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Editorials and Perspectives: Overview

Novel Strategies in Immunosuppression: Issues in Perspective

Webber, Allison1; Hirose, Ryutaro2; Vincenti, Flavio1,2,3

Author Information
doi: 10.1097/TP.0b013e3182145306

Abstract

Despite significant improvements in acute rejection rates, long-term renal allograft survival has remained unchanged since 1995 (1). The major causes of late allograft loss include chronic allograft nephropathy (CAN; a useful but limited term, because it lacks specificity) and death with a functioning graft (2). The perception that most grafts are lost due to the inexorable progression of calcineurin inhibitor (CNI) nephrotoxicity (2) is being challenged by the findings of the DeKaf studies (3–5) and others (6–9) that chronic immune injury mediated by antidonor antibodies may account for the majority of late graft losses. Thus, a new paradigm for immunosuppression for the long-term maintenance of the renal allograft needs to emerge. CNIs, although largely responsible for improved short-term outcomes, have failed to improve long-term outcomes (10). CNIs seem to be more effective in inhibiting acute T-cell-mediated alloresponses than chronic humoral antidonor injury. CNIs are also associated with nephrotoxicity and multiple metabolic derangements, including hypertension, hyperlipidemia, and glucose intolerance, which may contribute to the significant amount of cardiovascular disease seen in the transplant population—the leading cause of death with a functioning graft (11–14). Thus, improvement in long-term allograft outcomes may depend on new agents with novel mechanisms of action, devoid of the toxicities associated with CNIs. To meet this need, nonprotein drugs targeting intracellular pathways and biologic agents targeting B- and T-cell surface receptors and ligands are in phase II and III clinical trials. This review will explore emerging and future immunosuppression strategies, developed with the goal of reducing patient risk for premature death and improving the long-term outcomes of renal allograft recipients.

THE FAILURE OF DRUG MINIMIZATION STRATEGIES

Given their toxic metabolic profiles and the perception that CNIs contribute to late allograft loss from CAN (2), a multitude of trials have sought to reduce CNI exposure by discontinuing CNIs within months after the transplant when the risk of rejection recedes or by avoiding CNIs altogether (15–21). However, it is not clear that CNI-sparing regimens can improve long-term outcome. In fact, CNI-sparing regimens could undermine the immunologic balance between the renal allograft and the recipient. Reduction in the dose or target level of CNI or conversion to the mammalian target of rapamycin (mTOR) inhibitors may not achieve sustained improvement in renal function, and only a selected group of patients benefit from this strategy. In the Spare-the-Nephron trial, patients converted from CNI to sirolimus experienced a glomerular filtration rate benefit at 1 year, but this seemed to diminish at 2 years (22). In the Renal Conversion (CONVERT) trial conversion from CNI to sirolimus was successful only in patients with good renal function and no proteinuria (18). CNI avoidance studies incorporating mycophenolic acid, mTOR inhibitors, and steroids have had mixed results and have not been embraced by transplant physicians, because of adverse effects, high discontinuation rate, or lack of efficacy (15–21). The quest to spare CNI remains an important goal to preserve renal function, itself a determinant of cardiovascular morbidity. Unfortunately, the currently approved roster of immunosuppressive drugs has failed to provide a safe and an effective alternative to CNI.

Trials investigating the avoidance or withdrawal of steroids have shown variable results. Most steroid withdrawal protocols have been associated with an increase in acute rejection, and a recent meta-analysis confirmed this finding (23–25). In a double-blinded, randomized, placebo- controlled multicenter 5-year trial comparing early steroid withdrawal (7 days posttransplant) with steroid maintenance therapy, investigators reported higher rates of acute rejection in the steroid-free arm. Importantly, there was also a higher incidence of CAN in the steroid withdrawal arm. Although limited by several factors, including the fact that CAN was not a predefined endpoint with the difference between groups observed only in a post hoc analysis, it is still an intriguing finding and may suggest that chronic immune-mediated injury is more prevalent in the steroid withdrawal group. There was no difference in overall patient and allograft survival between steroid inclusive and steroid withdrawal groups at 5 years (24).

At the end of the trial, patients withdrawn from steroids had statistically significant improvement in serum triglycerides, but no differences were observed with respect to high-density lipoprotein, low-density lipoprotein cholesterol, blood pressure, or new-onset diabetes (24). However, a recent meta-analysis did show a significant reduction in these cardiovascular risk factors in patients in whom steroids are avoided or withdrawn (25). Still, there was no measurable effect on patient or graft survival (25). In view of the higher acute rejection rates in steroid withdrawal protocols, this strategy should be used selectively.

CAN: THE SHIFT TOWARD IMMUNE- OR HUMORAL-MEDIATED INJURY AS CAUSE

CNI-based regimens, especially after the introduction of mycophenolate mofetil, have been regarded as effective in reducing the rate of acute rejection. But this notion is undermined by recent findings that a subacute, chronic alloimmune response is playing a dominant role in late allograft loss (3–7, 26–28). Two important observations from these studies support this notion. Cosio et al. (26) showed that inflammation within areas of fibrosis and tubular atrophy was associated with poor graft survival, even when the inflammatory cells in the renal allograft did not reach the threshold for a Banff rejection. Gaston et al. in the DeKaf trial showed that chronic antibody-mediated rejection (AMR), as defined by circulating donor-specific antibody (DSA), or the presence of C4d on biopsy and corresponding histologic abnormalities was associated with late allograft dysfunction (5). The DeKaf study noted that the presence of DSAs and C4d deposition in peritubular capillaries was associated with a statistically significant decrease in graft survival at 24 months postbiopsy in their cross-sectional cohort (5). Einecke and Halloran studied the phenotype of late graft failure in 234 consecutive for-cause biopsies from 173 patients and found that histopathologic features strongly associated with graft loss were microcirculation changes (glomerulitis, peritubular capillary multilayering, capillaritis, and glomerulopathy) and interstitial fibrosis. AMR, defined as a circulating DSA with microcirculation changes with or without C4d deposition, was the most frequent diagnosis associated with graft loss. CNI toxicity and cellular-mediated rejection were rare in grafts that subsequently failed (6).

Thus, it is clear that CNIs have failed to improve long-term allograft survival. The reason for this failure may be the relative ineffectiveness of CNIs in combating acute and chronic humoral-mediated injury, despite the clear association of CNIs with improved cellular rejection rates. Furthermore, the minimization and withdrawal protocols of CNI, implemented to combat late allograft loss by minimizing nephrotoxicity and metabolic derangements from CNI, may in fact contribute to late allograft loss from chronic and subacute immune-mediated injury.

INHIBITORS OF NOVEL PATHWAYS IN B-CELL AND PLASMA CELL ACTIVATION

The recognition that chronic antibody-mediated injury may be responsible for late allograft loss has spawned interest in the pursuit of novel B-cell therapeutic targets. Current therapies used in desensitization protocols and for treatment of acute and chronic AMR include plasmaphersis, intravenous immunoglobulin (IVIG), and rituximab (29, 30). Plasmapheresis acutely depletes anti-human leukocyte antigen antibodies but is only a temporizing measure, limited by the immediate rebound of antibodies postpheresis. IVIG combats the humoral response by its neutralization of circulating alloantibody, inhibition of complement activation, and its ability to modulate cell-mediated immunity through Fc receptors (31). Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb) targeting B cells, causes depletion of B cells through complement-dependent cytotoxicity, antibody- dependent cellular cytotoxicity, and promotion of apoptosis, and it has been used in desensitization protocols and therapy for AMR (30, 32).

Long-term follow-up of these patients treated with the aforementioned therapies for desensitization or AMR is disappointing, with reduced allograft survival compared with unsensitized patients or patients who have not experienced AMR episodes. This poor prognosis is largely attributable to the presence and persistence of DSA (8). Furthermore, minimal success has been reached with any of these agents in treating chronic AMR. The prognosis once transplant glomerulopathy develops is poor (33). Interestingly, recent studies using new assays to identify alloantibody secreting cells in the plasma cell fraction of the bone marrow found that anti-thymocyte globulin, IVIG, and rituximab had no in vivo impact on long-lived CD 138+ CD20 plasma cells (34).

More promising targets for controlling humoral immunity include the B-cell activating factors (BAFF), also known as B-lymphocyte stimulator (BLyS) and a proliferation- inducing ligand (APRIL). These tumor necrosis factor-family ligands act as antiapoptotic survival factors critical for the maturation of the B-cell lineage. Specifically, BAFF signals through three receptors: the BAFF-receptor, the B-cell maturation protein (BCMA), and the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (35). APRIL signals through the latter two. Belimumab, a fully human mAb, has been developed to target BAFF and was shown to be effective in the treatment of systemic lupus erythematosis (36–38). The University of Pennsylvania is currently enrolling patients in a 1-year, phase II study evaluating the efficacy and safety of belimumab for use in desensitizing sensitized patients before kidney transplantation (clinical trials.gov). The efficacy of belimumab as a desensitization agent has yet to be established.

Atacicept is a transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobin (Ig) fusion protein that inhibits B-cell stimulation by blocking both BLyS and APRIL ligands. Importantly, in a lupus-prone mouse model, atacicept impacted serum levels of IgM and plasma cells (39). In a phase Ib, double-blind, placebo-controlled, dose-escalating trial, Dall'Era et al. (40) found a dose-dependent reduction in immunoglobulin levels in atacicept-treated patients, most notably affecting IgM levels and a dose-dependent reduction in total and mature B cells. Given its role in lowering B-lymphocyte numbers and immunoglobulin levels, atacicept may prove to be a promising new agent in the armamentarium for desensitization protocols and treatment of AMR in kidney transplant recipients. At present, no clinical studies in transplantation are being considered.

Two novel agents that have the potential of transforming the therapeutic approach to AMR and sensitization are bortezomib and eculizumab. Bortezomib, a selective inhibitor of the 26s proteasome, induces apoptosis of rapidly dividing, metabolically active cells with extensive protein synthesis, including normal plasma cells. Inhibiting the proteasome prevents the activation of transcriptional activator nuclear factor kappa B, which also facilitates cell apoptosis. In vitro treatment with bortezomib was shown to reduce the number of bone marrow-derived plasma cells and limit the production of alloantibody (41).

In a case series, Everly et al. treated six patients with mixed acute cellular rejection or AMR refractory to current therapies with a single cycle of bortezomib (four administrations of 1.3 g/m2 over 11 days). In all patients, bortezomib reversed the rejection, improved renal function, and decreased DSA. Several other anecdotal reports have been published on the efficacy of bortezomib in reversing AMR (41–43).

However, Sberro-Soussan et al. (44) reported no effect of bortezomib as a single agent in lowering DSA in four patients with subclinical AMR. This study was limited by the late institution of bortezomib (1–5 months postbiopsy results) and its lack of follow-up biopsies posttreatment, which may have shown histologic improvement. Bortezomib used as a desensitizing agent has also had mixed results (45, 46). Because almost all the reported series using bortezomib to control AMR have been associated with the use of multiple other agents (i.e., pheresis, IVIG, rituximab, thymoglobulin), it is imperative that controlled rigorous trials be performed to more accurately evaluate the effectiveness of bortezomib. Furthermore, bortezomib is associated with potentially severe side effects including disabling neuropathy (41–46).

The second agent is eculizumab, the humanized anti-C5 antibody, currently Food and Drug Administration approved for the treatment of paroxysmal nocturnal hemoglobinuria (47). In renal transplant patients, it has shown promise in the treatment of atypical hemolytic uremic syndromes and antiphospholipid syndromes (48–51). Recently, its potential role in AMR has been explored with promising results (22, 52, 53). In addition, eculizumab has recently been studied posttransplant as a sole agent in 16 high-titer DSA-sensitized recipients. This cohort was compared with 51 sensitized historic controls not treated with eculizumab. The incidence of AMR in the first month posttransplant was significantly reduced in the group treated with eculizumab (6.25% vs. 40%), but six patients with high DSAs developed evidence of chronic humoral rejection suggesting a complement-independent mechanism for antibody-mediated damage or a mechanism of complement activation upstream from C5 (54). These findings suggest that eculizumab may be best used short term to protect the kidney from DSA-induced, complement-mediated injury, but ultimately needs to be coupled with specific therapy that lowers the titers of DSA. The full therapeutic potential of eculizumab is currently limited by its expense. Agents targeting the complement cascade will likely attract more investments by pharma or biotech.

MAINTENANCE IMMUNOSUPPRESSION FOR THE NEXT DECADE

How will maintenance immunosuppression therapy evolve over the next decade? And will CNI remain the cornerstone of immunosuppression regimens? And will the Holy Grail of transplantation, a nontoxic tolerance-inducing regimen, finally be available to the majority of transplant recipients? Although none of these questions are readily answered, current trends in immunosuppression are already shaping the drug regimens that will emerge in the future. The predominant trend is the clinical development of novel agents that provide efficacy similar to CNI-based regimens but without their toxicities, especially the nephrotoxicity. Therapeutic pragmatism is driving immunosuppression strategies toward minimization or monotherapy rather than drug-free regimens (55–59). A transformational immunosuppression agent may ultimately emerge that can be administered safely in long-term monotherapy and lack both nephrotoxicity and metabolic side effects. Using biomarkers rather than drug levels to individualize immunosuppression would facilitate a proper balance between controlling alloimmune responses and maintaining a healthy immune system for surveillance.

Two agents currently in clinical trials have the potential of partially fulfilling this promise. The first is belatacept, a fusion receptor protein that inhibits signaling through the CD28 receptor by binding to its ligand CD86 and CD80, and the small molecule tofacitinib a Janus kinase 1/3 inhibitor (55, 58, 60). Although these two agents differ in structure, mechanism of action, and administration, their clinical trials and registration paths are almost identical (Table 1). Tofacitinib inhibits signaling through the common gamma chain and thus can almost shut down the signal 3 pathways (i.e., the proliferative signals for T and B cells) preventing rejection by tilting the host immune response toward immunodeficiency. The results of the phase IIa and IIb clinical trials suggest that absent validated biomarkers, careful calibration of the exposure to tofacitinib may be required to provide a proper balance between immunosuppression and immunodeficiency (60, 61).

TABLE 1
TABLE 1:
Clinical development profile of belatacept and tofacitinib

A more radical shift in the immunosuppression landscape is the emergence of biologics for chronic maintenance therapy. The mAbs and fusion receptor proteins in the transplant pipeline are potentially transformational in scope because of the specificities of their targets, the importance of the pathways that they inhibit, their lack of side effects associated with traditional immunosuppressive agents, and their route of administration. Because of their human/humanized backbone, these agents have long half-lives and prolonged biologic effects requiring intermittent administration. However, clinical trials with biologics are challenging and may have even higher rates of failure than those with small molecules, as exemplified by the number of discarded antibodies: anti-CD154 (CD40L) mAbs, efalizumab, anti-CD86/80 mAbs, and TGN1412, the super agonist mAb to CD28 (62).

The first attempt at using biologics for maintenance therapy was with Hu5C8, a humanized mAb to CD154 (63). Blockade of the CD40-CD154 pathway results in the inhibition of B cells and the humoral alloimmune response. Similarly, blockade of CD40-CD154 inhibits T-cell activation, which is dependent on the CD40-CD154 pathway through the upregulation of CD80/86 (Fig. 1). Anti-CD154 therapy in kidney transplantation in non-human primates was extremely effective in prolonging graft survival (57). The first CNI-free and steroid-free clinical trial in kidney transplantation with Hu5C8 administered every 2 to 4 weeks intravenously was halted when several patients developed thromboembolic events (63). This complication was likely related to the upregulation of CD154 on platelets and its role in stabilizing clot (64, 65). Despite the failure of Hu5C8, the CD40-CD154 pathway remains a promising therapeutic target and is therapeutically relevant in many disorders including autoimmunity, lymphoma, and organ transplantation.

FIGURE 1.
FIGURE 1.:
Novel strategies targeting humoral alloimmunity. For decreasing the potential immunogenicity associated with rituximab (a chimeric monoclonal antibody [mAb]), several humanized/fully human anti-CD20 mAbs are in clinical development including ocrelizumab, ofatumumab, and AME-133. Epratuzumab is a humanized mAb targeting CD22, a receptor on mature B cells. Several biologics targeting the CD40-CD154 pathway are also in development, mainly for the treatment of lymphoma, systemic lupus erythematosus, and autoimmune diseases. At present, only ASKP1240 (Table 2) is being tested in transplantation. Belimumab, a mAb, and atacicept, a fusion protein, target BLyS and APRIL, B-cell survival factors. Finally, bortezomib is a first generation proteasome inhibitor, used in the treatment of plasma cell dyscrasias, which has shown promise in desensitization protocols and the treatment of antibody-mediated rejection in transplantation. BAFF, B-cell activating factors; BLyS, B-lymphocyte stimulator; BCMA, B-cell maturation protein; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; BCR, B cell receptor; APRIL, a proliferation-inducing ligand.
TABLE 2
TABLE 2:
Monoclonal antibodies targeting CD40

Several novel antibodies are being developed to target CD40, which is not present on platelets and does not share the thrombotic or embolic complications of CD154 (Table 2). Whether anti-CD40 mAbs alone are effective in solid organ transplantation remain to be determined. Of potentially greater interest may be the concomitant use of anti-CD40 and costimulation blockade (66, 67). The combination of CD40-CD154 blockade with CTLA4Ig in experimental transplant studies induced indefinite graft survival and, in some instances, tolerance (66, 67). It is likely that these two antibodies will be tested together whenever both or at least one become available clinically.

Several combinations of biologics can, in fact, be envisioned as potentially inducing tolerance. CTLA4Ig and efalizumab (anti-LFA1 mAb) have been demonstrated to be synergistic in experimental transplantation (68). This combination is unlikely to be tested clinically because of the potential risk of posttransplant lymphoproliferative disease and progressive multifocal leukoencephalopathy. Another intriguing combination is belatacept and alefacept (62). These two biologics offer complementary inhibition of both naive T cells and memory T cells (69, 70). Memory T cells play a crucial role in acute and chronic rejection of renal allografts and are a significant barrier to transplantation tolerance (71–73). One strength of CNIs is their ability to inhibit both the de novo generation of CD8+ memory T cells and the function of preexisting memory T cells (74). Belatacept is effective in preventing activation of naive T cells but not memory T cells, because memory T cells do not require costimulation for their activation. Alefacept, a fusion receptor protein combining LFA3 with IgG, binds to CD2 on T cells and inhibits its ligation by LFA3 on antigen-presenting cells (75). CD2 receptors are more densely expressed on memory cells than naive cells, and therefore, alefacept is more effective in inhibiting and depleting memory T cells (75). Alefacept is currently approved for use in psoriasis. It is likely that the combination of alefacept and belatacept will be tested by industry-sponsored trials or in investigator-initiated studies. Safety, rather than efficacy, is likely to be the greater concern of these biologic combinations.

At present, a promising CNI-free or rapid steroid withdrawal regimen includes belatacept and a short induction course of thymoglobulin with mycophenolate mofetil or sirolimus (76). This regimen was used in a small proof of concept renal transplant trial (30 patients in each arm) and resulted in a low rejection rate and no safety signals. A larger confirmatory trial would be needed to establish the effectiveness and the safety of this regimen. Using a similar protocol (but with anti-interleukin-2 antibody induction) in a study supported by the Immune Tolerance Network, we have been able to maintain a patient on belatacept monotherapy for over 2 years with no rejection (Fig. 2). Whether this patient developed operational tolerance remains to be determined.

FIGURE 2.
FIGURE 2.:
The belatacept regimen of a transplant recipient treated in a trial supported by the Immune Tolerance Network. The patient is 59 years old with type 2 diabetes. At 1 year, the kidney biopsy was normal, and donor-specific antibodies were undetected, which prompted withdrawal of sirolimus. S.Creat., serum creatinine.

The ultimate therapeutic goal in solid organ transplantation is the induction of robust immunologic tolerance rather than operational tolerance that may be destabilized by heterologous immune responses. Operational tolerance applies to patients who maintain normal and stable renal function with minimal immunosuppression, whereas immunologic tolerance refers to nonreactivity to one set of antigens (the allograft in the case of transplant) while maintaining reactivity to others. The current regimens to induce tolerance rely on hematopoietic cell or bone marrow infusions from the same kidney donor and have limited impact for wider application because of the associated toxicities (77, 78). In fact, despite over a decade of experimentation with these regimens, only a handful of patients have successfully achieved tolerance. The lessons learned from these clinical trials may still be useful in designing future trials in tolerance. An intriguing, yet not validated approach advocated by Terasaki and coworkers is the use of donor-specific transfusions followed by clonal deletion with a variety of agents, most recently bortezomib to pave the way to drug-free transplantation (79, 80).

Ultimately, tolerance and organ shortage may find a common solution in the emerging field of tissue engineering and repopulating decellularized xenografts with a recipient's own induced pluripotent stem cells (81–83). This game-changing technology may require another quarter of a century to become a reality.

CNI-based regimens in their current form may be used for a few more years, especially for patients at high immunologic risk. However, a new era is upon us, with the introduction of new agents that are devoid of the nephrotoxicity and metabolic derangements associated with CNIs. Whether the replacement of CNIs with biologic-based regimens will ultimately amount to simply trading some toxicities for others has yet to be elucidated. Long-term safety of these agents will have to be established. Nonetheless, the promise of simplified immunosuppression regimens devoid of toxicites will be fulfilled. Recipients of solid organs can look forward to a future of prolonged graft function, survival, and better quality of life.

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Keywords:

Immunosuppression; Biologics; Tolerance

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