1. Using Belatacept Allan D. Kirk, MD, PhD, FACS
Professor of Surgery and Pediatrics
Scientific Director, Emory Transplant Center
Vice Chair for Research, Department of Surgery
Emory University, Atlanta, Georgia
a study of context?
The
Emory
Transplant
Center

2. Fixing this is best achieved by going back to the fundamental question

3. What makes an immune response?
What makes a decision?
Specificity
Context
Magnitude
Immunity is best viewed as a decision, one that spans the entire spectrum of apathy, aggression, aversion…so what makes a decision?

4. The Pathways of Immune Decision Making
Signal 2
Signal 1
Signal 3
AEB
Anti-CD25
TOR
JAK
Cp690
CD2
LFA-1

5. Long-Term Skin and Heart Allograft Survival Induced by Combined Blockade
CTLA4-Ig
T Cell
CD28
CD40 B7
CD154
Anti-CD154 +
APC
H-2d
H-2k
BALB/c Skin
C3H Recipient
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
Larsen, et al, Nature 1996; 381:434-6.

6. Proc Natl Acad Sci USA 1997; 94:8789-8794.
CTLA4-Ig
hu5c8
CTLA4-Ig and hu5c8
Proc Natl Acad Sci USA 1997; 94:

9. Costimulation Blockade, DST & Rapamycin Context-based Approach
Allo
Auto
Auto
Allo
J Immunol 2003; 170:

10. Conceptual Design of a Context-based Regimen
Signal 2
Signal 1
Signal 3
AEB
Anti-CD25
TOR
JAK
Cp690
CD2
LFA-1

11. Immunosuppressive Regimen for FDA-sponsored Trial NCT00565773
Kirk, et al. Am J Transplant. 2012; 12(S3)

12. Renal Function for Patients Treated with Alemtuzumab Induction and Belatacept/Sirolimus maintenance (n=20)
Kirk, et al. Am J Transplant. 2012; 12(S3)

13. IgA nephropathy on biopsy
Status of NCT
20 patients
3 patients
5 patients
10 patients
Live donor, PRA<20%, age 45 years (20-69)
12 male:8 female
16 Caucasian:4 African American
EBV seropositive
1 SS rejection at day 10
4 converted to MMF
9 BM, 11 no BM
no chimerism
Creatinine 1.1 ( ; n=19)
No DSA
Sirolimus Wean
No Wean
7 patients
Enrolled
Eligible
IgA nephropathy on biopsy
Ulcerative colitis
DSA
stable on bela + sirolimus or MMF
patient election
No rejection
Clean biopsy, no DSA
signed separate consent
Successful
Failed
1 year
7 patients on once monthly immune therapy 3 2

14. Repopulation Through Homeostatic Activation
Accepted for Publication, AJT 2014

15. Homeostatic Activation Balanced by Compensatory Regulation
Accepted for Publication, AJT 2014

16. Preservation of CMV-specific Immunity Despite Depletion
IFN-γ
TNF-α
Pre month month
CMV pp65
ICCS
%CD4+ CMV reactive T cells
%CD8+ CMV reactive T cells

17. 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

18. Detection of CD8+ dual cytokine producers in response to allo-specific donor and 3rd party after renal allograft
Pre-transplant Month Month Month Month-36
Resting
vs Donor
vs 3rd Party
TNF-α
IFN-γ

19. Thank You!