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

What makes an immune response?What makes a decision?

1. Specificity

2. Context

3. Magnitude

AEB

Anti-CD25

TOR

JAKCp690

CD2

LFA-1

AEB

Signal 2 Signal 1 Signal 3

The Pathways of Immune Decision Making

• 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

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 Allo

Auto

J Immunol 2003; 170:2776-82.

AEB

Anti-CD25

TOR

JAKCp690

CD2

LFA-1

AEB

Signal 2 Signal 1 Signal 3

Conceptual Design of a Context-based Regimen

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)

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

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 pp65ICCS

%CD8+ CMV reactive T cells%CD4+ 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

Thank You!