visit of north american delegation of hospital ceo's to the sheba medical center dr gal markel...
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Visit of North American Delegation of Hospital CEO's to the Sheba Medical Center
Dr Gal MarkelElla Institute of Melanoma
5.2.20121
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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
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Killingmarker
Killercell
Killingreceptor
Tumor
Killingmarker
Killercell
Killingreceptor
Tumor
CEACAM1
Killercell
Killingreceptor
Tumor
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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
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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
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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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