translation of tcrs to the clinic - european medicines agency · tcr:pmhc affinity (µm) tolerant...
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Translation of TCRs to the clinic –
MAGE-A1 TCR gene therapyof Multiple Myeloma
as an example
GERALD WILLIMSKYExperimental and Translational Cancer ImmunologyInstitute of Immunology (Charité - Universitätsmedizin Berlin)and German Cancer Research Center (DKFZ)
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BMBF program „Personalized Medicine“
MAGE-A1 TCR gene therapy of Multiple Myeloma
TCR Consortium
A. PezzuttoM. ObenausJ. KoppM. VaeglerD. HoserG. Willimsky
T. BlankensteinW. UckertE. KiebackV. Scheuplein
D. SchendelC. WehnerS. Hauck
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BloodTcells
LTR LTRTCR+
Graftingofnewantigenspecificity
genetransfer
Redirected T cell therapy
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Interaction between T cells and target cells isa three body problem: TCR - peptide - MHC
peptideMHC
TCR
target cell
T cell
TCR:pMHC affinity (µm)
tolerant repertoire
non-tolerant repertoire
100 10 1
p:MHC affinity (nm)
therapeutic efficacy20 000 10 000 5 000 2 500
10 nM 1 nMtumor rejection
can be achievedCancer Cell 23: 516-526 (2013)
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• best possible risk-benefit ratio for target antigen:
Ø TSA (e.g. neoantigens) > CT > differentiation Ag
• most efficient rejection will occurwhen cancer cells are recognized as foreign:
Ø TCRs with optimal-affinity
POINTS TO CONSIDERFOR ADOPTIVE T CELL THERAPY
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CHAPTER HEADERTUMOR-SPECIFIC ANTIGENS AS TARGETHow to obtain therapeutic TCRs?
Cancer-freeenvironment
§ humanizedmouse
Humanwithcancer
§ TIL§ PBMC
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muTCRab-KOhuTCRab-Tg
HLA-A2-Tg
H2-KO
huTCR locus-Tg mice
• Mice are not tolerant for mosthuman tumor antigens
• Human TCRs from non-tolerant repertoire in cancer free mice
Transgenic mice with a diversehuman T cell antigen receptor repertoire
Li et al., Nat Med 16: 10129 (2010)Li et al., Nat Prot 8: 1567 (2013)
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Peripheral T cells in huTCR-locus Tg mice
muTCRab-KOhuTCRab-Tg
HLA-A2-Tg
H2-KO
huTCR locus-Tg miceCD8
49
22
CD
4
MHC I: humanTCR: human
CTL to various human TAA (>10)CTL to cancer viruses (>10)CTL to various human TSA (>30)
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Engels et al, 2013Kammertoens et al, 2013
MAGE-A1270 300| |
Human –ALAETSYVKVLEYVIKVSARVRFFFPSLREA-
Mouse –AFAETSKMKVLQFFASINKTHPRAYPEKYAE-
* **** *** *
pMHC affinity is important
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muTCRab-KOhuTCRab-Tg
HLA-A2-TgH2-KO
Antigen immunizationMouse T cell
carrying human TCRIsolation of TCR and transfer
into human T cells
X
Humanized mouse model for TCR generation
MAGE-A1TCR
CD8
naive immunisized Clonalexpansion
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Mouse-derived MAGE-A1 TCRhas higher functional affinity
TCR from ABabDIITCR from human*Non-transduced
TCR from human*
human TCRs from mouse
Peptide pulsed T2 cells Melanoma cells
* Ottaviani et al., 2005,Cancer Immunol Immunother 54,1214
CANCER-ASSOCIATED ANTIGENS AS TARGET
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R&D Pre-clinical Clinical
1.SA 2.SA CTA(planned)
IMPDsubmission
StudysynopsisManufacturing
licence
Datasummaries
Studyconcept
Oct.2013 Oct.2015 Q12017
Timeline MAGE A1 TCR gene therapyof Multiple Myeloma
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Potential safety concerns
§ MAGE-A1 expression in healthy tissues
§ Allo-reactivity
• T1367 was generated in mice expressing a single HLA class I molecule (in part applies also for an allogeneic human environment)
§ cross-reactivity
• Promiscuous TCR recognition has been reported
• T1367 was positively and negatively selected based on a
mouse peptide repertoire
SAFETY OF T1367 T CELL THERAPY
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• Limitedexpression innormaltissues (testis,placenta,embryonic tissue,mTECs)
MAGE-A1
MAGE-A1278-286
HN- -COOH
Expressionintumors:• Multiplemyeloma• Lungcancer (NSCLC)• Melanoma• Breast cancer• Coloncancer• Hepatocellular carcinoma• Cholangiocellular carcinoma
MAGE-A1
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Restricted MAGE-A1 expression
CANCER-ASSOCIATED ANTIGENS AS TARGET
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No evidence for off-target recognition
More than 100 HLA-A2peptide ligands
CANCER-ASSOCIATED ANTIGENS AS TARGET
Peptide Sequence IC50 (nM)MAGE-A1 KVLEYVIKV 4.69MAGE-B5 KVLEYLAKV 4.11MAGE-B16 KVLEFVAKV 4.97
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No evidence for allo-recognition
CANCER-ASSOCIATED ANTIGENS AS TARGET
normalized
AM
AI
Am
ala
Bel
loB
M14
BSM CLA
DU
CA
FH
OR
KA
S011
Kas
116
KE
KLO
LCLW
01LC
LW02
LCLW
03M
T14B
OZB
RM
LSA
SPO
TAB
089
TISI
VAVY WIN
WT2
4W
T49
XL-IN
DT2
+ M
1
0
20
40
60
80
100
norm
aliz
ed %
IFNg
HLA-A* HLA-B* HLA-C*AMAI 68:02 53:01 04:01AMALA 02:17:01 15:01:01 03:03:01Bello 02:02 11:01 41:01 52:01 12:02 17:01BM14 03:01 07:02 07:02
BSM 02:0101 15:010101 03:0401CLA 02:06:01 24:02 08:01 35 7DUCAF 30:02 18:01 05:01HOR 33:0301 44:0301 14:03KAS011 01:0101 37:01 06:02
KAS116 24:020101 51:01 12:03KE 02:01 29:02 44:03 44:05 02:02 16:01
KLO 02:08 01:01:01:01 08:01:01 50:01:01 07:01:01:01 06:02:01:02LCLW01 03:01 24:02 15:01 35:01 03:03 04:01LCLW02 02:01 26:01 38:01 44:02 05:01 12:03LCLW03 02:01 23:01 15:01 58:01 03:04 07:01MT14B 31:01 40:01 03:04OZB 02:09 03:01:01 38:01 35:02 04:01:01 12:03:01RML 02:04 51:0101 15:02
SA 24:020101 07:0201 07:02SPO 02:01 44:02 05:01TAB089 02:07 46:01 01:02
TISI 24:020101 35:08 04:01VAVY 01:01 08:01 07:01WIN 01:01 57:0101 06:02WT24 02:0101 27:0502 02:0202WT49 02:05:01 58:01:01 07:18XLI-ND 02:10 30:01 13:02 40:06:01:01 06:02 08:01
LCLsrepresentingmorethan75%forHLA-A*,60%forHLA-B* and78%forHLA-C*ofthealleleswithintheGermanpopulation
LCL panel
*Normalized to IFNg productionof MAGE-A1 loaded T2 cells
*
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MAGE-A1 recognition motif-related human self-peptides
Alaninescan
CANCER-ASSOCIATED ANTIGENS AS TARGET
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SAMD9 is recognized at high peptide concentration
CANCER-ASSOCIATED ANTIGENS AS TARGET
SAMD9:SterileAlphaMotif DomainContaining Protein9
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SAMD9 is not naturally presented
T cells
CANCER-ASSOCIATED ANTIGENS AS TARGET
SAMD9:SterileAlphaMotif DomainContaining Protein9
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Limitations inxenograft cancer models
• humanTcellsinmicepoorlyexpandorsurvive(species-specificfactors)• humanTcellsinNSGmiceacquirefunctionalactivity,butmayelicitlethalgraft-versus-hostdisease(GvHD).
Biodistribution andpharmacokineticsofT1367-transducedTcellscanbeaddressedonlyintheautologoushost,theMMpatient
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Does TCR gene therapy lead to rejection or relapse of tumor?
Syngeneic mouse tumor cells expressing human antigen
and HLA-A2
HLA-A2+ mouse T cells expressing human TCR
HLA-A2+
Human MHC-transgenicmouse (HHD)
1
2
3
A pre-clinical model for analysis of TCR efficacy
Mouse target cell
Mouse T cell
a
b2mCD8HHD
Antigen
TCR
human mouse
a1a2
a3
Va Vb
Ca Cb
Leisegang et al., JCI 126:854 (2016)
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In vivo function of TCR modified T cells
à TheTCRrepertoireagainstMAGE-A1278 islikelyskewedtowardslowaffinityinhumans
MC703-A1(MAGE-A1+ / HHD+)
Tumor size ≈ 500 mm3
adoptive T cell transfer
HHD x RAG-/-
CANCER-ASSOCIATED ANTIGENS AS TARGET
Obenaus et al., Nat Biotechnol 33:402 (2015)
TCR from human*human TCRs from mouse
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• Chimericmouse/humanTCR• Target:Cancer-germlineantigen• Vector:GammaretroviralMP71• Indication:Relapsed/refractoryMultipleMyeloma
MAGE-A1 TCR gene therapy: Study Information
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TCR a- and b-chain gene expression cassettes
TCRVb
TCRVb
TCR Vb
TCRVb
TCRVb
IRES
IRES
PRE
P2A
P2A
MPSV-LTR
SD SA
MPSV-LTR leader
TCRVa
TCRVa
TCRVa
TCRVa
TCRVa
a + b
aib
bia
apb
bpa
Single chain
IRES
P2A
MP71
WT-1 TCR
Leisegang et al., J. Mol. Med. 86: 573-583 (2008)
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Transgene cassette determines TCR expression level
7
1
1
12
29
0
43
30
43
MFI
MFI
MFI
WT-
1 te
tram
er
IFN-g (pg/ml)
619
94
128
706
2095
71
a+b
aib
bia
apb
bpa
Vb2
28
17
22
44
52
7neg.
P2A
IRES
SingleC
ount
s
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Optimization of TCR genes improvesT cell functionality
VaCa
VbCb Human TCR (wild type)
Murinization (mu)Preferential pairing of tg TCR chains(Cohen, 2006)
Disulfide bond (cys)Preferential pairing of tg TCR chains(Kuball, 2007)
Codon optimization (co)Enhanced tg TCR expression level(Scholten, 2006)
Others
Ø increase the avidity of therapeutic TCRØ replace wild type TCR
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9 amino acids of the mouse TCR C-regionsenhance human TCR expression
C
TCR53 tg T cells / RCC26
12
8
6
4
2
0
10
IFN
-g(n
g/m
l)
TCR
TCRa:50 aa
N C1 2 3
TCRa C-region
TCRb:38 aa
41 2 3N C
TCRb C-region
SDVP
KAIAH
M
Va Vb
Ca Cb
Sommermeyer et al., J. Immunol.184: 6223-6231 (2010)
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§ Modification of retrovirus vector
MP71-TCR:
High-performance g-retrovirus vectorfor TCR gene therapy
TCRVβ TCRCβ TCRVa TCRCa
CD8
NY-
ESO
-1 te
tr. MFI 232 MFI 903 TCR gene-modified T cells:§ High expression level of tg TCR § Homogeneous population§ High functional activity
§ Optimization of TCR gene cassette
2A
§ Engineering of TCR genes
cys cys**
Codon optimizationMinimal murinization
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T2 MM cell line
MAGE-A1 TCR T1367 is primarilyactive in CD8+ T cells
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CD4-Depletion
Transduction
Expansion
Cryopreservation
Leukapheresis
pMP71-T1367mmc
293HEK-GALV
ProducerClone
MasterCellBank
WorkingCellBank
Manufacturingprocess
Spectra Optia®Apheresis System
CliniMACS®
Cryopreservation
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Starting materialCD4- cells
Activationbead bound antibodies
+Selection
Transduction1x90min,800g,32°C100mlpureVirus
CultivationUp to 12days inWaveReactor
CD4depl.leucapherisatePBMCs
Adherencedepletion of monocytes
GMPTransduction Protocol
SpectraOptia®ApheresisSystem)CD4+cell-depletionwithCliniMACS®,Miltenyi
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MeanpMP71vectorcopynumberpercell
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Buffy coat(control)
Leukapheresisproduct,RV transduced
MAGE-A1 TCR T1367 transduced T cells havestem cell–like memory phenotype
CD
4
CC
R7
CD
62L
CD3+ CD8+ CD45RA+ CD45RO- CD62L+ CCR7+ CD8 CD45RA CD45RA
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Phase I trial of MAGE-A1+ Multiple Myeloma
Cohort n Tcells/kg
1 3 1x105
2 3 1x106
3 3 1x107
4 3 1x108
(5 3 1x108)
T CELL THERAPY OF MULTIPLE MYELOMA
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Identifying MAGE-A1+ myeloma
CANCER-ASSOCIATED ANTIGENS AS TARGET
4%
3%
8%
3%
9%
0%
25%
50%
MAG
E-A1
positivesa
mples
focal
1-5%
10-30%
40-60%
80-100%
(n=99)
A B
C D
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• Heterogenous expressionpatternofMAGE-A1withinatumor
• CorrelationbetweenextramedullarydiseaseandhomogenousMAGE-A1expression
• ManypatientswithMAGE-A1expressingmyelomaareprimaryrefractorytoeitherabortezomib orlenalidomide basedregimen
Patientselection
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Standardization of the manufacturing process: “Master Processes”
• technologyplatforms(GMPfacility,medicaldevicestatus)
• genericvectorsdocumentedinadossier(solutionforbottlenecksforacademiaasasmallcustomer)
• establishmentofINDs forestablishedproductsthatcanbeusedasablueprinttodevelopprocessesandproductsthatarederivedfromtheexistingprocess
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BerlinSchoolof IntegrativeOncology
GermanCancerConsortium (DKTK)
GermanCancerAid PriorityProgram‘TranslationalOncology’ExploringmutantimmunogenicepitopesforTcelltherapyofcancer
ThomasBlankensteinMatthiasObenausElisaKiebackVivianScheupleinWolfgangUckertMatthiasLeisegang
KathrinBorgwaldSabrinaHornKristinRetzlaffKaterinaThiedeDanaHoserGeorgePapafotiouJaquelineWaldeck
Principles and Applications of Adoptive TCell Therapy
BMBFprogram „Personalized Medicine“
AntonioPezzuttoLutzUharekIoannis Anagnostopoulos
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