Cancer immunology > what should happen (immunosurveillance)

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1 11 th Perspectives in Lung Cancer Vaccines: any expectations? J Vansteenkiste Dept Pulmonology q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and conclusion 1

2 Cancer immunology > what should happen (immunosurveillance) -> tumor cell destruction Adapted from: Finn, NEJM 358: , 2715, 2008 Cancer immunology > what happens (tumor escape) -> tumor cell destruction Adapted from: Finn, NEJM 358: , 2715,

3 Cancer immunology > what we want to happen (immunotherapy) immunotherapy -> tumor cell destruction Adapted from: Finn, NEJM 358: , 2715, 2008 > mode of delivery q Peptide o AG in liposome q Recombinant protein o AG + adjuvans (MAGE-A3 A3 ASCI) o EGF q Recombinant live vectors o AG expressed in modified viral vector (TG4010) q Whole tumour cells o autologous cells (GVAX) o allogeneic cells q Dendritic cells o loaded with AG or fused with whole tumour cells q Others o gangliosides (phase III study in SCLC negative) * Giaccone et al, J Clin Oncol 23: , 6864, 2005 Stimuvax is registered trademark of Merk KGaA - Lucanix of NovaRx Corp 3

4 > mode of delivery / phase III q Peptide o AG in liposome q Recombinant protein o AG + adjuvans (MAGE-A3 A3 ASCI) o EGF q Recombinant live vectors o AG expressed in modified viral vector (TG4010) q Whole tumour cells o autologous cells (GVAX) o allogeneic cells q Dendritic cells o loaded with AG or fused with whole tumour cells q Others o gangliosides (phase III study in SCLC negative) * Giaccone et al, J Clin Oncol 23: , 6864, 2005 Stimuvax is registered trademark of Merk KGaA - Lucanix of NovaRx Corp Cancer vaccination > conditions for a successful strategy 1 Specifity [preclinical] o tumour specific vs tumour associated AGs 2 Expression [preclinical] o broad expression in defined population 3 Immuno activity [mechanism of action] o vaccine leads to effective humoral and/or cellular response 4 Clinical effect [phase I-II] o cancer sensitive to immune killing 5 Outcome effect [phase III] o patient outcome should improve 4

5 Cancer vaccination > conditions for a successful strategy 1 Specifity [preclinical] o tumour specific vs tumour associated AGs 2 Expression [preclinical] o broad expression in defined population 3 Immuno activity [mechanism of action] o vaccine leads to effective humoral and/or cellular response 4 Clinical effect [phase I-II] o cancer sensitive to immune killing 5 Outcome effect [phase III] o patient outcome Lung should cancer: improve major local and general immunosuppression -> always adjuvants or cytokines needed to boost vaccination effect q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and conclusion 5

6 > MAGE-A3 A3 antigen q No expression in normal cells tumour q Really tumour specific, expressed (RT-PCR) in: o NSCLC* IA IB IIA IIB IIIA IIIB IV 16% 35% 47% o Head & neck 49%, bladder 35%, melanoma 56% * Sienel et al, Eur J Cardiothorac Surg 25: , 134, 2004 > MAGE-A3 A3 compound (ASCI) q MAGE-A3 A3 antigen o Purified ProtD-MAGE-A3/ A3/His recombinant fusion protein PD MAGE-A3A3 His-tail 109 aa 312 aa 7 aa q Adjuvant: GSK proprietary adjuvant system (AS02B) o QS-21: Saponin o MPL : Monophosphoryl lipid A o Oil-in in water emulsion 6

7 >MAGE-A3 A3 proof of concept phase II R study Resected NSCLC p-stage IB / II complete resection MAGE-A3 A3 rt PCR + PS 0-1 N=122 R N=60 MAGE-A3 A3 ASCI 300 µg im q3w x5 -> q3m x8 (27 m total) Placebo same schedule Stratified by: stage: IB vs II histology: squamous vs non-squamous LN procedure: limited vs dissection Primary endpoint: disease-free interval Vansteenkiste et al, ASCO IASLC 2008 > MAGE-A3 A3 phase II R: safety q 182 patients (122 MAGE-A3, A3, 60 placebo) q 1214 MAGE-A3 A3 doses administered q MAGE-A3 A3 immunotherapeutic overall well tolerated o mild: grade 1 or 2, local or systemic, reactions q Grade 3 or 4 events: 96% of the total MAGE-A3 A3 doses administered (117/1214) in 48 patients o o only three grade 3 events, possibly related to MAGE-A3 A3 leading to withdrawal of 1 patient (COPD exacerbation) 7

8 MAGE-A3 A3 phase II R study > disease-free interval (median FU 44 mo) Disease Free Interval MAGE-A3A3 Placebo HR = 075 (95%CI ) one-sided logrank P = 0122 Time from surgery (months) DFI: Interval from the date of surgical resection to the date recurrence HR: Hazard ratio calculated by Cox analysis MAGE-A3 A3 ASCI > perspective of adjuvant treatment q Positive signal of activity of MAGE-A3 A3 treatment o first double-blind, blind, placebo-controlled controlled trial with cancer immunotherapy in early stage NSCLC o 25% reduction in the relative risk of cancer recurrence q MAGE-A3 A3 treatment very well tolerated o suitable for long-term maintenance treatment, and suitable for most patients (including old age, co-morbidity ) 8

9 > MAGE-A3 A3 phase III: MAGRIT study MAGE-A3 A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy worldwide multicenter, randomized, double-blind, blind, placebo-controlled controlled ph III trial expected N=10,000 screened -> N=2270 patients randomized primary endpoint: disease-free survival Resected MAGE-A3 (+) NSCLC No chemo Decision for chemo Chemo Up to 4 cycles of chemo Randomization Randomization MAGE-A3A3 immunotherapy Placebo MAGE-A3A3 immunotherapy Placebo > MAGE-A3 A3 phase III: MAGRIT study North America (2) Canada United States Latin America (2) Argentina Brazil Europe (20) Austria Belgium Czech Republic Estonia Finland France Germany Greece Hungary Israel Ireland Italy Netherlands Norway Poland Russia Spain Sweden Switzerland UK Asia (9) Australia China Hong Kong India Japan South Korea Singapore Taiwan Thailand ClinicalTrialsgov NCT

q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and

Overexpressed by most human carcinomas, including NSCLC o Loss of polarity of expression: entire cell surface o N-terminal ectodomain aberrantly glycosylated o High MUC1 levels are

10 q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and conclusion > MUC1 antigen intracellular component: may interact with intracellular kinases (EGFR, Her2neu) 1 may be involved in inhibiting cell cell adhesion 2 q MUC1 in cancer o Overexpressed by most human carcinomas, including NSCLC o Loss of polarity of expression: entire cell surface o N-terminal ectodomain aberrantly glycosylated o High MUC1 levels are associated with immunosuppressionand poor prognosis 3 1 Li et al, Mol Cancer Res 1: , 775, Ohno et al, Eur J Cancer 42: , 263, Agrawal et al, Mol Med Today 4: , 403,

phosphatidylcholine) > MUC1 phase II R Stage IIIB/IV disease control after first-line therapy PS 0-2 No brain mets No immune disease N=88 R N=83 Stimuvax 1000 µg sc

11 > MUC1 compound q MUC1 antigen: BLP25 lipopeptide o S T A P P A H G V T S A P D T R P A P G S T A P P - Lys (PAL) G q Adjuvant o Monophosphoryl Lipid A: non-specific immune stimulation o Liposomal components: enhanced immune recognition o Cholesterol o DMPG (dimyristoyl phosphatidylglycerol) o DPPC (dipalmitoyl phosphatidylcholine) > MUC1 phase II R Stage IIIB/IV disease control after first-line therapy PS 0-2 No brain mets No immune disease N=88 R N=83 Stimuvax 1000 µg sc qw (x8) -> q6w + BSC BSC only Stratified IIIB dry vs IIIB wet vs IV Primary endpoint: overall survival Other endpoints: safety Butts et al, J Clin Oncol 23: , 6681,

12 > MUC1 phase II R: overall survival Butts et al, J Clin Oncol 23: , 6681, 2005 > MUC1 phase II R: overall survival stage III B P=00692 Butts et al, J Clin Oncol 23: , 6681, 2005 stage IV 12

> MUC1 phase III: START study Stimulating Targeted Antigenic Responses To NSCLC worldwide multicenter, randomized, double-blind, blind, placebo-controlled controlled ph III trial N = 1320 patients

13 > MUC1 phase III: START study Stimulating Targeted Antigenic Responses To NSCLC worldwide multicenter, randomized, double-blind, blind, placebo-controlled controlled ph III trial N = 1320 patients primary endpoint: survival Participating countries in Europe: Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Romania, Russia, Ukraine, Sweden, Spain, UK Leuven ClinicalTrialsgov Lung Cancer Group NCT q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and conclusion 13

14 > TGF-β2 allogeneic cells q Antigen ( belagenpumatucel ) o based on cocktail of 4 different NSCLC cell lines o processed to cell suspension o cryopreserved q Adjuvans o lowering of TGF-β2 activity by TGF-β2 antisense gene modification -> increase immunogenicity q Administration o vaccinate every month up to 16 times > TGF-β2 allogeneic cells: phase II Nemunaitis et al, J Clin Oncol 24: , 4730,

15 q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and conclusion > regf-p64k [EGF based cancer vaccine] q Antigen o human recombinant EGF, conjugated to the P64K Neisseria meningitides recombinant protein q Adjuvans o oil emulsion by montanide ISA51 q Administration o days 1, 7, 14, and 28, and monthly thereafter 15

16 > regf-p64k [EGF based cancer vaccine] log-rank P=010 log-rank P=00002 Neninger, J Clin Oncol 26: , 1458, 2008 q Cancer immunology, immunotherapy, vaccination q Agents in phase III development o MAGE-A3 A3 ASCI o MUC1 antigen o TGF-β2 allogeneic cells o regf-p64k q Other agents q Overview and conclusion 16

17 > overview MAGE-A3A3 BLP25 Lucanix regf-p64k Class full protein peptide in liposome allogeneic cells full protein Disease setting post-surgery surgery post-ctrt advanced advanced Specificity ++ +? + Expression +/- +? ++ Immuno- activity Phase II RCT/placebo RCT/BSC Open/dose RCT/BSC Phase III ongoing target 2270 ongoing target 1322 ongoing target 700 ongoing target 230 > conclusion q Lung cancer has important immunosuppressive environment o historical results with non-specific agents disappointing q Recent vaccination strategies include well defined antigens with strong adjuvants, studied in well defined populations o better AG recognition o better immune effector cell activation o better estimation of clinical potential o low toxicity 17

strong adjuvants, studied in well defined populations o better AG recognition o better immune effector

18 > conclusion q Lung cancer has important immunosuppressive environment o historical results with non-specific agents disappointing q Recent vaccination strategies include well defined antigens with strong adjuvants, studied in well defined populations o better AG recognition o better immune effector cell activation o better estimation of clinical potential o low toxicity YES! Thank you for your kind attention 18

ΤΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ. Δημήτρης Μαυρουδής Παθολόγος - Ογκολόγος Πανεπιστημιακό Νοσοκομείο Ηρακλείου

ΤΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ. Δημήτρης Μαυρουδής Παθολόγος - Ογκολόγος Πανεπιστημιακό Νοσοκομείο Ηρακλείου ΕΛΙΞΕΙΣ ΣΤΗΝ ΑΝΟΣΟΘΕΡΑΠΕΙ ΤΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ Δημήτρης Μαυρουδής Παθολόγος - Ογκολόγος Πανεπιστημιακό Νοσοκομείο Ηρακλείου LUNG CANCER INCIDENCE LUNG CANCER MORTALITY LUNG CANCER Non-small Cell Lung