Conflicts of interest · Manel Juan MD, PhD. Head of Immunotherapy Section Servei Immunologia - CDB...
Transcript of Conflicts of interest · Manel Juan MD, PhD. Head of Immunotherapy Section Servei Immunologia - CDB...
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Dado el carácter y la finalidad exclusivamente docente y eminentemente ilustrativa de las explicaciones en la clase de esta presentación, el autor se acoge al artículo 32 de la Ley de la propiedad intelectual vigente respecto al uso parcial de obras ajnas com imágenes, gráficos u otro material contenidas en las distintas diapositivas.
Todas las imágenes presentadas se incluyen como citas necesarias para ilustrar las explicaciones de esta clase.
• 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 Advisory Board of Grifols.
• Investigator of the CART19-BE-01 trial, evaluating the role of ARI-0001 cells in patients with B-cell malignancies. Approval dossier in preparation, but I do not benefit personally (or economically) from it.
Conflicts of interest
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Emerging Immunotherapies in Cancer
- TABLE III: IMMUNO ONCOLOGY THERAPEUTIC STRATEGY–
Future Directions for CAR-T Therapy
Manel Juan MD, PhD. Head of Immunotherapy Section Servei Immunologia - CDB Hospital Clínic de Barcelona / H Sant Joan de Déu / BST Thursday, Sept 26th 2019 (12:15 – 12:35) Casa de Convalescència,
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scFv
Signaling Domains
TM
T-cell
?
Concept Product = Drug
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Possible “future directions” for CARs
1. As a immunotherapeutic tool:
2. As a product - drug.
3. As “a health concept”
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Cytotoxic lymphocyte
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T-cell Cytoxicity: TA recognition & more
Ag
TcR
1 3
2
HLA
T-cell Cytoxicity: TA recognition & more
Ag TcR 1
3
2
HLA
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T-cell Cytoxicity: TA recognition & more
Ag TcR 1
3
2 HLA
Cytotoxicity
Proliferation/ Cytokines
Survival
Tumor Cell 1.- C
ytolyti
c Effe
ct
2.- Proliferation / Production of Cytokines
3.- Survival
Cytotoxic T-cells
Esquema del autor
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Ag receptors for cytotoxic lymphocytes
Humphries C, Nature 504, S13-S15 2013
CAR = Chimeric Antigen Receptor
Sònia Guedán Carrió & Anna Boronat Barado Chapter 6. Monografías SEI – Elsevier. “Inmunoterapia antitumoral con linfocitos genéticamente modificados (CAR): una realidad con futuro”
Antibody TcR Complex
1ª description “T-bodies” by Prof Zelig Eshhar (1995), Weizmann Institute of Science, Israel.
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scFv
Transducting Domains
(CD3ζ, CD28, …)
TM
CARs in T-cells = CARTs
T-cell “Cytotoxic”
14 Movieprovided by Dr. Beatriz Martin
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Tisa-cel (Kymriah) & axi-cel (Yescarta): Results in LDCGB R/R
Schusteretal.NEJM2018Zuma1
• Phase 2, JULIET & ZUMA-1.
Lockeetal.LancetOncology2018
Juliet
FDA / EMA approval of CART19 treatment (T-cell with anti-CD19 CAR):
August-October 2017 / July 2018
USA: Novartis ALL & DLBL <25 y: 475,000 $ / patient response ) NICE = £282,000 per patient (Sep 5, 2018) 320 m€ Spain : 320 m€ (160 + 160) It is anticipated that soon for adult ALL
Kite NHL DLBCL: USA 373,000 $ / patient Spain: 320m€ (140 + 140)
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18 FULL OF LIFE v, 66 yo (2011), in his RV parked at his home in New Jersey
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CODING SEQUENCE OF CAR ANTI-CD19
CGCCTTTT………… ……. ...TGTCGTGA
ATGG…. ...GGCCG
CACTCCCA.…Gly+Ser... Gly+Ser……. GAGCTGA
CACCACG……….. ……..……TTTACTGC
AAACGGGG……….. ……AAGGAGGA
AGAGTGAA…
…CTCGCTAA
V L
V H
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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Possible”future directions” of CARs 1. As a immunotherapeutic tool:
- Different structures: (a) scFv - Affinities - Specificities (b) Signaling (increase function vs reduce SAE)
(c) Combinations: Dual, iCAR, 4G, ... - Cells:
(i) CART: total T-cells, subpopulations, ... (ii) CAR-NK (iii) CAR-?
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Basado en: Sònia Guedán Carrió y Anna Boronat Barado Capítulo 6. Monografías SEI – Elsevier. “Inmunoterapia antitumoral con linfocitos genéticamente modificados (CAR): una realidad con futuro”
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CAR evolution
Casucci & Bondanza (2011). J Cancer 2011; 2:378-382
Cytotoxicity
1G
Cytotoxicity
Proliferation/ cytokine production
2G
Survival
3G
Classic CARs Current CARs Prototype CARs
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CAR evolution
TRUCKs
T cells Redirected for Universal Cytokine Killing
4G (armored CARs)
Based on Casucci & Bondanza (2011). J Cancer 2011; 2:378-382
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CARs: 4th GENERATION (II) DUAL CARs COMBINATED
THERAPY (MoAb) ARMORED CARs
iCARs
Cho et al., 2018, Cell 173, 1–13
Possible “future directions” for CARs
2. As a product ‒ drug: - Criopreserved vs fresh product. - Autologous (including iPSC) vs allogenic
(UCART) - Lentivirus, gene editing (SB, TALENs,
CRISPR, …) - Several growing protocols defining cell
profiles of cells.
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From TILs to T-cell modified therapy
PATIENT
LYMPHOCYTES
Blood
Leukoapheresis T-cell expansion by CD3 + CD28 beads
lymphocytes against tumor
Monitoring
Lymphocyte transduction
* *
UNDER GMP CONDITIONS
T-cell infusion Cryopreservation
Cell expansion
UCARs: 4th GENERATION (III)
UCART
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Tumor cell
TAA (TSA) 1.- C
ytolyti
c effe
ct
2.- Proliferation / Cytokine 3.- Survival
1st signal
2n & 3rd signal Cytotoxic T-cell
scFv
CD3ζ
CD137 (4-1BB)
CD8hinge & TM
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CELL CANCER IMMUNOTHERAPY
CARTs
&
“CELLbots” (engineered
T-cells)
Knowledge + Infrastructures (Clean Rooms) + Rules/Quality
Figure made by author
NK
TA
Vaccines
TcR
SCT/ DLIs Allo-
recognition
TILs
DCs
Celltherapy=>A
dvancedtherapy
product=“Drug
“
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Possible “future directions” for CARs
3. As “health concept”: - Drug vs transplantation (or different
equivalent process) - Commercial vs Academic - From the bench the bedside vs
centralized centers for production of Infusion
Scheme adapted by author fom the list of
Diamonds 50,000 €
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Californium 252 30,000,000 €
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CART19 1,000,000,000 € (3000 patients?)
2 1
Antimatter 60,000,000,000,000 €
Plutonium 4,000 €
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Gold 34 €
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Rhino horn 110 €
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Anti-C5 20,000 €
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How much is 1 g?
“Bussiness insider”, September 2014
The “most expensive” things in our world.
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Pharma(vsAcademic)CARTs(SWOTanalysis)
• Distancebetweenhospitalandmanufacturingcenter.
• HighPrice/patient.
• Afterapprovalproductmaintainedwithoutchanges:slowimprovements.
• AcademicCARTproposals.
• Newproductsbyevolutionoftheknowledge.
• Justfewindications.
• Accreditation:“Pharma”decidesinsomeway???!!!
• Centralizedapproval(FDA,EMA,…):responsibleofhomogeneityofproduct.
• Specificityanddocumentationinindication
• Easytobeacceptedbythepatient/family.
• “Hierarchical”structureoftheteam
• Presentlimitationsofothercancertherapies.
• Todefineallogenicproducts(universalCARTs).
• Tostabilizetheoptionofcellularimmunotherapy.
W
T
S
O
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Overallresponse
ALL CLL NHL
81%/76%
50%/26%
40%/19%
SchubertML/SchmittMHumGeneTher.2016Jul31
SuccessofCARs:Patientsnnearto1000
Commertialdevelopment Academicdevelopment
“Take home messages” and discussion Academic Cell Immunotherapy approaches are options of treatment for patients (?): • By now “Hospital exemption” is the only way to use them
(otherwise, cost for approval is beyond “academic” economical options). Medical laboratories as “producers”.
• Academic proposals should allow a faster evolution of treatments (lower global budgets, no need of “profits” and “returns of inversion”, … ).
• Direct relation and “internal consistency” between “public research grants” and “public health system”.
• Loss of the conditionings of the “pharma lobbies”: rules for autologous cell treatments nearer to SCT than to drugs, ...
• Production can be done near to the patient!!!
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Academic CART products are possible!!! • And maybe the main option for treating “rare”
tumours (paediatric) and make them accessible for our “European Health Systems”
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CELL CANCER IMMUNOTHERAPY
CARTs
&
“CELLbots” (engineered
T-cells)
Knowledge + Infrastructures (Clean Rooms) + Rules/Quality
Figure made by author
NK
TA
Vaccines
TcR
SCT/ DLIs Allo-
recognition
TILs
DCs
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