Cancer immunology - Imedeximedex.com/lung-cancer-congress-europe/archive/2012/assets/... · Cancer immunology > what we want to happen ... No expression in normal cells tumour Lung

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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


Cancer immunology> what should happen (immunosurveillance)



http://www.LLCG.be

-> tumour cell destruction

Adapted from: Finn, NEJM 358: 2704-2715, 2008

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Cancer immunology> what happens (tumour escape)



http://www.LLCG.beAdapted from: Finn, NEJM 358: 2704-2715, 2008

-> tumor cell destruction

Cancer immunology> what we want to happen (immunotherapy)

i himmunotherapy



http://www.LLCG.beAdapted from: Finn, NEJM 358: 2704-2715, 2008

-> tumour cell destruction

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Interact with the immune system to treat cancer

Lung cancer immunotherapy

“Supportive” enhancement of

already stimulated immune system

‘Ag-independent’immune response



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



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

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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



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

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n

a

t



http://www.LLCG.be

TG4010 recruiting –target 1000

1E10 recruiting –target 1082

Advanced

Talactoferrin recruiting 1100 / recruited 720

Ipilimumab recruiting –target 920 / other RCTs

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n

Modul

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Setting Phase 3



Advanced



TG4010 iti

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a

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c

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a

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N = 10498



http://www.LLCG.be



Advanced



i

o

n

Modul


Setting Phase 3

• targetPost surgery MAGE-A3 recruited –

target 2270 (MAGRIT)


Advanced



TG4010 iti

V

a

c

c

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• target• compound• ph2 data• ph3 development



http://www.LLCG.be



Advanced



i

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Modul

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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%



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



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



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



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



http://www.LLCG.be

Randomization

MAGE-A3immunotherapy

Placebo


Randomization


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




http://www.LLCG.be

Randomization


Placebo


Randomization


Placebo


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Setting Phase 3



Advanced



TG4010 iti

V

a

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http://www.LLCG.be



Advanced



i

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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



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



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



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



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



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



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:


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



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:


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Lung cancer immunotherapy> phase III development



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



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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Thank you for your kind attention



http://www.LLCG.be

Leuven, Gothic Town Hall (1448)

Cancer immunology - Imedeximedex.com/lung-cancer-congress-europe/archive/2012/assets/... · Cancer immunology > what we want to happen ... No expression in normal cells tumour Lung

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