1
PILC – Amsterdam 9-10 March 2012PILC Amsterdam 9 10 March 2012
Vaccines as adjuvant treatment.C. Dooms
Respiratory Oncology Unit
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Respiratory Oncology UnitDept. Pulmonology
Univ. Hospital LeuvenLeuven Lung Cancer Group
Cancer immunology> what should happen (immunosurveillance)
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
-> tumour cell destruction
Adapted from: Finn, NEJM 358: 2704-2715, 2008
2
Cancer immunology> what happens (tumour escape)
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.beAdapted from: Finn, NEJM 358: 2704-2715, 2008
-> tumor cell destruction
Cancer immunology> what we want to happen (immunotherapy)
i himmunotherapy
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.beAdapted from: Finn, NEJM 358: 2704-2715, 2008
-> tumour cell destruction
3
Interact with the immune system to treat cancer
Lung cancer immunotherapy
“Supportive” enhancement of
already stimulated immune system
‘Ag-independent’immune response
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
• BCG, IFN, …• TLR 9 agonists• Talactoferrin• Anti-CTLA4 Ab
Immunomodulation
Talactoferrin alpha = a recombinant human lactoferrin
Lung cancer immunotherapy> immunomodulation
o oral agent acting by dendritic cell recruitment and activation in gut-associated lymphoid tissue +
proliferation of CD8 cytotoxic T cells and NK cells (1 recruited/1 ongoing phase 3 NSCLC trial)
Ipilimumab = mAb against CTLA-4o mAb blocking inhibitory cytotoxic T lymphocyte Ag 4
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
=> enhanced T-cell response against tumouro PFS improvement when added to 1st line chemo for
advanced NSCLC (Lynch, ASCO 2010)o several phase III NSCLC trials (1 ongoing, others planned)
Kelly et al, Expert Opin Biol Ther 10:1379-1386, 2010
4
Interact with the immune system to treat cancer
Lung cancer immunotherapy
“Active” specific priming of immune
system
‘Adaptive Ag-specific’ immune
response
“Supportive”non-specific
enhancement of innate immune
response
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
• BCG, IFN, …• TLR 9 agonist• Talactoferrin• Anti-CTLA4 Ab
• tumour Ag vaccin• tumour cell vaccin
Cancer vaccinationImmunomodulation
Lung cancer immunotherapy> phase 3 development
Setting Phase 3
Post surgery MAGE-A3 recruited –target 2270 (MAGRIT)
Post chemoradio BLP25 recruited –enrolled 1476 (START)
Advanced
Lucanix recruiting –target 700
rEGF ongoing/planned–target 230/1000
TG4010 iti
V
a
c
c
i
n
a
t
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
TG4010 recruiting –target 1000
1E10 recruiting –target 1082
Advanced
Talactoferrin recruiting 1100 / recruited 720
Ipilimumab recruiting –target 920 / other RCTs
i
o
n
Modul
5
Lung cancer immunotherapy> phase 3 development
Setting Phase 3
Post surgery MAGE-A3 recruited –target 2270 (MAGRIT)
Post chemoradio BLP25 recruited –enrolled 1476 (START)
Advanced
Lucanix recruiting –target 700
rEGF ongoing/planned–target 230/1000
TG4010 iti
V
a
c
c
i
n
a
t
N = 10498
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
TG4010 recruiting –target 1000
1E10 recruiting –target 1082
Advanced
Talactoferrin recruiting 1100 / recruited 720
Ipilimumab recruiting –target 920 / other RCTs
i
o
n
Modul
Lung cancer immunotherapy> phase 3 development
Setting Phase 3
• targetPost surgery MAGE-A3 recruited –
target 2270 (MAGRIT)
Post chemoradio BLP25 recruited –enrolled 1476 (START)
Advanced
Lucanix recruiting –target 700
rEGF ongoing/planned–target 230/1000
TG4010 iti
V
a
c
c
i
n
a
t
• target• compound• ph2 data• ph3 development
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
TG4010 recruiting –target 1000
1E10 recruiting –target 1082
Advanced
Talactoferrin recruiting 1100 / recruited 720
Ipilimumab recruiting –target 920 / other RCTs
i
o
n
Modul
6
No expression in normal cells tumour
Lung cancer vaccination> target: MAGE-A3 antigen
No expression in normal cells tumour
Really tumour specific, expressed (RT-PCR) in:
o NSCLC*
IA IB IIA IIB IIIA IIIB IV
16% 35% 47%
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
o Head & neck 49%, bladder 35%, melanoma 56%
* Sienel et al, Eur J Cardiothorac Surg 25: 131-134, 2004
MAGE-A3 antigen
Lung cancer vaccination> compound: MAGE-A3 immunotherapeutic
go Purified ProtD-MAGE-A3/His recombinant fusion protein
Immunoadjuvant and delivery system :
PD MAGE-A3 His-tail
109 aa 312 aa 7 aa
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
o QS-21: Saponin
o MPL®: Monophosphoryl lipid A : potentiates immune response
o Oil-in water emulsion : improves Ag presentation to DC
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Resected NSCLCMAGE-A3 ASCI 300 µg i.m.
q3w x5 -> q3m x8 (27 m total)
Lung cancer vaccination> ph2: randomised MAGE-A3 trial
N=122
• p-stage IB / II• complete resection• MAGE-A3 rt PCR +• PS 0-1
q3w x5 > q3m x8 (27 m total)
Placebosame schedule
Stratified by:• stage: IB vs. II• histology: squamous vs. non-squamous
R
N=60
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Primary endpoint: disease-free interval
Vansteenkiste et al, ASCO 2007 - IASLC 2008
s o ogy squa ous s o squa ous• LN procedure: limited vs. dissection
MAGE A3
Lung cancer vaccination> ph2: MAGE-A3: disease-free interval
MAGE-A3Placebo
Dis
ease
Fre
e In
terv
al
HR = 0.75 (95%CI 0.46 – 1.23)one-sided logrank P = 0.122
median FU 44 mo
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Time from surgery (months)
g
DFI: Interval from the date of surgical resection to the date recurrenceHR: Hazard ratio calculated by Cox analysis
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MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy• worldwide multicenter, randomized, double-blind, placebo-controlled ph III trial
Lung cancer vaccination> ph3: MAGE-A3 MAGRIT study
worldwide multicenter, randomized, double blind, placebo controlled ph III trial
• expected N=10,000 screened -> N=2270 patients randomized
• primary endpoint: disease-free survival
Resected MAGE-A3 (+) NSCLC
Decision for chemoChemo No chemo
Up to 4 cycles of chemo
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Randomization
MAGE-A3immunotherapy
Placebo
Up to 4 cycles of chemo
Randomization
MAGE-A3immunotherapy
Placebo
Clinicaltrials.gov NCT00480025
MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy• worldwide multicenter, randomized, double-blind, placebo-controlled ph III trial
Lung cancer vaccination> ph3: MAGE-A3 MAGRIT study
worldwide multicenter, randomized, double blind, placebo controlled ph III trial
• expected N=10,000 screened -> N=2270 patients randomized
• primary endpoint: disease-free survival
Resected MAGE-A3 (+) NSCLC
Decision for chemoChemo No chemo
Up to 4 cycles of chemo
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Randomization
MAGE-A3immunotherapy
Placebo
Up to 4 cycles of chemo
Randomization
MAGE-A3immunotherapy
Placebo
Clinicaltrials.gov NCT00480025
9
Lung cancer immunotherapy> phase 3 development
Setting Phase 3
Post surgery MAGE-A3 recruited –target 2270 (MAGRIT)
Post chemoradio BLP25 recruited –enrolled 1476 (START)
Advanced
Lucanix recruiting –target 700
rEGF ongoing/planned–target 230/1000
TG4010 iti
V
a
c
c
i
n
a
t
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
TG4010 recruiting –target 1000
1E10 recruiting –target 1082
Advanced
Talactoferrin recruiting 1100 / recruited 720
Ipilimumab recruiting –target 920 / other RCTs
i
o
n
Modul
Mucinous glycoprotein: expression in
Lung cancer vaccination> target: MUC1 antigen
g y p ptumour (>80% NSCLC) & normal cellso higher expressiono more limited glycosilationo over entire surface of cancer cells
Role of MUC1 in cancer cellso disturbed cell-cell adhesion
GSTAPPAHGVTSAPDTRPAP
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
o invasion and metastasiso intracellular interactions (tyrosine kinases)
o growth signalso protects cancer cell from anti-tumour immune response
o immune escape
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BLP25 = lipopeptide (25 AA) with MUC1 specificity
Lung cancer vaccination> compound: BLP25
p p p ( ) p yo STAPPAHGVTSAPDTRPAPGSTAPP - Lys(PAL)G
Immunoadjuvant & delivery system :o Monophosphoryl Lipid A: to potentiate non-specific
immune response/stimulationo Liposomal components: to enhance immune
recognition – Ag presentation to APC
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
o Cholesterolo DMPG (dimyristoyl phosphatidylglycerol)o DPPC (dipalmitoyl phosphatidylcholine)
BLP25 induces a cellular immune response characterized
by T-cell proliferation and IFN-gamma production.
Stage IIIB/IVBLP25 1000 µg s.c.
qw (x8) -> q6wN=88
Lung cancer vaccination> ph2: randomised BLP25 trial
• disease control afterfirst-line therapy
• PS 0-2• No brain mets• No immune disease
qw (x8) -> q6w+ BSC
BSC only
R
Stratified IIIB ‘dry’ vs. IIIB ‘wet’ vs. IV
N=83
priming cyclophosphamide 300 mg/m2
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Primary endpoint: overall survivalOther endpoints: safety, HRQoL, immune response
Butts et al, J Clin Oncol 23:6674-6681, 2005
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Lung cancer vaccination> ph2: randomised BLP25 trial: OS
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.beButts et al, J Clin Oncol 23:6674-6681, 2005.Butts et al, J Cancer Res Clin Oncol 137:1337, 2011.
Lung cancer vaccination> ph2: randomised BLP25 trial: OS
stage IV
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
stage III B MS : 31 vs 13 mo
Butts et al, J Clin Oncol 23:6674-6681, 2005.Butts et al, J Cancer Res Clin Oncol 137:1337, 2011.
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Stimulating Targeted Antigenic Responses To NSCLC• worldwide multicenter, randomized, double-blind, placebo-controlled phase 3 trial
Lung cancer vaccination> ph3: BLP25 START study
worldwide multicenter, randomized, double blind, placebo controlled phase 3 trial• planned N = 1320 patients• primary endpoint: survival
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Romania, Russia, Ukraine, Sweden, Spain, UK
Participating countries in Europe:
Clinicaltrials.gov NCT00409188
Stimulating Targeted Antigenic Responses To NSCLC• worldwide multicenter, randomized, double-blind, placebo-controlled phase 3 trial
Lung cancer vaccination> ph3: BLP25 START study
worldwide multicenter, randomized, double blind, placebo controlled phase 3 trial• planned N = 1320 patients• primary endpoint: survival
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Romania, Russia, Ukraine, Sweden, Spain, UK
Participating countries in Europe:
Clinicaltrials.gov NCT00409188
13
Lung cancer immunotherapy> phase III development
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.beAdapted from Decoster et al, Ann Oncol e-pub 2011
Lung cancer vaccination> conclusion
Lung cancer : immunosuppressive environmento historical results with non-specific agents disappointing
Recent vaccination strategies include well definedantigens with strong adjuvants, studied in welld fi d l ti
.Respiratory Oncology Unit
Univ. Hospital LeuvenLeuven Lung Cancer Group
http://www.LLCG.be
defined populationso better AG recognition – immune effector cell activationo better estimation of clinical potentialo low toxicityo >10,000 patients in ph3 studies
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