Presentation on theme: "Using Belatacept Allan D. Kirk, MD, PhD, FACS"— Presentation transcript:
1 Using Belatacept Allan D. Kirk, MD, PhD, FACS Professor of Surgery and PediatricsScientific Director, Emory Transplant CenterVice Chair for Research, Department of SurgeryEmory University, Atlanta, Georgiaa study of context?TheEmoryTransplantCenter
2 Fixing this is best achieved by going back to the fundamental question
3 What makes an immune response? What makes a decision?SpecificityContextMagnitudeImmunity 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 2Signal 1Signal 3AEBAnti-CD25TORJAKCp690CD2LFA-1
5 Long-Term Skin and Heart Allograft Survival Induced by Combined Blockade CTLA4-IgT CellCD28CD40B7CD154Anti-CD154+APCH-2dH-2kBALB/c SkinC3H RecipientBrief induction with CTLA4-Ig plus anti-CD154 produced indefinite cardiac allograft survival and >50d skin graft survivalNeither agent alone was as effectiveCyA decreased CTLA4-Ig + anti-CD154 effectLarsen, et al, Nature 1996; 381:434-6.
6 Proc Natl Acad Sci USA 1997; 94:8789-8794. CTLA4-Ighu5c8CTLA4-Ig and hu5c8Proc Natl Acad Sci USA 1997; 94:
10 Conceptual Design of a Context-based Regimen Signal 2Signal 1Signal 3AEBAnti-CD25TORJAKCp690CD2LFA-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 NCT20 patients3 patients5 patients10 patientsLive donor, PRA<20%, age 45 years (20-69)12 male:8 female16 Caucasian:4 African AmericanEBV seropositive1 SS rejection at day 104 converted to MMF9 BM, 11 no BMno chimerismCreatinine 1.1 ( ; n=19)No DSASirolimus WeanNo Wean7 patientsEnrolledEligibleIgA nephropathy on biopsyUlcerative colitisDSAstable on bela + sirolimus or MMFpatient electionNo rejectionClean biopsy, no DSAsigned separate consentSuccessfulFailed1 year7 patients on once monthly immune therapy32
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-γTNF-αPre month monthCMV pp65ICCS%CD4+ CMV reactive T cells%CD8+ CMV reactive T cells
17 Trial SummaryPatients (37/37) treated with alemtuzumab, belatacept and sirolimus have experienced good outcomesNow enrolling DDRT recipientsBelatacept was tolerated by allSirolimus was poorly tolerated by someExcellent renal functionHomeostatic repopulation characterized by memory and regulatory phenotypes that results in a phenotypeThe 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 allograftPre-transplant Month Month Month Month-36Restingvs Donorvs 3rd PartyTNF-αIFN-γ