New biologic agents in development are likely to usher in a paradigm shift in the design and delivery of immunosuppression for organ transplantation. Thus far the use of biologic agents has been limited to perioperative induction as well as the treatment of rejection. In contrast, new biologic agents are being developed expressly for maintenance therapy in an attempt to improve the speciﬁcity of long-term immunosuppression without the requirement for and toxicity of daily agents such as CNIs. Chronic biologic therapy has been made possible largely through the perfection of protein humanization and the virtual elimination of long-term immunogenicity.23 At least two reasons underlie the shift in focus in the use of biologic agents. First, the targets of new biologics are typically non-depletional, thus lending themselves to chronic therapeutic use without undue global immunodeﬁciency. Second, biologics are expensive to produce, making economic models that rely on short-term use difﬁcult to develop. Long-term use allows for the development and implementation of a ﬁnancially viable model for production and distribution in small patient populations. The biologic that best epitomizes this paradigm shift is belatacept.24 Another biologic that appears promising is alefacept25, 26 (TableII).
Co-Stimulation Blockade: Belatacept
The CD28/B7 (CD80 and 86) co-stimulation pathway is an essential signal for T-cell activation. After 25 years of research the fusion receptor protein CTLA4-Ig (abatacept), a competitive antagonist for CD28 blocking CD80/CD86 binding, was approved for human use in the treatment of rheumatoid arthritis.27 Early experiments with co-stimulation blockade in transplantation were mixed. Prolongation of graft survival using co-stimulation blockade in rodent transplantation experiments could not be reproduced in NHPs.24, 28 CTLA4-Ig did not achieve as good afﬁnity to CD86 compared with CD80 and was the likely cause of failure in a more stringent animal model.24
Belatacept, a re-engineered CTLA4Ig with two amino acid substitutions in the CTLA4 binding domains, binds CD80 2-fold better and CD86 4-fold better than CTLA4-Ig and has a 10-fold more potent inhibition of T-cell activation in vitro versus CTLA4-Ig.29 The in vitro superiority of belatacept in blocking T-cell responses was conﬁrmed by better survival of renal allografts in an NHP model.24 In these experiments, a CNI-free regimen with belatacept and a combination of an anti-IL-2 receptor antibody and maintenance therapy with MMF and steroids resulted in marked prolongation of the survival of renal allografts.24
These ﬁndings led to the design of a Phase 2 multicenter clinical trial comparing the safety and efﬁcacy of a more intensive (MI) and a less intensive (LI) regimen of belatacept compared with cyclosporine.30 In this trial belatacept performed with equivalent efﬁcacy to cyclosporine and was associated with better renal function and histology. Lipid levels and blood-pressure values were similar or slightly lower in the belatacept groups. However, the development of post-transplant lympho-proliferative disorder (PTLD) arose as a safety concern. Three cases of PTLD were identiﬁed in the MI group versus none in the LI or cyclosporine arms. Recently, the results of the Phase 2 long-term extension trial have been published.31 Continued follow-up of 128 of the original 218 patients demonstrated that no patients who were treated with belatacept and 1 patient who was treated with cyclosporine developed PTLD during the extension follow-up period. Additionally, renal function was superior in belatacept-treated patients. There was an average calculated GFR of 77.2 ± 22.7 mL/min per 1.73 m2 versus 59.3 ± 15.3 mL/min per 1.73 m2 at 60 months in the belatacept- versus the cyclosporine-treated patients, respectively.
Given these promising results, two Phase 3 trials were undertaken, and data are available. The ﬁrst trial, Belatacept Evaluation of Nephroprotection and Efﬁcacy as First-line Immunosuppression Trial (BENEFIT)32 is a 3-year, randomized, Phase 3 trial. Adult patients receiving a living-donor kidney or standard criteria deceased-donor kidney were eligible. Patients received one of three regimens: MI belatacept, LI belatacept, or cyclosporine. Patients in all treatment arms received basiliximab induction and were maintained on MMF and cortico-steroids. At 1 year patients enrolled in the MI, LI, and cyclosporine treatment groups had 95%, 97%, and 93% patient and graft survival, respectively. The mean measured GFR was 65, 63.4, and 50.4 mL/min/1.73 m2 in the MI, LI-, and cyclosporine-treated patients, respectively (p < 0.0001 for both MI and LI versus cyclosporine).
The prevalence of chronic allograft nephropathy on protocol biopsies was lower in belatacept-treated patients compared with cyclosporine-treated patients. There was a higher incidence of acute rejection at 12 months in the belatacept-treated groups compared with the cyclosporine-treated group (22% MI; 17% LI; 7% cyclosporine). The incidence of acute rejection met the non-inferiority cutoff for LI versus cyclosporine groups but not for MI versus cyclosporine groups. Almost 100% of rejections occurred within the ﬁrst 6 months post transplantation. Interestingly, the mean measured GFR at month 12 was higher in belatacept-treated patients with acute rejection compared with cyclosporine-treated patients without acute rejection. Belatacept-treated patients had a signiﬁcantly lower mean blood pressure (MI 133/79 mmHg; LI 131/79 mmHg) compared with cyclosporine-treated patients (139/82 mmHg). By 12 months, 1, 2, and 1 patient in the MI, LI, and cyclosporine groups developed PTLD, respectively. Additionally, after month 12 two additional patients in the MI group developed central nervous system (CNS) PTLD. Four of the 6 patients who developed PTLD had known risk factors. One patient had Epstein-Barr virus (EBV) negative serology pre-transplant, 1 patient received lymphocyte-depleting therapy as treatment for an acute rejection, and 2 patients had both EBV-negative serology and received lymphocyte-depleting therapy. Lastly, 2 patients with EBV-negative serology received transplants from EBV-seropositive donors.
The second Phase 3 trial, Belatacept Evaluation of Nephroprotection and Efﬁcacy as First-line Immunosuppression Trial—EXTended criteria donors (BENEFIT—EXT)33 is a 3-year, randomized trial in patients who received a kidney transplant from an extended-criteria donor. Patients were treated with basiliximab induction, MMF, and corticosteroids. Patients were randomized to receive MI, LI, or cyclosporine. Both belatacept regimens were non-inferior to cyclosporine on the primary endpoint of patient and graft survival. The prevalence of biopsy-proven CAN was similar between the three groups. The mean measured GFR at 12 months was 52.1, 49.5, and 45.2 mL/min/1.73 m2 for the MI-, LI-, and cyclosporine-treated groups, respectively and was signiﬁcantly better in the MI-treated patients versus the cyclosporine-treated patients (p = 0.0083) but not for the LI group compared with cyclosporine (P = 0.1039). There was no difference in the incidence of acute rejection among the three groups. Mean systolic and diastolic blood pressure was lower for both belatacept groups compared with the cyclosporine-treated group.
The incidence of NODAT was signiﬁcantly lower in the MI group compared with the cyclosporine group; however, there was not a signiﬁcant difference in NODAT in the LI group compared with the cyclosporine group. One patient in the MI group and 2 patients in the LI group developed PTLD during the 12-month follow-up period. One additional patient in each of the belatacept groups developed PTLD after month 12. No patients in the cyclosporine group developed PTLD. Three of the 5 PTLD patients had negative EBV serology pre-transplant. None of the patients who developed PTLD were exposed to lymphocyte-depleting therapy.
Thus far belatacept is the only agent in clinical development that has demonstrated an advantage in renal preservation and a trend toward an improved cardio-metabolic proﬁle when compared with a CNI. So far the optimal use of belatacept seems to be in a lower intensity regimen utilized in low immunologic risk patients who are EBV positive. It is becoming clearer that when used in the right subset of patients, belatacept seems to confer improved long-term renal allograft survival compared with CNIs without additional safety concerns.