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 - Genevamjuan@clinic.cat

mailto: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 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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4

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Killer T cell attacking cancer.mp4

Tumoral cells

Changes in microenvironment

Immune memory(persistence)

Immune system:T-cell

Author’s figure

Immune System• Internal (we already

have it) and holistic.• Continuously effective

(from infections to tumours).

• Specific

7

Surgery

RADIOTHERAPY

ChemoTHERAPY

Imm

unotherapy

8

ANTITUMORAL CELL-IMMUNOTHERAPY

TILs CARTsDCs

Knowledge+ Infrastructures (Clean rooms) + Regulation / Quality

Author figures

NK

TA

Vaccines TcR

SCT / DLIsAllo-recog nition

scFv

Signaling domains(CD3ζ, CD28, …)

TM

What is a CART? T-cells engineered with CARs (Chimeric Antigen Receptor)

“Cytotoxic” T-cell

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.

11

An autologous product as a “live drug”

CAR T-cell

Lymphocyte transduction of CAR*

PATIENT

LYMPHOCYTES

Blood

Leukoapheresis

Monitoring

UNDER GMP CONDITIONS

*

CART+ lymphocytes against tumorCART infusion Cryopreservation

T-cell expansion byCD3 + CD28 beads

Cell expansion

CELL

THERAPY

Cell therapy => Advanced therapy product = “Drug“

CAR production

13

CART19 : August 2011, “seminal” articles

Hinge + Transmembrane

(CD8a)

scFv anti-CD19 = Tumor Antigen Recognition

Costimulatory domain(CD137 / 4-1BB = 2nd signal / 3rd signal)

Signaling domain

2nd generation CAR

VLVH

15

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)

46

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

24

Tabelle1

Verkauf

ALL54

CLL25

NHL24

Gráfico1

1. Quartal

2. Quartal

3. Quartal

Verkauf

26

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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9

60

Tabelle1

Verkauf

1. Quartal31

2. Quartal9

3. Quartal60

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

GMP facilities at HCB - UBC

D B

CellCleanrooms

VectorClean rooms

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

1.- Role of hospitals in developing new technologies:

“Academic” products of cell immunotherapies (specially CARTs) are possible (at least in Spain )!!! 😉😉

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)

…

Production of CAR vector (Lentiv)

Biorreactor Biorreactor

HCB

…

EudraCT 2019-001472-11

Spanish Hospitals

2.- CAR-T therapy in practice: ACADEMIC + INDUSTRIAL CARTs (collaboration)

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

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

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)

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 !!!