CAR-T cell Therapy...12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 0.8 1.0 Time, months t-ty...

CAR-T cell Therapy

Eleni Tholouli

© Copyright Greater Manchester Cancer. All rights reserved.

@GM_Cancer I #GMCC2019

T-Lymphocytes


Central role in regulating immune responses

by modulating function of Ag-presenting cells,

B-lymphocytes and other immune cells

https://blog.dana-farber.org/insight/2017/06/car-t-cell-therapy/

T-Lymphocytes


Central role in regulating immune responses through

- contact (receptor binding)


T-Lymphocytes


Central role in regulating immune responses through

- contact (receptor binding)

- cytokine release

- attract other immune cells

- direct killing of target cell


T-Lymphocytes


Cancer cells can fool the immune system by

- disguising as healthy cells

- express many antigens making receptor binding difficult

- find ways to turn off the immune system


Cellular Therapies

@GM_Cancer I #GMCC2019 https://blog.dana-farber.org/insight/2017/06/car-t-cell-therapy/

Inactive Lenti- or Retrovirus


Cellular Therapies

Inactive Lenti- or Retrovirus

transfected into T-Lymphocyte


Cellular Therapies

Chimeric Antigen Receptor T-cell =

CAR T-cell

CAR T-cell


CD19 CAR-T in R/R DLBCL

in 2014 In a small NCI cohort1,2 CRs were obtained by 5 out of 7

evaluable patients with chemotherapy-refractory

DLBCL/PMBCL2

4 out of 5 patients had ongoing responses in 20172


Early phase studies

CAR-T, chimeric antigen receptor T-cell; CR, complete response; DLBCL, diffuse large B-cell lymphoma; NCI, National Cancer Institute; PMBCL, primary mediastinal B-cell lymphoma; PR, partial response;

R/R, relapsed/refractory; SD, stable disease. 1. Kochenderfer JN et al. J Clin Oncol 2015;33:540–549; 2. Kochenderfer JN et al. Mol Ther 2017;25:2245–2253; 3. van der Steegen SJ et al. Nat Rev Drug Discov 2015;14:499–509;

4. Locke FL et al. Lancet Oncol 2019;20:31-42 (incl. suppl.).

PR SD

CR


Multi-cohort retrospective analysis of outcomes in R/R DLBCL/PMBCL*

Overall Survival

0

0.0

12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

0.8

1.0

Time, months

Eve

nt-

fre

e p

rob

ab

ility

0.6

0.4

0.2

Adapted from Crump, et al. 20171

7% COMPLETE RESPONSE (95% CI: 3–15)

26% OBJECTIVE RESPONSE (95% CI: 21–31)

20%

Response rates1,**

CONSISTENTLY POOR OUTCOMES ACROSS REFRACTORY SUBGROUPS INDICATE

A SIGNIFICANT UNMET NEED FOR PATIENTS WITH R/R DLBCL/PMBCL

Median OS: 6.3 months (95% CI: 5.9, 7.0 months)

SCHOLAR-1 in Rel/Ref DLBCL

*Refractory disease defined as progressive disease as best response to any line of therapy, stable disease as best response to >4 cycles of first-line therapy or 2 cycles of later-line therapy, or relapse

≤12 months after autologous stem cell transplant (as defined by SCHOLAR-1 inclusion criteria). **Response rates and OS were estimated from the time salvage therapy for refractory disease was initiated.

CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; OS, overall survival; PMBCL, primary mediastinal B-cell lymphoma; R/R, relapsed/refractory. 1. Crump M et al. Blood 2017;130:1800–1808

N=636

ZUMA-1 in DLBCL/PMBCL


N=101

Median follow-up time: 27.1 months (IQR 25.7–28.8)

Median PFS: 5.9 months (95% CI: 3.3–15.0)

Ongoing response2

12 months 44%

18 months 40%

24 months 39%

0 2 6 8 10 12 14 20 22 4 16 18 24 26 32 28 30

20

40

60

80

0

100

Time, months

Pro

gre

ssio

n-f

ree s

urv

ival, %

PFS

Adapted from: Locke FL et al. Lancet Oncol 2019;20:31–42

0 2 6 8 10 12 14 20 22 4 16 18 24 26 32 28 30

20

40

60

80

0

100

Time, months

Ov

era

ll s

urv

ival, %

N=101

Median OS: NR (95% CI: 12.8–NR)1

Patients surviving2

12 months 60%

18 months 53%

24 months 51%

OS

Adapted from: Locke FL et al. Lancet Oncol 2019;20:31–42

CI, confidence interval; CR, complete response; IQR, interquartile range; PR, partial response. 1. Locke FL et al. Lancet Oncol 2019;20:31–42 (incl. suppl.); 2. Neelapu SS et al. Poster 2967. Presented at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition, 1–4

December 2018, San Diego, USA.

JULIET in DLBCL

@GM_Cancer I #GMCC2019 1. Schuster SJ et al. Abstract 1684. Presented at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition, 1–4 December 2018, San Diego, USA.

2. Schuster SJ et al. NEJM 2019; 380:45-56

ELIANA in paediatric ALL


Maude SL et al. NEJM 2018; 378:439-448


NICE appraised and commissioned

CD, cluster of differentiation; DLBCL, diffuse large B-cell lymphoma; NHL, non Hodgkin lymhpoma; PBMC, peripheral blood mononuclear cell; PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory; VH , variable heavy; VL, variable light.; ALL, Acute Lymphoblastic Leukaemia.

1. van der Steegen SJ et al. Nat Rev Drug Discov 2015; 14: 449–509; 2. Gilead Sciences Ltd. YESCARTA® (axicabtagene ciloleucel) Summary of Product Characteristics; 3. Novartis. Kymriah (tisagenlecleucel) Summary of Product Characteristics.

Anti-CD19 scFv

Transmembrane

Hinge

Licensed indications

Gene transfer

Activation domain

Costimulatory domain

Axi-Cel (Axicabtagene ciloleucel)

YESCARTA® (ZUMA-1)

Kite, a Gilead Company1,2

Tisagen (Tisagenlecleucel)

KYMRIAH® (JULIET, ELIANA)

Novartis1,3

γ-retrovirus

Adult R/R DLBCL &

PMBCL,

after ≥2 lines of

systemic therapy2

Lentivirus

CD28 4-1BB

CD3ζ CD3ζ

VL

VH

FMC63 VL

VH

FMC63

Adult R/R DLBCL &

paediatric R/R ALL

after ≥2 lines of

systemic therapy3

NICE Jan 2019 March 2019 / Dec 2018

• Build a UK Eco system

• Build knowledge

• Increase access

Advanced Therapy

Treatment Centre Network


INNOVATE UK

iMATCH

Manchester:

The Christie, MFT

MW-ATTC

Midlands & Wales:

Birmingham, Cardiff,

Nottingham

Cell and Gene Therapy

Catapult

London Advanced Therapy

Network

Northern Alliance

Edinburgh, Glasgow,

Newcastle, Leeds

Adapted from iMATCH - NNOVATE UK

• NHSE commissioned

• JACIE-IEC accredited

• Manufacturer accredited

CAR-T centres wave-1


NHSE selected CAR-T therapy centres

London

Manchester

Newcastle

Birmingham

Bristol

Adapted from www.england.nhs.uk

http://www.england.nhs.uk

• Royal Manchester Children’s Hospital, MFT

• Manchester Royal Infirmary, MFT

• The Christie

Manchester CAR-T centres



London

Manchester

Newcastle

Birmingham

Bristol



• The Marsden, Leeds, Cambridge

• Glasgow, Cardiff

CAR-T centres by 2020



London

Manchester

Newcastle

Birmingham

Bristol

Glasgow

Cardiff

Leeds

Cambridge



Each infused CAR T-cell can result in

death of >100,000 tumour cells per day


CAR T-cells are serial killers!

Video: Provided by Dr. Laurence Cooper and Prof Sattva Neelapu

CAR-T expansion and persistence


CAR-T treatment timelines

CAR-T, chimeric antigen receptor T-cell; CRS, Cytokine Release Syndrome; TLS, Tumour Lysis Syndrome.

FOLLOW-UP PERIOD

Leukapheresis

Day -5 -4 -3

CAR-T MANUFACTURING

Day 0

CAR T-cell infusion

Day 10-14 Day 28

DAILY

MONITORING

Discharge Lymphodepleting

chemotherapy

Cyclophosphamide

500mg/m2

Fludarabine

30mg/m2

Referral

Consider bridging

therapy

Day 90

First tumour

assessment

CLINIC follow-up (15yrs) AMBULATORY 1hr to

CENTRE IN-PATIENT AMBULATORY

Cytopenias, Infections, Late effects,

B-cell aplasia

CAR-T

related neurotoxicity CRS

Chemo / disease related

TLS TOXICITY

MONITORING

Wash-out

period

Cytokine Release Syndrome (CRS)

Severe systemic inflammatory response

Most common complication → 60-100%

Onset 1-3 days post infusion, median duration 7 days

Severity and frequency correlates with

• T-cell activation and expansion

• High disease burden at time of infusion

• CAR constructs with CD28 costimulatory domain

Pathophysiology

@GM_Cancer I #GMCC2019 Neelapu et al, N Eng J Med 2017;377:2531-44; Schuster et al, N Eng J Med

2017; 377:2545-54; Maude et al, N Eng j Med 2018; 378:493-48; Shimabukuro-

Vornhagen et al J Immunother Cancer 2018

CRS Grading and Treatment - ASBMT




CRS

parameter

CRS

grade 1 CRS grade 2 CRS grade 3 CRS grade 4

Fever Temp

≥38oC Temp ≥38oC Temp ≥38oC Temp ≥38oC

with either

Hypotension None IV fluid bolus One

vasopressor

Multiple

vasopressors

and or

Hypoxia none Low-flow O2 High-flow O2

Non-invasive or

invasive

ventilation,

multi-organ

support

CAR-T Related Neurotoxicity (ICANS)

Pathophysiology unclear

Seen in 30-60%

Median onset 4 days post infusion, duration 2-4 days

with spontaneous resolution

Increased incidence with higher disease burden and

high T-cell expansion

Neurological Events


Blood

Brain Pericyte

Endothelium Endothelial activation

Altered blood–brain barrier

Increased vascular permeability

• Headaches, confusion, tremors

• Delirium

• Seizures • Cerebral oedema • Intracranial

haemorrhage

• Aphasia, apraxia, ataxia

• Paresis

Neelapu et al, N Eng J Med 2017;377:2531-44; Schuster et al, N Eng J Med

2017; 377:2545-54; Maude et al, N Eng j Med 2018; 378:493-48.

ICANS Grading and Treatment




Neurotox domain

Grade 1 Grade 2 Grade 3 Grade 4

ICE score 7-9 3-6 0-2 0 (patient unable to perform ICE)

Level of consciousness

Awakens spontaneou

sly

Awakens to voice

Awakens only to tactile stimulus

Patient is unarousable, stupor or coma

Seizures NA NA Any clinical seizures that resolve with intervention

Life-threatening prolonged seizures

Motor findings NA NA NA Deep focal motor weakness; hemiparesis or paraparesis

Raised ICP / Cerebral oedema

NA NA Focal/local oedema on neuroimaging

Diffuse cerebral oedema; Decerebrate; Cranial nerve VI palsy; Papilloedema;

Greater Manchester


Axi-Cel

or

Tisagen

AMELIA

AUTO1 AUTO3 AUTO4 BIANCA CARPALL CALM JCAR017

-BCM-001

UCART

19

N =

24

-

In

set-up

4

1

-

0

-

3

-

15

13

-

-

-

-

-

-

0

1

2

8

7

10

-

-

-

In

set-up

5

-

-

In

set-up

21

Patients undergoing CAR-T therapy

to date

Treatment

completed

NHS Clinical Trials

MRI

Christie

RMCH

CAR T-cell Therapy

• Two licenced and NICE approved CART products

in R/R DLBCL/PMBCL and paediatric ALL

• CR rates of up to 58% at 1-yr

• Durable remissions with a 2-yr OS at 40-50%

• Real World data comparable to trial data

• A number of early phase trials offering access in

new indications available

Summary Future


• Faster manufacturing timelines of CAR-T products

• New approved cancer indications and expansion

to solid tumours

• New approved non-cancer indications

• CAR-T used earlier in the treatment algorithm

• Better tolerated CAR-T products

• Expansion of CAR-T network centres

CAR-T cell Therapy...12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 0.8 1.0 Time, months t-ty...

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