotherapy section. Servei d’Immunologia – CDB Hospital Clínic de Barcelona Immunotherapy platform H Sant Joan de Déu / BSTThursday, October 31th 2019 (10:30)WTO, Room W – Centre William Rappard - [email protected]
mailto:[email protected]
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• No conflict with commercial interests or companies, except in what corresponds to educational talks sponsored by some companies and recent participation (S-5) as member of an Oncology AdvisoryBoard of Grifols no-related with CAR-T therapy.
• Responsible of production of CART product (ARI-0001 cells) in patients with B-cell malignancies (CART19-BE-01 trial). Dossier in preparation for approval by AEMPS … but no-personal (economic) profit from it.
Conflicts of interest
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Killer T cell attacking cancer.mp4
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Tumoral cells
Changes in microenvironment
Immune memory(persistence)
Immune system:T-cell
Author’s figure
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Immune System• Internal (we already
have it) and holistic.• Continuously effective
(from infections to tumours).
• Specific
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Surgery
RADIOTHERAPY
ChemoTHERAPY
Imm
unotherapy
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ANTITUMORAL CELL-IMMUNOTHERAPY
TILs CARTsDCs
Knowledge+ Infrastructures (Clean rooms) + Regulation / Quality
Author figures
NK
TA
Vaccines TcR
SCT / DLIsAllo-recog nition
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scFv
Signaling domains(CD3ζ, CD28, …)
TM
What is a CART? T-cells engineered with CARs (Chimeric Antigen Receptor)
“Cytotoxic” T-cell
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CAR = Chimeric Antigen Receptor
Sònia Guedán Carrió & Anna Boronat BaradoChapter 6. Monografías SEI – Elsevier. “Inmunoterapia antitumoral con linfocitos genéticamente modificados (CAR): una realidad con futuro”
Antibody TcR Complex
1ª decription “T-bodies” byProf Zelig Eshhar (1995), Weizmann Institute of Science, Israel.
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An autologous product as a “live drug”
CAR T-cell
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Lymphocyte transduction of CAR*
PATIENT
LYMPHOCYTES
Blood
Leukoapheresis
Monitoring
UNDER GMP CONDITIONS
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CART+ lymphocytes against tumorCART infusion Cryopreservation
T-cell expansion byCD3 + CD28 beads
Cell expansion
CELL
THERAPY
Cell therapy => Advanced therapy product = “Drug“
CAR production
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CART19 : August 2011, “seminal” articles
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Hinge + Transmembrane
(CD8a)
scFv anti-CD19 = Tumor Antigen Recognition
Costimulatory domain(CD137 / 4-1BB = 2nd signal / 3rd signal)
Signaling domain
2nd generation CAR
VLVH
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Success of CARs: Patients n=185 (now near 1,000 ) Diseases Relapsed Refractory Heavily pretreated
Overall responseALL CLL NHL
81%/76%
Schubert ML/ Schmitt M Hum Gene Ther. 2016 Jul 31
40%/19%
Acute lymphoblastic leukemia (ALL)
Chronic lymphocytic leukemia (CLL)41
Non Hodgkin lymphoma (NHL)
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50%/26%
Approvals by FDA & MDA as “live drugs” -> Commercial production
PATIENTS (Public Health Systems)“Conditioned” CENTRALIZED
approval
2010 2017-18
Gráfico1
ALL
CLL
NHL
98
Verkauf
54
25
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Tabelle1
Verkauf
ALL54
CLL25
NHL24
Gráfico1
1. Quartal
2. Quartal
3. Quartal
Verkauf
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24
50
Tabelle1
Verkauf
1. Quartal26
2. Quartal24
3. Quartal50
Gráfico1
1. Tertial
2. Tertial
3. Tertial
Verkauf
76
2
22
Tabelle1
Verkauf
1. Tertial76
2. Tertial2
3. Tertial22
Gráfico1
1. Quartal
2. Quartal
3. Quartal
Verkauf
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Tabelle1
Verkauf
1. Quartal31
2. Quartal9
3. Quartal60
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Barcelona: From “our patients” to “our” CAR ANTI-CD19: ARI-0001
CGCCTTTT………………. ...TGTCGTGA
ATGG…....GGCCG
CACTCCCA.…Gly+Ser...Gly+Ser……. GAGCTGA
CACCACG………..……..……TTTACTGC
AAACGGGG………..……AAGGAGGA
AGAGTGAA…
…CTCGCTAA
V HV L
CD8a(hinge +
transmembrane)
scFv A3B1 CD137 / 4-1BB(Signaling domain)
CD3ζ(Signalling domain)
CD8a(signal peptide)
LENTIVIRAL SEQUENCES
LENTIVIRAL SEQUENCE
S
EF-1 PROMOTER
gDNA / lentivirus
mRNA
CAR Protein (transmembrane)
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RNART-PCR
Overlapping of products
DATA BASES + PREVIOUS RESULTS
SPECIFIC PRIMERS
Coding sequence for the chimeric receptor antigen : CAR
Construct
+
CAR
VECTOR
CELL THERAPY
PBMCs
T-cell transduction of CAR
CD3ζ
4-1BBTransmembrane
VL scFvVH * Vector Packaging Construct
HEK-293t cell line
Lentivirus
CAR production
PCR products Construct
PATIENT
LYMPHOCYTES
BloodLeukoapheresis
T-cell expansion byCD3 + CD28 beads
CART+ lymphocytes against tumor
Monitoring
Lymphocyte transduction of CAR
* *UNDER GMP CONDITIONS
CART infusion Cryopreservation
Cell expansion
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GMP facilities at HCB - UBC
D B
CellCleanrooms
VectorClean rooms
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Production of CAR vector (Lentivirus)
HCB/UB
Buorreactor HCB
Production of CAR-T
HCB
CAR-T infusion
Phase I ALL/NHL-CLLARI-0001 (anti-CD19)
HSJD
HSJDHCB
Lymphoapheresis
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1.- Role of hospitals in developing new technologies:
“Academic” products of cell immunotherapies (specially CARTs) are possible (at least in Spain )!!! 😉😉
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Production of CAR vector (Lentiv)
HCB
Biorreactor HCB
CAR-T Production
N=11
CAR-T infusion
Phase II LLA ARI001 (CD19)
HCB
CUN
CAR-T Production
N=5
CAR-T infusion
Phase I-II MM ARI0002 (BCMA)
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Production of CAR vector (Lentiv)
Biorreactor Biorreactor
HCB
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EudraCT 2019-001472-11
Spanish Hospitals
2.- CAR-T therapy in practice: ACADEMIC + INDUSTRIAL CARTs (collaboration)
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Clinicleukapheresis
Transfer to manufacturing
site
Manufacturing center
Transfer to
bedside
Clinic deliver
to patient Academic
CART manufacturing
Hospital
< 1 hour
< 1 hour
Inside manufacturing production
Clinicleukapheresis
Transfer to manufacturing
site
Manufacturing center
Transfer to
bedside
Clinic deliver
to patient
Outside manufacturing side
+1 days
+1 days
CommercialCART
manufacturing
7-10 days
7-10 days
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Pharma (vs Academic) CARTs• Distance between hospital and
manufacturing center.
• High Price / patient.
• After approval product maintained w/o changes: slow improvements.
• Academic CART proposals.
• New products by evolution of the knowledge.
• Few indications (no low frq TA).
• Accreditation: “Pharma” decides in some way
• Centralized approval (FDA, EMA, …): responsible of homogeneity of product.
• Specificity and documentation in indication
• Central Approval: Easy to be accepted by the patient / family.
• “Hierarchical” structure of the team• Present limitations of other cancer therapies.
• To define allogenic products (universal CARTs).
• To stabilize the option of cellular immunotherapy.
W
T
S
O
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3.- Perspectives of using cutting-edge technologies in hospitals
- Options for “infrequent” targets (pediatric tumors, tTCR, etc...).
- Faster development of new concepts/methods and tuning of consolidated concepts/methods.
- Economical sustainability (lower prices but direct reinvestment)- Easier integration between clinicians and producers.- Need of change of the key concept of autologous cell therapy as a
drug -> new regulation ???- Adjustments regarding microenvironment and other therapies in
combination.
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Who is involved in ARI-0001 / CART19-BCN? (>175 professionals)
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Thanks !!!
����Cutting-Edge Health Technologies: Opportunities and Challenges�Landscape & Perspectives for Health Outcomes.� How CAR-T is likely to impact public health ... the “Spanish model”?Slide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9CAR = Chimeric Antigen ReceptorAn autologous product as a “live drug”Slide Number 12CART19 : August 2011, “seminal” articlesSlide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18GMP facilities at HCB - UBSlide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Who is involved in ARI-0001 / CART19-BCN? �(>175 professionals) Thanks !!!