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

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

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?

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

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.

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

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

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

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

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

IgA nephropathy on biopsy Status of NCT00565773 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 (0.9-1.9; 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

Repopulation Through Homeostatic Activation Accepted for Publication, AJT 2014

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

Preservation of CMV-specific Immunity Despite Depletion IFN-γ TNF-α Pre 12 month 24 month CMV pp65 ICCS %CD4+ CMV reactive T cells %CD8+ CMV reactive T cells

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

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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