Visit of North American Delegation of Hospital CEO's to the Sheba Medical Center

Dr Gal MarkelElla Institute of Melanoma

5.2.20121

Malignant melanoma

Accounts for 75% of skin cancer-related deaths

Leading cause of cancer-related death in age group of <30y

Incidence has tripled over last 30 years and continues to rise

Prognosis of Stage IV patients is 10% for 5 years

Israel is ranked 3rd worldwide in the prevalence of melanoma

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Ella Institute Research Laboratory

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Gaps in clinical management of melanoma

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• Focusing on microRNAs that control melanoma cell aggressiveness

• Delineation of the link between melanoma genomic mutations and microRNAs

Greenberg et al, PLoS ONE 04/2011Greenberg et al, PLoS ONE 11/2011

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Proof of concept with adoptive cell transfer therapy11 responders vs. 15 non-responders

miR signature: miR-F, -G, -H, -I

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CEACAM1 is a novel immune checkpoint

Killercell

Tumor

CEACAM1

Markel et al, J Immunol 2002 Markel et al, Eur J Immunol 2004Markel et al, J Clin Invest 2002 Markel et al, J Immunol 2006Markel et al, J Immunol 2004 Markel et al, Immunology 2008Markel et al, Blood 2004 Markel et al, Cancer Immunol Immunother 20109

Killingmarker

Killercell

Killingreceptor

Tumor

Killingmarker

Killercell

Killingreceptor

Tumor

CEACAM1

Killercell

Killingreceptor

Tumor

10

0.0

25.0

50.0

75.0

100.0

0 10 20 30 40

Targets blocked

Effectors blocked

Concentration (ng/ml)

% C

EA

CA

M1

ac

tivit

y

0.0

25.0

50.0

75.0

100.0

0 10 20 30 40

Targets blocked

Effectors blocked

Concentration (ng/ml)

% C

EA

CA

M1

ac

tivit

y%

CEAC

AM1

activ

ity

Affinity:2x10-9 (2nM)

EC50:5ng/ml

11 Ortenberg et al, Mol Cancer Ther 2012

0

500

1000

1500

2000

2500

0 5 10 15 20 25 30 35

Days post TILs injection

Tu

mo

r vo

lum

e m

m3

Control MRG1TILMRG1+TIL

MRG1ip

TIL iv

Inhibition of growth rate Tumor apoptosis in vivo

Control MRG1

TIL TIL + MRG1

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***

Ortenberg et al, Mol Cancer Ther 2012

CTLA-4PD-1CEACAM1

Not expressed by tumor cells

Not participating in antigen presentation

General stimulationGeneral and local stimulation

Local stimulation

HighHighLow

Tu

mo

rP

erip

her

y

Immune effects

Expected Immune

side-effects

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