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Cutting-

Edge Health Technologies: OpportunitiesandChallenges

Landscape& Perspectives for Health Outcomes.

HowCAR-T is likelyto impact

publichealth... the“Spanishmodel"?

Manel Juan. MD, PhD

Immunotherapysection.

Serveid"Immunologia-CDB Hospital Clínicde Barcelona

ImmunotherapyplatformH SantJoan de Déu/ BST

Thursday, October31

th

2019 (10:30)

WTO, RoomW-Centre William Rappard-Geneva

mjuan@clinic.cat •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 OncologyAdvisory

Boardof Grifolsno-relatedwithCAR-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

3 4

5Killer T cell attacking cancer.mp4

Tumoral cells

Changesin microenvironment

Immunememory

persistence

Immunesystem:

T-cell

Author"sfigure

Immune System

•Internal (we already have it) and holistic. •Continuously effective (from infections to tumours).

•Specific

7

Surgery

RADIOTHERAPY

Chemo

THERAPY

Immunotherap

y 8

ANTITUMORAL CELL-IMMUNOTHERAPY

TILsCARTsDCs

Knowledge+ Infrastructures (Clean rooms) + Regulation / Quality

Author figures

NK TA Vacc ines TcR SCT / DLIs Allo- recog nition scFv

Signalingdomains

TM

What is a CART?

T-cells engineered with CARs (Chimeric Antigen Receptor) "Cytotoxic" T-cell

CAR = ChimericAntigenReceptor

SòniaGuedánCarrió& Anna BoronatBarado

Chapter6. Monografías SEI -Elsevier. "Inmunoterapia antitumoral con linfocitos genéticamente modificados(CAR): una realidad con futuro"

Antibody

TcR Complex

1ª decription"T-bodies" by

ProfZeligEshhar(1995),

WeizmannInstituteof Science, Israel.

11

Anautologousproductas a “livedrug"

CAR T-cell

Lymphocyte transduction of CAR*

PATIENT

LYMPHOCYTES

Blood

Leukoapheresis

Monitoring

UNDER GMP CONDITIONS

CART+ lymphocytes against tumor

CART infusionCryopreservation

T-cell expansion by

CD3 + CD28 beads

Cell expansion

C E L L T H E R A P Y

Celltherapy=> Advancedtherapyproduct= "Drug"

CAR production

Hinge +

Transmembrane

(CD8a) scFv anti-CD19 = TumorAntigenRecognition

Costimulatory domain

(CD137 / 4- nd signal / 3 rd signal)

Signaling

domain 2 nd generation CAR V L V H 15

SuccessofCARs: Patientsn=185 (nownear1,000 )

Diseases

Relapsed

Refractory

Heavilypretreated

Overall response

ALLCLL NHL

81%/76%

Schubert ML/ Schmitt M Hum Gene Ther.2016 Jul 31

40%/19%

Acutelymphoblasticleukemia(ALL)

Chroniclymphocyticleukemia(CLL)

41

Non Hodgkin lymphoma(NHL)

46

50%/26%

Approvals by FDA & MDA as "live drugs" -> Commercial production

PATIENTS

(Public

Health

Systems)"Conditioned"

CENTRALIZED

approval

20102017-18

Barcelona: From "ourpatients" to "our" CAR ANTI-CD19: ARI-0001

CGCCTTTT............

....... ...TGTCGTGA ATGG.... ...GGCCGCACTCCCA....Gly+Ser...

Gly+Ser....... GAGCTGACACCACG...........

......AAGGAGGA

AGAGTGAA...

...CTCGCTAA V H V L CD8a (hinge + transmembrane) scFv A3B1

CD137 / 4

-1BB (Signaling domain) (Signalling domain) CD8a (signal peptide)

LENTIVIRAL

SEQUENCESLENTIVIRAL

SEQUENCE

S EF-1

PROMOTER

gDNA / lentivirus mRNA

CAR Protein (transmembrane)

17

RNART-PCROverlapping

of products

DATA BASES +

PREVIOUS RESULTS

SPECIFIC

PRIMERS

Coding sequence for the

chimeric receptor antigen : CAR

Construct

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