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Immunotherapy for lymphoma andresearch strategy in the local network
Anastasios Stathis, MD
SAMO Interdisciplinary workshop on immunotherapy
Anastasios Stathis, MD
Phase I and Lymphoma UnitOncology Institute of Southern Switzerland
Lucerne Apr 5, 2014
Explosion of new cancer therapeutics
>800 agents inclinical trials in2009
LoRusso PM et al. Clin Cancer Res 2010:16:1710-1718
143% increasefrom a decade ago
Targeted therapy for lymphoma
Modified from: A. Younes, Nat. Rev. Clin. Oncol. 8, 85–96 (2011)
Emerging therapeutic options inrelapsed/refractory NHL
Adapted from M.P. Chao. Cancer Manag Res. 2013; 5: 251–269
Structure of human CD20 molecule
• B cell-specific tetra-transmembrane protein localized to microvilli andconstitutively associated with membrane rafts
• no dissociation or internalization upon antibody binding
• role in B cell function not fully clear (regulator or component of acalcium channel), it forms homo-oligomers that physically associatewith the BCR
C1qC1q
mAbmAb
CD20CD20
MacrophageMacrophage
Mechanisms of actions of anti-CD20 antibodies
• CDC1-3
• ADCC1-3
• Apoptosis1-3
1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program; 2007: 233–242; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143
1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program; 2007: 233–242; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143
ADCC=antibody-dependent cellular cytotoxicity;CDC=complement-dependent cytotoxicity;MAC=membrane attack complex
ADCC=antibody-dependent cellular cytotoxicity;CDC=complement-dependent cytotoxicity;MAC=membrane attack complex
CD20CD20
B cellMACMAC
Vaccinal effect of monoclonal antibodies
• Priming antigen-specific T-cells through cross-presentation oftumor antigens released by dying cells
TypeI
TypeII
CD20 clusteringin B-cellmembrane
++ -
Type IType I
Two types of anti-CD20 mAbs
Cragg MS, et al. Curr Dir Autoimmun 2005 Glennie MJ, et al. Mol Immunol 2007Teeling JL, et al. Blood 2004
Induction of CDC ++ +
Induction ofADCC ++ ++
Induction ofapoptosis + ++
– = no activity; + = some activity; ++ = significant activity– = no activity; + = some activity; ++ = significant activity
Type IIType II
Event-Free Survival
5-year EFS (95%CI):Chlorambucil , 52% (42%-60%)R-Chlorambucil, 70% (61%-77%)Rituximab, 51% (40%-61%)
Zucca, E. et al, ICML; 2013
The IELSG-38 study
A phase II study of Chlorambucil in combination
with subcutaneous Rituximab followed by
maintenance therapy with subcutaneous
Rituximab in patients with extranodal marginal
zone B-cell lymphoma of mucosa associatedzone B-cell lymphoma of mucosa associated
lymphoid tissue (MALT lymphoma)
IELSG Annual Meeting 2014
• Low CD20 density
– Rituximab requires high CD20density for CDC
– Relatively low CD20 density in CLL
• Complement inhibition
Potential mechanisms for rituximab limitations
100
80
60
40
%C
DC
• Complement inhibition
– B-cell overexpression ofcomplement inhibitory proteinsmay reduce rituximab-mediatedCDC
• Carriers of the FcgRIIIa lowaffinity receptor polymorphism
Lower rituximab-induced CDCcorrelates with lower CD20 densityAntibodies bound per cell = number of CD20molecules per cell
Lower rituximab-induced CDCcorrelates with lower CD20 densityAntibodies bound per cell = number of CD20molecules per cell
20
0
0
CLL Lymphoma
CD20-ABC*CD20-ABC*
How to boost antibodies effectiveness
Adapted from M.P. Chao. Cancer Manag Res. 2013; 5: 251–269
How to boost naked monoclonal antibodies
• increase CDC
• increase ADCC
• enhance affinity for all variants of FcγRIIIa receptors
• reduce immunogenicity• reduce immunogenicity
– humanized and fully human mAbs
• overcome immune resistance
– e.g., by blockade of programmed death 1 (PD-1), aninhibitory receptor expressed by T cells
How to boost antibodies effectiveness
• Radio-immunotherapy
• Antibody-drug conjugates
• Bispecific antibodies
VeltuzumabOcrelizumab
Ofatumumab AME-133vGA-101PRO-31921
MurineMurine ChimericChimeric HumanizedHumanized Fully humanFully human EngineeredEngineered
Antibody technology has moved forwardsince the rituximab introduction
19871987 19941994 19971997 20062006 20092009
1f5 “serotherapy” in 4pts with refractory B-cell carcinoma
1f5 “serotherapy” in 4pts with refractory B-cell carcinoma
CD2B: phase I study in pts withrecurrent B-cell lymphomaCD2B: phase I study in pts withrecurrent B-cell lymphoma
Rituximab: FDA approval forrelapsed or refractory, lowgrade, CD20+, B-cell NHL
Rituximab: FDA approval forrelapsed or refractory, lowgrade, CD20+, B-cell NHL
Rituximab: approved for first-line use in B-cell lymphomasRituximab: approved for first-line use in B-cell lymphomas
Ofatumumab: approved in USfor CLL refractory to fludarabineand alemtuzumab
Rituximab: approved in Europefor untreated andrelapse/refractory CLL
Ofatumumab: approved in USfor CLL refractory to fludarabineand alemtuzumab
Rituximab: approved in Europefor untreated andrelapse/refractory CLL
mAb=monoclonal antibody; pts=patients; FDA=Food and Drug Administration (US); NHL=non-Hodgkin’s lymphomamAb=monoclonal antibody; pts=patients; FDA=Food and Drug Administration (US); NHL=non-Hodgkin’s lymphoma
Second generation of anti-CD20 monoclonal antibodies
S. Cang et al. J Hematol Oncol. 2012
Ofatumumab binding to a unique CD20 epitopelinked to more efficient CDC
Modified from B.D. Cheson J Clin Oncol. 2010
Ofatumumab• 42% ORR in CLL refractory to fludarabine and
alemtuzumab
• median duration of response of 6.5 months
• most common adverse reactions :– neutropenia and anemia– neutropenia and anemia
– pneumonia, bronchitis and upper respiratory tract infections
– diarrhea
– Fatigue, dyspnea, rash.
Wierda W G et al. JCO 2010;28:1749-1755
Third generation of anti-CD20 monoclonal antibodies
Adapted from S. Cang et al. J Hematol Oncol. 2012
GA101 (Obinutuzumab)Glycoengineered, Type II Anti-CD20 mAb
FDA approved (Nov 2013) 1st line CLL with Chlorambucil
Type IIanti-CD20 mAb1,2
GlycoengineeredFc region1
Increaseddirect cell death1
Increased ADCC1
1Mossner E et al. Blood. 2010;115(22):4393-402; 2Niederfellner G et al. Blood. 2011;118:358–67.mAb, monoclonal antibody.
Decreasedcomplementdependentcytotoxicity
• The presence of certain fucose residues on theFc region of an antibody may interfere with itsability to bind to immune effector cells1,2
GA101 Glycoengineering
1Ferrara C et al. J Biol Chem. 2006;281:5032–6;2Ferrara C et al. Proc Natl Acad Sci U S A. 2011;108:12669–74;3Mossner E et al. Blood. 2010;115(22):4393-402.
• Removal of fucose via glycoengineering mayincrease binding affinity to–and activation of–immune effector cells3
R
A
N
D
O
1
:
2GA101 + chlorambucilx 6 cycles
Chlorambucil x 6 cyclesPreviouslyuntreated CLLwith comorbidities
Total CIRS* score > 6
Stage I, n = 590Additional 190 patients
to complete stage II
Stage IaG-Clb vs Clb
Stage IbR-Clb vs Clb
GA101+Clb or R-Clb vs Clb in CLL pts withcomorbidities. The CLL11 trial
• GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 2–6, every 28 days• Rituximab: 375 mg/m2 day 1 cycle 1, 500 mg/m2 day 1 cycles 2–6, every 28 days• Clb: 0.5 mg/kg day 1 and day 15 cycle 1–6, every 28 days• Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb
O
M
I
Z
E
2
:
2
Rituximab + chlorambucilx 6 cycles
x 6 cyclesTotal CIRS* score > 6and/or creatinineclearance < 70 ml/min
Age ≥ 18 years
N = 780 (planned)
Stage IIG-Clb vs R-Clb
R-Clb vs Clb
*Cumulative Illness Rating Scale
26Hallek M, Abstr. 056, 12-ICML
Final results of the stage IIand update of stage I analysis
Stage II (total N=663)
G-Clb(n = 333)
R-Clb(n = 330)
HR 0.41, CI 0.23-0.74,p=0.002.
Goede V. (ASH 2013), Blood 2013 122:6
(n = 333) (n = 330)
ORR 78 65
CRb 21 7
Median PFS, months 26.7 15.2
HR, CI, p 0.39, 0.31-0.49, <0.0001
Median OS, months NR NR
HR, CI, p 0.66, 0.41-1.06, 0.09
Grade 3-5 AEs 66 47
IRR 20 4
Neutropenia 33 27
Infections 7 7
RClb over Clb: HR 0.66, CI0.39-1.11, p=0.113.
The GOYA Study
GA101 + CHOP
Rituximab + CHOP
Previously untreated
DLBCL1:1
1400 patients
Stratification
• Number of planned CHOP cycles (6 or 8)
• IPI score
• Region of study conduct
IPI, International Prognostic Index.
GA101
•1000 mg on days 1, 8, and 15 of cycle 1;day 1 of cycles 2–8, every 21 days
Rituximab
•375 mg/m2 on day 1 of cycles 1–8,every 21 days
• Phase III, open-label, multicenter, randomized
• Sites choose between use of 6 or 8 cycles of CHOP-21
New study proposalA phase I study of GA101 in combination with ABT199 inA phase I study of GA101 in combination with ABT199 inpatients with relapsed/refractory follicular lymphoma
Dr. A. Stathis
PD. Dr. E. Zucca
Phase I study of GA101 with ABT-199in R/R Follicular lymphoma: rationale
-Need to identify “no-chemotherapy” active regimens in FL
-Both GA101 and ABT-199 have single agent activity withacceptable toxicity profile in iNHLacceptable toxicity profile in iNHL
-GA101 with ABT-199 results in enhanced cell death androbust anti-tumor efficacy in xenograft NHL models (SampathD et al, ASH 2013)
Cell-Surface Antigens on the B Cell
B.D. Cheson & J.P. Leonard. N Engl J Med 2008
Targeting other antigens with new mAbs
Target Single agent RR
Epratuzumab CD22 45% FL, 15% DLBCL
Medi-551 CD1925% CLL, 24% DLBCL,
41% FLMedi-551 CD19
41% FL
Mogamulizumab CCR450% ATL, 34% PTCL, 39%
CTCL
Pidilizumab PD1 66% FL (w Rituximab)B-specific T-cell engager(BiTEs)
BlinatumomabCD19 57% DLBCL (B-ALL)
Blinatumomab Is a BispecificT-Cell Engaging (BiTE) Antibody
-CD3Antibody
VH
VL
CD3 T Cell
Blinatumomab
Bargou R, et al. Science. 2008;321(5891):974-977.
-CD19Antibody
VH
VL
Target AntigenCD19
RedirectedLysis
TumorCell
BlinatumomabBiTE®
Phase II study of Mogamulizumab (KW-0761) incutaneous and peripheral TCL
• A first-in-class defucosylated anti-chemokine receptor-4(anti-CCR4 humanized moAb)
• Approved in Japan in 2012 for R/R ATL
• Phase II study in 37 (PTCL-NOS:16, AITL:12, ALCL ALK-:1;• Phase II study in 37 (PTCL-NOS:16, AITL:12, ALCL ALK-:1;MF:7, C-ALCL:1)
• CCR4 assessed by IHC before study entry• KW-0761 dose: 1mg/Kgr/day iv weekly x8
• AEs: skin rash,infusion reactions, leuco- and lymphopenia• ORR 35% (34% in PTCL and 385 in CTCL), PFS 3 months,
OS not reached
Ueda R, abstr 151, ICML-12, Lugano 2013
Targeting the micorenvironment: Pidilizumabwith Rituximab in R/R FL. A phase II study
• The inhibitory programmed death (PD)-1 receptor isoverexpressed in intratumoral T cells in FL
• Pidilizumab is a humanized anti-PD1 moAb whichenhances function of antitumor NK and T cells
• Phase II study in gr1-2 FL
Westin JR, abstr 159, ICML-12, Lugano 2013
• Phase II study in gr1-2 FL• n=30 pts (all previous R and 69% previous chemo)• Pidilizumab 3mg/kgr iv q4 w x4 with R 375mg/m2 qw x4
with 8x maintenance Pidilizumab
• No gr3 or gr4 toxicities
• ORR: 66%, CR 52%
The era of ADCs?
Brenduximab Vedotin (Adcetris)Anti-CD30 conjugated to an antitubulin agent
MMAE – microtubule-disrupting agentprotease-cleavable linker
anti-CD30 monoclonal antibody
Brentuximab vedotin ADC
Apoptosis
G2/M cellcycle arrest
ADC binds to CD30
MMAE disruptsmicrotubule network
ADC–CD30 complexinternalized/ traffics to
lysosome
MMAE is released
Adapted from Ansell SM. Expert Opin Investig Drugs 2011;20:99–105 and Younes A, et al. N Engl J Med 2010;363:1812–21.
ADC, antibody–drug conjugate; MMAE, monomethyl auristatin E.
Pivotal Phase II study in relapsed orrefractory HL post-ASCT
102 patients with relapsed or refractory HL post-ASCT
• Relapsed or refractoryCD30+ HL
Follow-upTreatment (n=102)Eligibility
• Brentuximab vedotin1.8 mg/kg IV every
Younes A et al: J Clin Oncol, 2012, 30:2183-2189
CD30+ HL
• Age ≥12 years
• Measurable disease≥1.5 cm
• ECOG 0–1
• Prior ASCT
21 days
• Administered outpatientover 30 min
• Max 16 cycles for SD orbetter
• Restage at cycles 2, 4, 7,10, 13, 16
• Every12 weeks
94% of patients achieved tumour reduction
Response rate 75%(34% CR)
PFS notably longer in pts with CR
PFS 5.6 mo;PFS 5.6 mo;21.7 mo in CR
Side effects
Pivotal Phase II study in relapsed orrefractory systemic ALCL (sALCL)
Phase II study of brentuximab vedotin in 58 patients withrelapsed or refractory sALCL
• Relapsed or refractorysALCL
Follow-upTreatment (n=58)Eligibility
• Brentuximab vedotin 1.8mg/kg IV every 21 days
sALCL
• Age ≥12 years
• Measurable disease ≥1.5cm FDG-avid
• ECOG performancestatus of 0–1
mg/kg IV every 21 days
• Administered tooutpatients, >30 min
• Maximum 16 cycles forSD or better
• Restage† at cycles2, 4, 7, 10, 13, 16
• Every12 weeks
Pro B et al: J Clin Oncol, 2012, 30:2190-2196
97% of patients achieved tumour reduction
Response rate 86%(57% CR)
PFS independent of ALK status
11(4)Positiven at risk (events)
35 (7)Negative
11(4)
26 (16)
10 (5)
22 (19)
9 (6)
20 (20)
7 (8)
13 (21)
2 (9)
7(22)
0 (9)
3 (23)
0 (9)
0 (23)
16 (0)
42 (0)
Advani, R. et al. Presented at American Society of Hematology annual meeting, San Diego, CA, USA; 9–13 Dec 2011. Oral presentation: Abstract #443.
Adcetris - future directions
• Incorporation into standard first line regimens
– Phase III study of ABVD vs A+AVD in cHL (NCT01712490)
– Phase II with modified eBEACOPP in cHL (NCT01569204)
– Phase I study of CH(O)P+ A in CD30+ TCL (NCT01309789)– Phase I study of CH(O)P+ A in CD30+ TCL (NCT01309789)
• Salvage regimen before or consolidation after ASCTin HL
– Phase II study in R/R HL (NCT01393717)
– AETHERA Phase III maintenance post ASCT (NCT01100502)
• Development in other lymphoma subtypes
Adcetris in PTCL-NOS and AITL
• n=29 (11 AITL and 18 PTCL-NOS) R/R• 2 prior lines• primary refractoy 55%
Maximum Tumor Volume Reduction AITLPTCL ORR 36%, 50% inORR 36%, 50% in
AITL (4/11 CR)
Responses also inlow/undetectableCD30 by IHC
Oki Y, abstr 152, ICML-12, Lugano 2013
Comparison of CD30 expression by IHC and CD30mRNA levels in a large series of PTCL
• n=324 PTCLs diagnosed between 1999 and 2012• CD 30 expression by IHC and mRNA expression GEP• Correlation between IHC and mRNA data
100
IHC correlates wellwith mRNA
Bossard C, abstr 151, ICML-12, Lugano 2013
0
20
40
60
80
ALCL EATL ENKTL PTCLNOS
ATLLHTLV1+
AITL
score 4 (> 75%)
score 3 (50 - 75%)
score 2 (25 - 49%)
score 1 (5 - 24%)
score 0 (<5%)
Only 21% of PTCL(non ALCL) stronglyexpress CD30(6% in AITL)
58% of PTCL (nonALCL) expresssome level of CD30
Adcetris in DLBCL?
CD30 expressed in 20-25% of DLBCL
Higher level of expression in:- Younger patients- Younger patients- Non-GCB phenotype?- EBV+ non-GCB cases
Phase II study in CD30+ NHL:ORR, 40% in highly refractoryDLBCL
CD30
Barlett NL, et al. ASH 2013
CD30 expression defines a novel DLBCLsubgroup with favorable prognosis anddistinct gene expression signature
The favorable outcome of CD30 expression was mantained in both GBC and non GBC subtypes
S. Hu, et al. Blood 2013
Immunoconiugates for NHL treatmentusing MoAbs to deliver toxins to cells that have aspecific target receptor
Target FDA approvedindication
SGN-CD19A (anti-CD19 + toxin) CD19 -
SAR3419 (anti-CD19 + maytansinoid) CD19 -
DT2219ARL (anti-CD19 & anti-CD22 + immunotoxin) CD19 CD22 -
Inotuzumab Ozogamicin (anti-CD22 + calicheamicin) CD22 -
DCDT2980S (anti-CD22 + MMAE) CD22 -
DCDS4501A (anti-CD79b + MMAE) CD79b
LMB-2 (anti-CD25 antibody + immunotoxin) CD25 -
IMGN529 (anti-CD37 antibody + maytansinoid ) CD37
Brentuximab Vedotin, formerly SGN-35 (Adcetris®)(anti-CD30 + MMAE)
CD30 HL / ALCL
R/R CD22+ NHLs progressed after at least 1 priortherapy
At least one site of measurable disease
Phase I Study of Inotuzumab Ozogamicin +Temsirolimus in Patients With Relapsed or Refractory
CD22+ B-cell NHL (NCT01535989)
No signs of VOD or VOD-like symptoms in earlier lineof treatment
No chronic obstructive or chronic restrictivepulmonary disease
2014 AACR Meeting, April 9 2014
A phase I study of inotuzumab ozogamicin in combinationwith temsirolimus in patients with relapsed or refractory
CD22-positive B-cell non-Hodgkin lymphomas (NHL).
A. Stathis1, F. Hitz2, U. Novak3, F. Bertoni4, T. Terrot1, L. Moser1, I. Xenidou1 , L.Mazzucchelli5, M. Ghielmini1, C. Sessa1, E. Zucca1, F. Cavalli1.
1 Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 2 Department ofOncology and Hematology, Cantonal Hospital St.Gallen, Switzerland; 3 Institute of
Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland; 4
IOR-Institute of Oncology Research, Bellinzona, Switzerland, 5Institute of Pathology,Locarno, Switzerland
IMGN529 compound profile andmechanism of action
Antibody-dependentcellular cytotoxicity
(ADCC)
Delivery of cytotoxicagent (DM1)
IMGN529 is an anti-CD37 immunotoxin. Multiple mechanisms of action: apoptosis,CDC, ADCC, and cytotoxicity by maytansinoid delivery
CD37
Tumor cell
Effector cellAntigen
DM1
IMGN529
Fc Receptor
Complement
Apoptosis/growthinhibition by
direct signaling
Complement-dependentcytotoxicity
(CDC)
Potent activity in vitro and in vivo studies
CD37 staining similar to CD20
J. Deckert, et al. Blood, 2013
R/R FL, DLBCL, MZL, MCL failing at least one line oftreatment (must have included a rituximab-basedregimen)
A Phase I, Multi-center, Open-label study ofIMGN529 in adult patients with relapsed or
refractory NHL (NCT01534715)
regimen)
At least one site of measurable disease
No limitation on number of previous treatments
CD37 analysis only for the expansion cohort
2014 ASCO annual Meeting, May 30 2014
Preliminary findings from a phase I, multicenter, open-labelstudy of the anti-CD37 antibody-drug conjugate (ADC),
IMGN529, in adult patients with relapsed or refractory non-Hodgkin lymphoma (NHL).
Stathis, A.1, Maddocks, K.2 Flinn, I.3, Weitman, S.4, Palomba, M. 5; Ponte, J. 6;Deckert, J6; Murphy, M.6; Zildjian, S.6, Ruiz-Soto, R.6, Freedman, A.7
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland1; Ohio StateUniversity, Columbus OH2; Sara Cannon Research Institute, Nashville, TN3; Cancer
Treatment Research Center, San Antonio, TX4; Memorial Sloan Kettering CancerCenter, New York, NY5; ImmunoGen, Inc., Waltham, MA6; Dana Farber Cancer Institute,
Boston, MA7
ADCs: toxicities
Drug
Brentuximab Vedotin
Inotuzumab Ozogamicin
Toxicity
Neuropathy
Thrombocyopenia, Hepatic
SAR3419
DCDT2980S
DCDT2980S
Ocular toxicity, neutropenia
Neutropenia
Neutropenia
it has taken some time
1900 P. Ehrlich envisioned therapies using specific magic bullets
1975 G. Köhler and C. Milstein (Cambridge, UK) published a paperon the production of moAbs of predefined specificity
1980 Preliminary evidence of the clinical activity and feasibility of1980 Preliminary evidence of the clinical activity and feasibility ofmoAbs against either a human lymphoma-associated antigenor the idiotype (Lee Nadler, Boston; Ron Levy, Stanford)
1984 Nobel prize to Köhler and Milstein
1997 First FDA approval of a moAb to treat cancers: rituximab forrelapsed or refractory low-grade or follicular lymphoma
Breakthrough lymphoma therapies
• Aug 2011: Adcetris for HL after autoSCT or after two linesand ALCL after at least 1 line
• June 2013: Revlimid for MCL after at least two lines oftreatmenttreatment
• Nov 2013: Obinutuzumab with Clb for untreated CLL
• Nov 2013: Imbruvica for MCL after failure of at least oneline
Thank you for the attention and see you in Lugano
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