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 The Emory Transplant Center

3. What makes an immune response? What makes a decision? • Specificity • Context • Magnitude

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

5. Long-Term Skin and Heart Allograft Survival Induced by Combined Blockade APC T Cell + B7 CD28 CTLA4-Ig CD40 CD154 H-2d H-2k Anti-CD154 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. CTLA4-Ig hu5c8 CTLA4-Ig and hu5c8 ProcNatlAcadSci USA1997; 94:8789-8794.

9. Costimulation Blockade, DST & RapamycinContext-based Approach Allo Auto Auto Allo J Immunol 2003; 170:2776-82.

10. Anti-CD25 JAK Cp690 TOR CD2 Conceptual Design of a Context-based Regimen Signal 1 Signal 3 Signal 2 AEB AEB 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. Live donor, PRA<20%, age 45 years (20-69) 12 male:8 female 16 Caucasian:4 African American EBV seropositive Status of NCT00565773 Enrolled 20 patients 1 SS rejection at day 10 4 converted to MMF 9 BM, 11 no BM no chimerism 1 year Eligible Creatinine 1.1 (0.9-1.9; n=19) No DSA 20patients Sirolimus Wean No Wean stable on bela + sirolimus or MMF Clean biopsy, no DSA signed separate consent 7 patients 3 patients 10 patients patient election No rejection IgA nephropathy on biopsy Ulcerative colitis DSA Successful Failed 5 patients 5 patients 3 2 7 patients on once monthly immune therapy

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 Pre 12 month 24 month CMV pp65 ICCS TNF-α IFN-γ %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 12 Month-24 Month-30 Month-36 Resting vs Donor vs 3rd Party TNF-α IFN-γ

19. Thank You!