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Using Belatacept
Allan D. Kirk, MD, PhD, FACSProfessor of Surgery and Pediatrics
Scientific Director, Emory Transplant CenterVice Chair for Research, Department of Surgery
Emory University, Atlanta, Georgia
TheEmory
TransplantCenter
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What makes an immune response?What makes a decision?
1. Specificity
2. Context
3. Magnitude
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AEB
Anti-CD25
TOR
JAKCp690
CD2
LFA-1
AEB
Signal 2 Signal 1 Signal 3
The Pathways of Immune Decision Making
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• Brief induction with CTLA4-Ig plus anti-CD154 produced indefinite cardiac allograft survival and >50d skin graft survival
• Neither agent alone was as effective• CyA decreased CTLA4-Ig + anti-CD154 effect
H-2d
BALB/c Skin
H-2k
C3H Recipient
Larsen, et al, Nature 1996; 381:434-6.
CTLA4-Ig
T Cell CD28
CD40
B7
CD154
Anti-CD154
+APC
Long-Term Skin and Heart Allograft Survival Induced by Combined Blockade
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CTLA4-Ig
hu5c8
CTLA4-Ig and hu5c8
Proc Natl Acad Sci USA 1997; 94:8789-8794.
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Costimulation Blockade, DST & Rapamycin Context-based Approach
Allo
Auto Allo
Auto
J Immunol 2003; 170:2776-82.
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AEB
Anti-CD25
TOR
JAKCp690
CD2
LFA-1
AEB
Signal 2 Signal 1 Signal 3
Conceptual Design of a Context-based Regimen
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Immunosuppressive Regimen for FDA-sponsored Trial NCT00565773
Kirk, et al. Am J Transplant. 2012; 12(S3)
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Renal Function for Patients Treated with Alemtuzumab Induction and
Belatacept/Sirolimus maintenance (n=20)
Kirk, et al. Am J Transplant. 2012; 12(S3)
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Status of NCT00565773
20 patients
20 patients
3 patients
5 patients 5 patients
10 patients
Live donor, PRA<20%, age 45 years (20-69)12 male:8 female16 Caucasian:4 African American EBV seropositive
1 SS rejection at day 104 converted to MMF9 BM, 11 no BMno chimerism
Creatinine 1.1 (0.9-1.9; n=19)No DSA
Sirolimus Wean No Wean
7 patients
Enrolled
Eligible
IgA nephropathy on biopsyUlcerative colitis
DSA
stable on bela + sirolimus or MMF
patient electionNo rejection
Clean biopsy, no DSA signed separate consent
Successful Failed
1 year
7 patients on once monthly immune therapy
3
2
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Repopulation Through Homeostatic Activation
Accepted for Publication, AJT 2014
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Homeostatic Activation Balanced by Compensatory Regulation
Accepted for Publication, AJT 2014
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Preservation of CMV-specific Immunity Despite Depletion
IFN-γ
TNF-
α
Pre 12 month 24 month
CMV pp65ICCS
%CD8+ CMV reactive T cells%CD4+ CMV reactive T cells
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Trial Summary
• Patients (37/37) treated with alemtuzumab, belatacept and sirolimus have experienced good outcomes
• Now enrolling DDRT recipients• Belatacept was tolerated by all• Sirolimus was poorly tolerated by some• Excellent renal function• Homeostatic repopulation characterized by memory and
regulatory phenotypes that results in a phenotype • The regimen allows some patients to transition to belatacept
monotherapy
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Detection of CD8+ dual cytokine producers in response to allo-specific donor and 3rd party after renal allograft
Pre-transplant Month 12 Month-24 Month-30 Month-36
Resting
vs Donor
vs 3rd Party
TNF-α
IFN-γ
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Thank You!