De novo belatacept in clinical vascularized composite allotransplantation

Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)‐based. As such, most recipients have experienced CNI‐related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI‐based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI‐based regimen to a belatacept‐based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept‐based regimen, transitioned to a CNI–free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI‐associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA.     

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation

A majority of kidney transplant recipients receive calcineurin inhibitor‐based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor‐intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor‐intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long‐term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.     

Mycophenolate Mofetil and Calcineurin-Inhibitor Reduction: Recent Progress

Mycophenolate mofetil (MMF) in combination with calcineurin inhibitors (CNIs) has greatly contributed to acute rejection rate reduction. Because of its immunosuppressive potency it was initially thought that MMF would help in reducing/avoiding CNI-related nephrotoxicity. Elective avoidance of CNI in induction and maintenance MMF-based immunosuppression has resulted in an increased risk for acute and chronic rejection. A recent meta-analysis suggests that CNI elimination in patients on MMF with progressive renal dysfunction is associated with a better outcome, although more data are needed to support any recommendation. So far, the more conservative approach involving CNI minimization with MMF has been associated with amelioration of renal function and low risk for rejection, providing an adequate risk/benefit balance. However, MMF with belatacept might pave the way for CNI-free induction and maintenance immunosuppression. Meanwhile, the assessment of immunological risk by new monitoring tools could be a prerequisite to further implement such CNI sparing strategies.     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

De Novo Belatacept in a Human Immunodeficiency Virus–Positive Kidney Transplant Recipient

Benefits of belatacept‐based immunosuppressive regimens in human immunodeficiency virus (HIV)–positive renal transplant recipients include avoidance of drug interactions between calcineurin inhibitors and highly active antiretroviral agents and decreased likelihood or severity of nonimmune toxicities such as new‐onset diabetes after transplant, hyperlipidemia and hypertension. We report a successful case of de novo belatacept at >18 mo from transplant in an HIV‐positive black man aged 50 years who received his first transplant from a living related kidney donor. To our knowledge, this case is the first reported of belatacept use in an HIV‐positive renal transplant recipient.     

Immunosuppression and Results in Renal Transplantation

Keeping a balance between the effective prevention of rejection and the side effects of immunosuppressants is a key point for long-term renal transplantation success. Today antibody induction (either basiliximab or depleting polyclonal antibodies for high-risk patients) together with an initial combination therapy of calcineurin inhibitor (CNI), mycophenolate, and steroids is recommended and results in excellent early outcomes. Yet despite the significant decrease in the incidence of acute rejection, long-term graft loss has remained rather constant over the last 25 yr. Thus new immunosuppressive combination strategies, avoiding or minimising CNIs, have been a goal in many randomised controlled trials during the last decade. Although it is too early to reach conclusions about the success of these strategies, some results are rather encouraging, in particular strategies including novel biotherapies like belatacept. This review updates the current knowledge and indications of modern immunosuppressants in the setting of renal transplantation and offers an overview of the regimen strategies available to minimise long-term side effects and prolong the survival of both patients and allografts.Patient summary Modern immunosuppression strategies with calcineurin inhibitors (CNIs) and mycophenolate have reduced incidence of acute rejection but failed to improve long-term renal outcome. Efforts to minimise or replace CNIs have led to encouraging results, but long-term follow-up and integration of new drugs in these strategies are required to really improve long-term results after renal transplantation.     

Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates

Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the nonlifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin‐based regimens. In this study, we used a nonhuman‐primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7‐specific costimulation blockade with and without adhesion blockade with LFA3‐Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3‐Ig reduced CD2^hi memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model.     

Novel immunosuppression: small molecules and biologics

Kidney transplantation today has excellent short-term outcomes that have paralleled the use of new immunosuppressive agents introduced in the 1990s. In addition to reducing acute rejection, the goals for developing new agents is to improve long-term outcome, minimize nephrotoxicity, and reduce infectious, cardiovascular, and malignancy-related complications. Novel small molecules and biological agents currently in clinical development may help to minimize the use of calcineurin inhibitors and steroids. These small molecules include FTY720, a sphingosine phosphate-receptor modulator, FK778, an inhibitor of pyrimidine synthesis, CP-690550, a JAK3 inhibitor, and AEB-071, a protein kinase C inhibitor. The biological agents include drugs targeting interleukin-15, anti-CD40, belatacept (LEA29Y), a second-generation CTLY4Ig that blocks the interaction between CD80/86 and CD28 costimulatory pathways, and efalizumab, a humanized anti-LFA1 monoclonal antibody. These new agents currently in preclinical and clinical trials appear promising and may represent the emergence of novel immunosuppressive agents that can deliver immunosuppression without long-term toxicity.     

Corticosteroids and methotrexate as adjuvants to costimulation blockade in non‐human primate renal transplantation

Belatacept, the CD28‐B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28‐B7‐specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.     

De novo thrombotic microangiopathy after kidney transplantation

Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post-transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS. Here, we review the etio-pathogenesis, diagnosis and treatment options for de novo post-transplant TMA. It is usually in the setting of calcineurin inhibitor use, mammalian target of rapamycin inhibitor use, or antibody mediated rejection; recently genetic mutations in complement regulatory genes for Factor H and Factor I similar to those described in aHUS have been reported in up to a third of these patients. Systemic signs of TMA are frequently absent, and a renal allograft biopsy is often needed to establish the diagnosis. Although withdrawal of the offending agents is usually the first line of treatment and resolution of laboratory abnormalities has been documented with this approach in several case reports and case series, available retrospective data demonstrate lack of benefit in long-term graft outcomes. Co-stimulation blockage with belatacept provides an effective alternate immunosuppressive strategy for these patients. Anti-complement therapy with eculizumab is effective in some cases; further work is required to define which patients with TMA (with and without concomitant antibody-mediated rejection) would benefit from receiving this treatment, and what biomarkers can be used to identify them.     

Optimization of de novo belatacept-based immunosuppression administered to renal transplant recipients

Kidney transplant recipients administered belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept-based maintenance regimens. Steroid-sparing, belatacept-based immunosuppression (following T cell–depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept-based regimen for minimizing early cellular AR occurrence.     

ASP2409, A Next‐Generation CTLA4‐Ig,Versus Belatacept in Renal Allograft Survival in Cynomolgus Monkeys

Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile; however, higher incidence of acute rejection and posttransplant lymphoproliferative disorder are the shortcomings of this agent. In this study, ASP2409, a new cytotoxic T‐lymphocyte associated protein 4‐immunoglobulin possessing 14‐fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys. ASP2409 monotherapy dose‐dependently prolonged renal allograft survival. Low‐dose ASP2409 in combination with a subtherapeutic dose of tacrolimus showed much longer median survival time than monotherapy. Similar allograft survival results were observed in regimens based on high‐dose ASP2409, belatacept, and therapeutic‐dose tacrolimus. The results of renal allograft histopathology with high‐dose ASP2409‐based regimens were not inferior to the belatacept‐based regimen. Moreover, higher frequencies of FoxP3‐positive regulatory T cells in renal allografts were observed in ASP2409‐ and belatacept‐based regimens compared with tacrolimus‐based regimens. No serious side effects related to ASP2409 administration were found during the study. These data suggest that ASP2409 is a promising candidate for calcineurin inhibitor‐sparing or ‐avoidance regimens.     

Immunosuppression with Belatacept‐Based,Corticosteroid‐Avoiding Regimens in De Novo Kidney Transplant Recipients

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1‐year, randomized, controlled, open‐label, exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based, steroid‐avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept‐mycophenolate mofetil (MMF), belatacept‐sirolimus (SRL), or TAC‐MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty‐nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept‐MMF, belatacept‐SRL and TAC‐MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen.     

The future role of target of rapamycin inhibitors in renal transplantation

Immunosuppressant nephrotoxicity is among the major contributors to chronic renal allograft failure, which is the primary cause of graft loss. Because of a lack of alternatives to the inherently nephrotoxic calcineurin inhibitors for maintenance immunosuppression, long-term survival rates for renal allografts have not increased in proportion to the rise in short-term graft survival. Clinical studies have shown that mammalian target of rapamycin-based immunosuppression in combination with calcineurin inhibitors, mycophenolate mofetil, or azathioprine is safe and efficacious. These data suggest that a target of rapamycin antagonist (sirolimus/everolimus) should be used initially in combination with calcineurin antagonists in order to prevent early acute rejection. After 3-6 months, a maintenance immunosuppressive regimen can then be individually tailored to each patient on the basis of their clinical and histological status. Those patients at high immunological risk should remain on full-dose triple therapy. All other patients should receive either a calcineurin inhibitor or corticosteroid-sparing regimen, with a maintenance dose of a target of rapamycin inhibitor. This regimen should result in less immunosuppressant nephrotoxicity and a reduction in the serious side effects of steroids, such as diabetes and osteoporosis. Whether the proposed individually designed immunosuppressive regimen, based on protocol biopsies and mammalian target of rapamycin inhibition, will result in prolonged graft and patient survival remains to be determined.     

Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long‐Term Renal Allograft Function

Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized belatacept‐based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n = 535) with a historical cohort receiving a tacrolimus‐based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low‐intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior estimated GFR (belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade‐based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor–free immunosuppression.     

Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors

The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.     

Immunosuppression: practice and trends

Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ-by-organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart-lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished.     

Protein therapies and antiproliferatives: a new paradigm in immunosuppression

The development of immunosuppressive therapies has focused on inhibiting effects of the activated T cell. The introduction of powerful immunosuppressive agents that interrupt the effects of T-cell activation, such as the calcineurin inhibitors (CNIs), has revolutionized solid organ transplantation. However, the ubiquitous location of their targets causes a number of side effects, which can compromise recipient health and long-term allograft survival. Therefore, a common goal in the development of emerging immunosuppressive strategies is to maintain efficacy and minimize toxicities related to these immunosuppressant compounds. The rationale for CNI-free regimens that exploit combinations of antiproliferative and protein therapeutic agents is attractive. Recently, studies employing these agents in CNI-free regimens have begun to offer additional insight into both the potential benefits and limitations of currently available strategies. The currently available biologic agents provide either too potent immunosuppression (eg, T-cell depletion) or inhibit an aspect of T-cell activation too limited to provide adequate rejection prophylaxis (eg, interleukin 2 receptor [IL-2R] blockade). Growing evidence suggests that costimulation blockade, particularly those protein therapeutics targeting CD28 and CD40, provides the correct balance between immunosuppressive and low toxicity, with a more specific, nondepleting, and timely targeting of the immune response. Already, results from a phase 2 trial suggests that combination with a costimulation blockade using belatacept with mycophenolate mofetil as a maintenance therapy after induction with an IL-2R blocker is closest to fulfill this promise. Belatacept represents an emerging immunosuppression paradigm with maintenance protein therapy that fulfills the need of more selective immunosuppression with reduced toxicities, which offers the potential of improving long-term outcomes in renal transplant.     

Improvement of drug-induced chronic renal failure in lung transplantation.

BACKGROUND: Nephrotoxicity is a frequently encountered adverse effect of calcineurin inhibitors (cyclosporine and tacrolimus)-combined immunosuppressive regimens. METHODS: We have compared the glomerular filtration rate in 14 patients who underwent lung transplantation, before and after replacement of azathioprine by mycophenolate mofetil and reduction of associated calcineurin inhibitors doses. RESULTS: After a mean follow-up of 16+/-4 months with the modified immunosuppressive regimen, the mean glomerular filtration rate increased by 20% with no change in lung function. CONCLUSION: By its strong immunosuppressive effect, mycophenolate mofetil allows the decrease of associated calcineurin inhibitor doses, with subsequent improvement of renal function without jeopardizing the transplanted lung.     

Rapamycin in transplantation: a review of the evidence

Rapamycin in transplantation: A review of the evidence. The calcineurin inhibitors have been the mainstays of immunosuppression for solid organ transplantation over the last two decades, but nephrotoxicity limits their therapeutic benefit. Rapamycin is a new drug with both immunosuppressant and antiproliferative properties that has a unique mechanism of action distinct from that of the calcineurin inhibitors. It has a role as a maintenance immunosuppressant either alone or in combination with a calcineurin inhibitor and can also be used to treat refractory acute rejection. Theoretical evidence suggests that it may limit the development and progression of chronic rejection in transplant recipients, but this has yet to be confirmed. This review examines the current in vitro animal and human work underlying the use of rapamycin and, in addition, comments on the pharmacokinetics and side-effect profile of this promising new agent.