chen_cellualr therapy after allogenic vell trans 2015

7/23/2019 CHEN_Cellualr THerapy After Allogenic Vell Trans 2015

http://slidepdf.com/reader/full/chencellualr-therapy-after-allogenic-vell-trans-2015 1/56

Cellular Immunotherapy

BMedSC

Frederick Chen

Consultant Haematologist

NHSBT & Cancer Sciences



Father of Modern Immunotherapy:Immunisation against co po!

"icture #$% painting shoing Jenner

'accinating (ames "hipps%

)ellcome *i+rary, *ondon%



Enhancing immunity

- Active immunisation:

. Preventative Vaccines

. Therapeutic vaccines- /endritic Cell 'accine

- Passive immunisation:

. Haemopoietic Stem Cell Transplant

. Adoptive T cellular therapy- /onor *ymphocytes Infusion

Immunotherapy

E. Donnall Thomas

Ralph Steinman

HansJochen !ol"



Enhancing immunity:

#rom in#ections to cancer$ #rom prevention to therapy

. Preventative Vaccines

- Hepatitis B

- H"0

. Therapeutic vaccines: Cancer Vaccines

- /C 'accine: eg% melanoma

Prostate

HCC

- BC1 for Bladder Ca

- "eptide 'accines eg% M*

Cancer Vaccines



- Hep B vaccine prevents hepatocellular carcinoma:

. 450 million carriers of Hep B worldwide

. 1/2million new cases of HCC/year

. Reduction in HCC incidence by 50%in Taiwan since 1!0"s #$H Can& 1'( )*+$1',

- HPV vaccine – for prevention of Cervical Carcinoma

. - million new cases / year

. .accination pro&ramme for teena&e &irls



/endritic cell Cancer 'accine

PROVENGE® b !en"reon

. 1st approed C cancer accine

. or adanced prostate cancer

. *3tends life by monts for 0(000

%&A approval

Share price



- 2Replacement' ACT

- HSCT- Solid (rgan Transplantation

- Cancer ACT . virusassociated malignancies

3 )onviral

Enhancing immunity: #rom in#ections to cancer$ #rom prevention to therapy

Adoptive Cellular Immunotherapy

EBV#associate" primar tumours e$%: 6T7

)asoparyn&eal carcinoma)8 T9cell 7ympomaHod&:in"s disease

&elanoma

C''

(novial cell sarcoma

C&V "isease

EBV#assocaite" Post#)ransplant

'mphoproliferative !isease *P)'!+



*eukapheresis

C(*EC(*E SpectraSpectracell processor cell processor



Patient with leukaemia

Chemotherapy+/- radiotherapy

Conditioning

Patient with leukaemia Post transplant



Immune Reconstitution mimic+s antiviral

response

Read months for post-transplant reconstitution

From google search



eukaemia

Relapse

!nfections "#$D

Causes o# death

Postallogeneic Haemopoietic Stem Cell Transplant

,over -... per#ormed / year in 0!1

%&'

(%' (%'



Immunotherapeutic solutions #or HSCT



nti3leukaemia Immunotherapy

non3specific4target unknon5



Patient with leukaemia

Chemotherapy

+/- radiotherapy

Patient with leukaemia Post transplant

Relapsed

leukaemia

D!



Adoptive Immunotherapy: &2I

)o. of patients

Diagnosis *tudied E#aluale, Complete remission '

C

Cytogenetic relapse 57 50 40 (80)

Hematologic relapse 124 114 88 (77)

Transformed phase 42 3 13 (3)

!olycythemia "era#$!% 2 1 1

&$'#$% 7 58 15 (2)

&'' 55 20 3 (15)

$$* 25 17 5 (2)

E0T-1% sur#ey



Targeted Immunotherapy



Immune response

- T lymphocytes

6cellular immunity7

- C&3 ,cytoto4ic1

- C/8 6Th#, Th97

- egulatory C/8

- B cells and anti+odies

6Humoral Immunity7

- skin, mucosal linings, sali'a, gastric ;uices

- Complement system

- Inflammatory mediators eg% cytokines

- Neutrophils, Macrophages

- )! cells

- Toll3like receptors

I))ATE I550)IT6

)onspeci#ic "ut immediate

and rapid

A&APTIVE I550)IT6

Speci#ic$ has memory$ ampli#ies



!ey to recognition o# antigen "y cytoto4ic T cell

"asis o# Tissue 5atching in Transplantation

Cytoto2ic T-lymphocytes

!nfected Cell

)anomer peptid

( amino acids)

($HC +)

0ird3s eye #iew



-7 *irmingham: C5V in#ection as

model #or antigenspeci#ic

immunotherapy

using H2A tetramers



Prior to use o# ganciclovir$ C5V Pneumonitis post*5T 8as associated 8ith 9. mortality

Scale o# the pro"lem

(,$ %chmidt et al- ./$325 1005- 11)

< i H* T t f i th



<sing H*3Tetramers for immunotherapy

-7 &iagnostic H2A Tetramers

6H*3Tetramers3 ( ltman, " Moss, Science #==>7

PE

0iotin4#idin-PE

C D 5

TetramerC6

;7 H2A tetramers #or immunomagnetic

isolation

6M Co++old, " Moss (?M 9@@A7

PE-Tetramer-ound C6-specific CT can e selected

with anti-PE magnetic eads

T Cell

PE

Discard non-specific T cells

*elected C6-specific

CD5+ T cells

4nti-PE m4 ound to

magnetic 4C* microeads

agnetic column$4-Tet

C6



CD8

T e t r a m e r

-; C&3s

The cliniMacs machine can be used to select Tcells to clinical grade

<< C&3s

Positi#e selection

11' purity



Radiotherapy

C5V I)%ECTI()

D

P

Targeted Adoptive Immunotherapy:

&irect trans#er o# C5Vspeci#ic &2I

Phase I/II trial

immunosuppressed

D

;=.mls P*

or P*SC



&ay Post Transplant

.

-

;

>

?

=

@

9

3

<

. ;. ?. @. 3. -.. -;. -?. -@. -3. ;..

.

-...

;...

>...

?...

=...

@...

9...

3...

C5Vspeci#ic cells

Viral 2oad

.7=4-.@

T cells

In#used

C/6-specific T cells e2pand in vivo following

transfer

- In 3/< ,3<1 viraemia resolved completely

- 0se o# anciclovir reduced "y ?3

- )o Adverse side e##ects7 )o VH&

(utcome o# Phase - Trial

. Very #e8 cells 8ere needed ,mean .7= 4 -.B@ CT2

. ;=.4 #old e4pansion in vivo

. 0p to << purity 8ith H2A tetramers



C5V TRIA2S

Phase I Trial

*,oB-NH(B) # R.!+

/001

ACEASPECT 50&

Phase II trial

0o*/)HS*T/Cell 5edica*,oB-NH(B) # R.!+

/010

I5PACT Si"

Phase II / III

Cell 5edica/)HS*T

*NH(B) –lo$istical support+/002

Ran"omise" Controlle" )rials3Proof of principle4 trial

Adoption "y

clinicians

Clinical Practice

ACE ASPECT



ACEASPECT

- Colla+oration ith Industry: Cell 5edica- Funding from **- Multi3centre trial: -. 0! SCT centres

"atient ecruitment

100 101 102 103 104

CD8 FITC

BC 4 Strept-select 25.11.08.001

R2

Single reagent Streptamers can "e dissociated #rom "ound cells

C5V speci#ic C&3 T cell reconstitution in ACE Trial .3/

&ays post HSCT

c e l l n u m

" e r / m

l

. =. -.. -=. ;.. ;=..

; -.. =

? -.. =

@

-.. =

0T?

N*0

0*?

- Selection #rom unrelated stem cell harvest- minimises risk and incon'enience to donors- off3 the shelf cryopreser'ed cells



9% ?B0

Epstein *arr Virus ,E*V1



symptomatic or mild symptoms

1landular Fe'er 6infectious Mononucleosis7

Chronic acti'e ?B0 infection

Fulminant infections

E*V I)%ECTI() S6)&R(5ES

Burkitts lymphoma 6endemic 'ariant7

Hodgkins lymphoma

Nasopharyngeal carcinoma

Nasal N T cell lymphoma

/iffuse large B cell lymphoma of the elderly

/iffuse large B cell lymphoma of CNS in HI0

Posttransplant lymphoproli#erative disorder ,PT2&1

E*VASS(CIATE& T05(RS

Epstein *arr Virus ,E*V1

?B0 is cancerogenic



- E*Vdriven

- Epidemiology . "ost HSCT : #3AD 55

. "ost Solid Ergan Transplant A3#@D55 . "ost Cord Blood transplant: #@D 55

- Standard treatment: . eduction in immunosuppression

. itu!ima+ G43 CHE" chemotherapy >@3@D response . Need for no'el treatment eg% Immunotherapy

PostTransplant 2ymphoproli#erative

&isease



PostTransplant 2ymphoproli#erative disease



)he 'ancet 0olume 8A, Issue $=8#, "ages =3#, -<<=

<se of gene3modified 'irus3specific T lymphocytes to control ?pstein3Barr3'irus3related

lymphoproliferation

C%M ooney, C%J%C Ng, S *oftin, C% Smith, C *i, % rance, M% Brenner, H%? Heslop, C%M ooney, M% Brenner /epartment of 0irology and Molecular Biology, St (ude ChildrenKs esearch Hospital, Memphis, TN $#@A

T # ll # d ti i th ith E*V i#i CT2 i HSCT



Ten years #ollo8up o# adoptive immunotherapy 8ith E*Vspeci#ic CT2 in HSCT

,-<<> ;..=D Heslop et al7 *lood ;.-.1

)o CT2 prophyla4is:

##D of transplants

de'eloped "T*/

Prophyla4is:

#9 de'eloped ?B0

reacti'ation +ut no

"T*/

>rd party E*VCT2 #or postS(T PT2&

,T7Haue$ &7Cra8#ord$ *lood ;..91



Revie8 o# E*V targeted cellular immunotherapy

,using in vitro e4panded E*V CT21

% Merlo et al% Haematologica 9@#@

Cancer 5mmunotherap

607

)ransplant immunotherap

807



(utcome o# E*Vtargeted cellular immunotherapy



E4 vivo selection

H*3multimers $ hrs

Cytokine Capture > hrs



-Rapid selection #rom HSCT donors

-I%)

Cyto+ine Capture System F Clini5ACS ,5iltenyi1

-Pool o# ;> E*V peptides

Blood, pril 9@#@-@ patients treated

-=. CR ,>/@1

-Early PT2& responded

-> Patients 8ith late PT2&-8ith multiorgan #ailure died



Engineered T cell

Immunoreceptors



THE C()TEGT



T cell engineering

P

Cancer patient

Infuse cancer3

specific T cells

Retroviral TCR or CAR Transduction into T 2ymphocytes #or

immunotherapy

1ene encoding

tumour3specific

TC

TC or C

modified T cell

1ene

transfer

TCRtd Adult P* C&3 T cells

utologous

or donor

lymphocytes



1th ctoer 2014

CAR -< th



CAR-< therapy

Phase I/IIa Trial

- @ B3** 69A children & young adults, A older patients7

- #$ ere post3HSCT relapses

- 9> in #st to 8th relapse,

primary refractory,

# relapsed T3** 6C/#=G7

'hopeless cases''

7 t



7 relapses

3 no response

0 C6 78 % mo

1 patients had sstained remissions

(%tandard sal"age therapy

40 C6)

7utcome



To4icity Complications

- No 10H/ or off3target reacti'ities

- Cytokine release syndrome

- @D se'ere IT<- I*> +locker TociliLuma+

- +sence of B cells C

- eturn of B cells relapse 6M/ monitoring7

- "atients need i%'% Immunoglo+ulin replacement therapy



Immunotherapeutic solutions #or HSCT



ra#tVersusHost &isease

,VH&1



4cute "6$D



Antin J7 ) Engl J 5ed ;..;D>?9:>@?;

2ichenoid 2esions o# Chronic ra#tversusHost &isease



Measures against 10H/

- Prevention

. donor selection, H* matching

. T cell /epletion: Campath% T1

. Cyclosporin G Methotre!ate

- -st line treatment . steroids

- ;nd line treatment

. Tacrolimus, Mycophenolate Mofetil 6MMF7

. Campath, T1

. anti3TNF, anti3C/9A

. "<0

. "hotopheresis

. Mesenchymal Stem Cells



5esenchymal Stem Cells asImmunosuppressive therapy

3 Eriginally found in marro cultures, +ut can +e isolated from'irtually all tissues and e!panded up to large num+ers%

3 5SC inhi"it many immune responses$ pro"a"ly througha variety o# secreted and cell sur#ace #actors%



5esenchymal Stromal Cells ,5SC1

MSC differentiate into +one, fat and cartilage% In 'i'o, MSC also pro+a+ly de'elop into stromal elements of

+one marro and lymph nodes, and pro'ide trophic support for HSC and lymphocytes

Images:(1, edc9, scie+, MM1

FatBone Cartilage

Immunological "roperties of MSCImmunological "roperties of MSC



Immunological "roperties of MSCImmunological "roperties of MSC

/o not pro'oke a strong alloresponse

Nauta & Fi++e

Blood ##@:8==

re immunosuppressi'e

2Treatment of se'ere acute graft3'ersus3host



/ays after HSCT

*e Blanc et al Lancet. 2004 May 1;363(9419):1439-41

*i'er

1'H/

marker

1ut

1'H/

marker

Treatment of se'ere acute graft 'ersus host

disease ith third party haploidentical mesenchymal

stem cells



Cell Therapy approaches

- 5n vitro e4pansion culture 93 months . E*V /C5V CT2

. TI2

. CI!

. 5SC

. T Reg

- E9 vivo selection

. ntigen3specific T cells

- H*3multimers 3 hrs

- Cytokine Capture >@ hrs

. T3eg . rapid selection

- Engineered T cells 8 days

. T Cell eceptor transduced lymphocytes

. Chimeric ntigen eceptor transduced lymphocytes



Factors that determine the Efcacy o targetedimmunotherapy

• Target Antigen– Cancer-specifc– Sel antigens eg. cancer testis

• TCR/CAR quality– specifcity– Anity– avidity

• T-cell iology

– Exhausted cells– !"ung cells

• !mmunomodulation– Chec"point inhiitors# C#A$ % &'( inhi)it"rs– #y*ph"depleti"n



-. 3

-. =@

-. -.

-. 93

chen_cellualr therapy after allogenic vell trans 2015

Documents