Evolution of Immunosuppression in Renal Transplantation

THE EVOLUTION OF Immunosuppression in Renal Transplantation

Target AudienceThis educational monograph is directed toward physicians who are involved in renal transplantation, and/or evaluate and treat patients before and after kidney transplants.

Program OverviewTransplantation is associated with high costs in human terms and medical expenses. It is important to continue to improve the outcomes—patient and graft survival, graft function, and quality of life—for kidney transplant patients, who generally wait years for transplants.

Posttransplant immunosuppression regimens involve a balancing act. The therapeutic goal—prevention of rejection—is weighed against the risks of immunodefi ciency complications—infection, cancer—and non-immune toxicities, such as anemia, hypertension, hyperlipidemia, diabetes, and nephrotoxicity. Immunosuppression can seldom, if ever, produce permanent unresponsiveness to donor antigens; organ transplant recipients require adequate immunocompetence for life. New agents and new regimens offer hope for the future of reduced risk of immunodefi ciency complications and non-immune toxicity. New non-depleting protein drugs—monoclonal antibodies and fusion proteins—offer promise of a more favorable balance.

There is a signifi cant unmet educational need among the renal transplant team and the referring nephrologists: the need to more fully understand optimal regimens for enhancing graft and patient survival posttransplant, and the need to react to adverse changes in their status. The primary objective of this monograph is to meet the medical education needs of physicians and allied health professionals who care for patients undergoing transplantation. This will permit knowledge of potential improvements in patient care to be delivered to those who may benefi t.

Learning ObjectivesUpon completion of this activity, participants should be better able to:1. Defi ne the key issues in immunosuppression in transplantation 2. Describe the evolution and successes of immunosuppression over the past 10 years 3. Discuss the unmet needs in immunosuppression for transplantation 4. Identify the potential of selective immunosuppression candidates in development to meet these

needs

Faculty

Philip F. Halloran, MD, PhD, OCProfessor of MedicineDivision of Nephrology and Transplantation Immunology Director, Alberta Transplant Institute Canada Research Chair in Transplant Immunology University of Alberta Edmonton, Alberta, Canada

Sundaram Hariharan, MDChief of NephrologyProfessor of MedicineMedical College of WisconsinMilwaukee, WI

Stuart Knechtle, MDRay D. Owen Professor of TransplantationUniversity of Wisconsin–MadisonMadison, WI

Thomas C. Pearson, MD, DPhilLivingston Professor of SurgeryDepartment of SurgeryEmory University School of MedicineAtlanta, GA

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Mohamed H. Sayegh, MDWarren E. Grupe and John P. Merrill Chair in Transplantation Medicine Professor of Medicine and Pediatrics Harvard Medical School Director, Transplantation Research Center Brigham and Women’s HospitalBoston, MA

Disclosure of Confl icts of InterestPostgraduate Institute for Medicine (PIM) assesses confl ict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant confl icts of interest that are identifi ed are thoroughly vetted by PIM for fair balance, scientifi c objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in health care and not a specifi c proprietary business interest or a commercial interest.

The faculty reported the following fi nancial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

The planners and managers reported the following fi nancial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

Physician Continuing Medical EducationAccreditation StatementThis activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Postgraduate Institute for Medicine and DRIVE Medical Consulting & Communications. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit DesignationThe Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.25 category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

Name of Faculty or Presenter Reported Financial Relationship

Philip F. Halloran, MD, PhD, OC Has no relationships to report

Sundaram Hariharan, MD Consulting Fees: Bristol-Myers Squibb, Novartis AG Speakers’ Bureaus: Wyeth, Fujisawa

Stuart Knechtle, MD Ownership Interest: Bristol-Myers Squibb

Thomas C. Pearson, MD, DPhil Has no relationships to report

Mohamed H. Sayegh, MD Consulting Fees: Genzyme

Name of Faculty or Presenter Reported Financial Relationship

Trace Hutchison, PharmD Has no relationships to report

Jan Hixon, RN, BA, MSN Has no relationships to report

Linda Graham, RN Has no relationships to report

Christine de Vries Has no relationships to report

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Disclosure of Unlabeled UseThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The Postgraduate Institute for Medicine (PIM), DRIVE Medical Consulting & Communications (DRIVE), and Bristol-Myers Squibb (BMS) do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, DRIVE, or BMS. Please refer to the offi cial prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DisclaimerParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

MediaPrinted Monograph

Method of ParticipationThere are no fees for participating and receiving credit for this activity. During the period November 2005 through November 2006, participants must: 1. Read the learning objectives and faculty disclosures. 2. Study the educational activity. 3. Complete the Post-Test by recording the best answer to each question on the Answer Key on the Post-Test and Evaluation Form. 4. Complete the Evaluation Form. 5. Mail or fax the Post-Test and Evaluation Form to the Postgraduate Institute for Medicine.

A statement of credit will be issued only upon receipt of a completed Post-Test and Evaluation Form and will be mailed to you within 3 weeks.

Postgraduate Institute for Medicine367 Inverness ParkwaySuite 215Englewood, CO 80112Fax: (303) 790-4876

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Introduction

The primary objective in contemporary transplant immunosuppression is safe control of rejection. This requires that we achieve a balance between immunosuppression and its potential complications: immunodefi ciency complications (infection, certain cancers) and non-immune toxicity. In the past decade, new immunosuppressive drugs have improved this balance and improved outcomes after renal transplantation. However, some of these newer drugs require frequent therapeutic drug monitoring, and many are associated with acute and chronic toxicities.

New biologic agents have been developed to address these problems, including monoclonal antibodies and fusion proteins. These agents are not immunogenic, have long half-lives and prolonged biologic effects, thus allowing intermittent administration, and have minimal non-immune toxicity. The equivalent potency, and greater specifi city and selectivity of the new biologic agents render them less toxic than earlier immunosuppressive drugs. They present opportunities to replace the drugs that are associated with most of the long-term, non-immune toxicities, such as the corticosteroids and the calcineurin inhibitors. This monograph reviews the evolution of immunosuppressive strategies and assesses the ability of new drugs to approach an improved balance.

The immune response to a kidney transplantOrgan transplantation between genetically non-identical individuals typically results in immunologic rejection of the organ through T-cell-dependent mechanisms, including T-cell-mediated rejection and/or antibody-mediated rejection.

Organ transplantation activates the innate immune system and antigen presentation. Following transplantation, dendritic cells of both donor and host origin in the graft and surrounding tissues become activated and move to T-cell areas of secondary lymphoid organs, where the antigen-bearing dendritic cells engage alloantigen-reactive naïve T cells and central memory T cells.

The alloimmune response in the lymphoid tissues can be represented by the 3-signal model, as depicted in Figure 1.1 The Major Histocompatibility Complex (MHC) class I and II antigens on the surface of the dendritic cells engage and trigger T cells with cognate T-cell receptors. This constitutes “signal 1,” transduced through the CD3 complex.

Dendritic cells provide costimulation, or “signal 2,” delivered when CD80 and CD86 on the surface of dendritic cells engage CD28 on T cells. Signals 1 and 2 activate three signal transduction pathways: the calcium-calcineurin pathway, the RAS–mitogen-activated protein (MAP) kinase pathway, and the nuclear factor-kB pathway.

These pathways activate transcription factors that trigger the expression of many new molecules, including interleukin-2, CD154, and CD25. Interleukin (IL)-2 activates the “target of rapamycin (TOR)” pathway to provide “signal 3,” which is the trigger for cell proliferation. Lymphocyte proliferation also requires nucleotide synthesis. Proliferation and differentiation lead to a large number of effector T cells. Within days of receiving a transplant, the patient’s immune response generates the agents of allograft rejection: effector T cells and alloantibodies. Activated CD4+T cells produce IL-2, which helps activated CD8+T cells to clonally expand and develop effector functions (eg, expression of interferon [IFN]-g, perforin, and granzyme A and B). They lose their homing molecules for lymphoid organs and acquire homing molecules for infl amed sites. They home to the graft, create infl ammation, and attract more effector T cells and monocytes, which then become activated macrophages.

Allograft rejection is mediated by the activated T cells and macrophages that accumulate in the transplanted organ. The migration of these cells into the organ is aided by endothelial changes in stressed, infected, or injured tissue by adhesion molecules and chemokine receptors expressed by lymphocytes that have been activated by antigen in the lymph node.

Cytokines and chemokines produced during this process play critical roles in determining the content of the infi ltrate and its patterns of activation. The mechanism of tissue injury is probably related to a delayed-type hypersensitivity mechanism, in which T cells and activated macrophages release products

4


Figure 1: The 3-Signal Model of the Immune Response and Sites of Possible Immunomodulation

Within days posttransplant, the patient’s immune response generates the agents of allograft rejection: effector T cells and alloantibodies. The T-cell response when engaged by antigen-presenting cells in the lymphoid organs can be represented by the 3-signal model. Also shown are the sites of action of some of the approved immunosuppressive drugs and those currently in clinical trials, and those showing promising results in preclinical studies. In this illustration, the IL-2 is shown acting on the IL-2-producing cell; however, in the generation of effector T cells, the IL-2 from the activated CD4+T cells may act principally on the receptors of the CD8+ effector T-cell precursors to promote their clonal expansion and differentiation. © 2004 Massachusetts Medical Society. Used with permission.1

Host exposure to intact MHC alloantigens displayed on donor APCs (direct allorecognition) results in acute rejection because of substantial expansion of T cells of multiple specifi cities. Alternatively, host exposure to donor alloantigens that have been processed and presented by host APCs (indirect allorecognition) leads to the activation of a limited T-cell repertoire with restricted ability to recognize graft targets. This process contributes to chronic rejection.

Challenges and the Future of ImmunosuppressionThere are 3 possible strategies for effecting immunosuppression: lymphocytes can be depleted, lymphocyte traffi c can be diverted, or lymphocyte response pathways can be blocked. Each of the 3 signals of the immune cascade has been used as a target of inhibition in the search for the improved balance in immunosuppression. Any of these actions can produce the desired therapeutic effect of suppressing graft rejection, but excessive lymphocyte depletion or blocking heightens the risk of immunodefi ciency consequences. Moreover, all of the small-molecule drugs carry signifi cant non-immune toxicity. This monograph will discuss the effi cacy and safety of these approaches.

Another area of challenge in transplantation is the treatment of subgroups of recipients with high immunologic risk (African Americans, retransplants, and recipients with high-panel reactive antibodies), high medical risks (older age, diabetes, and vascular disease), or high donor risk (expanded criteria donor [ECD] kidneys, older donors). All of these reduce the chances of successful transplantation.

Interest is shifting toward the preservation of function and prevention of complications in the many patients with transplants performed in previous years. Global immunosuppression has improved acute graft survival in recent years but the disease phenotypes that emerge as risks to long-term survival must now be understood. Prevention of late graft loss and premature patient death due to immune and non-immune toxicities of immunosuppressive agents is a major emerging issue in transplantation.

5

Belatacept(LEA29Y)


Emerging opportunities to improve outcomes include the development of precisely targeted, selective immunosuppressive agents with more favorable safety profi les. New immunosuppressive strategies exploit normal mechanisms of T-cell activation. For example, intervening to inhibit costimulatory signals (signal 2) to reduce T-cell activation may allow control of the alloimmune response without compromising the patient. This monograph describes recent developments in this evolution of immunosuppression in renal transplantation.

A Decade of Evolution and Progressive Successes

Immunosuppressive trends for solid organ transplantation have undergone a signifi cant shift over the past decade. In 1990, most regimens used corticosteroids in combination with the calcineurin inhibitor (CNI), cyclosporine, and the antimetabolite, azathioprine (AZA).2,3 By June 2001, many new immunosuppressive agents had become available, including tacrolimus and improved formulations of cyclosporine, such as cyclosporine micro-emulsion. New immunosuppressants, including mycophenolate mofetil (MMF) and mycophenolate sodium, the TOR inhibitor sirolimus, antibody agents, such as antithymocyte globulin, and the IL-2 receptor antibodies, daclizumab and basiliximab, were added to the armamentarium. 3

Because T cells play a central role in graft rejection, most of these immunosuppressive drugs target T cells, with the most successful drugs acting in the early phases of T-cell activation. Cyclosporine and tacrolimus, for example, prevent T cells from producing cytokines critical for T-cell proliferation, such as interleukin-2. Sirolimus (rapamycin) blocks signal transduction via the interleukin-2 receptor. Azathioprine and mycophenolate, both inhibitors of purine synthesis, also inhibit T-cell proliferation. Monoclonal antibodies directed at T cells, such as OKT3 (muromonab-CD3), act by depleting T cells and blocking the T-cell antigen receptor.

These advances have led to improvement in survival for both patients and grafts, but there are still problems with these agents. Immunosuppression with these drugs is nonspecifi c and is associated with a substantial risk of opportunistic infections and cancer. These drugs also have side effects, such as the nephrotoxic effects of cyclosporine and tacrolimus and the diabetogenic effects of tacrolimus. Table 1 summarizes immunosuppressive therapies currently in clinical use.

6


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THE EVOLUTION OF Immunosuppression in Renal Transplantation 8

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toda

y in

clud

e a

vari

ety

of d

rugs

for p

rim

ary

imm

unos

uppr

essi

on a

s w

ell a

s fo

r mai

nten

ance

ther

apy.


Immunosuppressive Strategies in Current Practice

The original transplant immunosuppressive drug was azathioprine (AZA), the mainstay until about 1983. AZA is associated with leukopenia, bone marrow depression, and macrocytosis, and requires blood-count monitoring. When cyclosporine was introduced, AZA became a second-line drug, sometimes used in combination regimens (cyclosporine and AZA). Corticosteroid use remained universal. In the period 1983 to1995, immunosuppressive strategies were based on cyclosporine, AZA, glucocorticoids, antithymocyte and antilymphocyte globulin, and muromonab CD3 (OKT3). Although the use of these therapies signifi cantly improved graft outcomes over earlier regimens, their burden of toxicity was substantial, and rejection rates were high.

The modern era in immunosuppression emerged after 1995 with the use of tacrolimus and mycophenolate. Sirolimus, introduced in 1999, also contributed to this evolution. Today, most patients have a low probability of rejection and early graft loss. However, many issues remain.

The small-molecule immunosuppressive agents (CNI, TOR inhibitors, and purine synthesis inhibitors) do not saturate their targets at clinically tolerable doses and, therefore, require careful dosing and monitoring. Cyclosporine is a calcineurin inhibitor and can cause nephrotoxicity, hemolytic-uremic syndrome, hypertension, neurotoxicity, posttransplantation diabetes mellitus, and hyperlipidemia, and, therefore, requires monitoring. Tacrolimus confers superior control of rejection with fewer adverse effects. The incidence of hypertension and hyperlipidemia is lower with tacrolimus than with cyclosporine, while posttransplantation diabetes mellitus and neurotoxicity incidence is higher. Some experience indicates that polyoma virus complications may be more frequent with tacrolimus, especially combined with mycophenolate mofetil (MMF). Sirolimus causes hyperlipidemia and increases the nephrotoxicity of calcineurin inhibitors when used in combination. It also is associated with thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, and interstitial lung disease. The adverse effects of MMF include gastrointestinal symptoms (mainly diarrhea), neutropenia, and mild anemia.

Depleting protein immunosuppressive agents destroys T cells, B cells, or both. T-cell depletion may produce severe systemic symptoms, related to the release of cytokines, and increases the risks of infection, posttransplant lymphoproliferative disease, and possible late rejection. Recovery of immune functions may take months or years. OKT3 produces the most profound cytokine-release syndrome (fever, chills, hypotension). Polyclonal antibody antithymocyte globulin produces less cytokine-release syndrome, but produces thrombocytopenia, leukopenia, and serum sickness.1 The monoclonal antibody, alemtuzumab (anti-CD52), binds to CD52 on all T and B cells and produces prolonged depletion. Alemtuzumab has been associated with myeloid hematologic toxicities, comprising long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia, and a heightened risk of fever or infection.20 The monoclonal antibody, rituximab, is B-cell-depleting; however, this depletion does not affect most plasma cells, which lack CD20.

The non-depleting, anti-CD25 monoclonal antibodies, daclizumab and basiliximab, target semi-redundant T-cell activation pathways and reduce immune responsiveness without depleting or compromising immune function. However, they are only moderately effective and are used in combination regimens, where they reduce rejection by about one third. 1

The direction of development in immunosuppression is toward the long-term use of non-lymphocyte–depleting proteins that effectively inhibit T-cell proliferation by selectively binding to and blocking costimulation signals to prevent rejection, while avoiding the toxicities and immune compromise associated with toxic, small-molecule drugs. The fusion protein, belatacept (LEA29Y), now in Phase 3 clinical trials, illustrates this development. Belatacept is a second-generation cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) fusion protein that binds to CD80 and CD86 and inhibits signal 2 in the T-cell activation pathway. In Phase 2 clinical trials, it was shown to be as effective as cyclosporine at preventing rejection, without the toxicities associated with cyclosporine.1

9


Table 2: Potential Immunosuppressive Drug Protocols

Immunosuppressive therapy includes antibody induction therapy during the peritransplant period, primary and adjunctive maintenance immunosuppression, and treatment for acute graft rejection.1

TREATMENT OF ACUTE REJECTION

INDUCTION THERAPY

Anti-CD25 antibody (basiliximab, daclizumab) Polyclonal antithymocyte globulin Anti-CD25 antibody + Polyclonal antithymocyte globulin Alemtuzumab (experimental)

MAINTENANCE THERAPY

CNI + MMF prednisoneCyclosporine + sirolimus prednisoneSirolimus + MMF prednisoneSirolimus prednisoneTacrolimus monotherapy

MAINTENANCE THERAPY

GlucocorticosteroidsIf unresolved: Muromonab-CD3 or ATG

Optimizing Immunosuppressive Regimens

Current immunosuppressive strategies (see Table 2) generally rely on combinations of agents and are designed to meet 3 different needs: antibody induction therapy during the peritransplant period, primary and adjunctive maintenance immunosuppression, and treatment for acute graft rejection. Hundreds of potential combinations exist, and many new protocols have emerged, often including a reduced reliance on glucocorticoids and calcineurin inhibitors. However, controlled clinical trials have not been conducted on many of these combinations, and their use relies on clinical experience and varies by transplant center.

Antibody Induction TherapyAntibody-based induction immunotherapy is used in the early transplant period to reduce the early immune system activity against the transplanted organ and to condition the system to adapt to the graft. Induction with depleting or nondepleting antibodies is used for the majority of kidney transplant recipients. During this period, the use of antibody-based therapy allows for avoidance or dose reduction of calcineurin inhibitors, possibly reducing the risk of early nephrotoxicity and delayed graft function, and provides better prevention of early acute rejection.

Nondepleting anti-CD25 monoclonal antibodies are widely administered early in the posttransplant period because they are moderately effective but almost free of side effects. The anti-CD25 monoclonal antibodies, daclizumab and basiliximab, are approved for induction therapy.3 The depleting antibodies —usually polyclonal anti-lymphocyte antibodies—are now more commonly used than monoclonal anti-CD3, especially in situations of high immunologic risk. The choice of depleting polyclonal antibody preparations is shifting away from equine antithymocyte globulin to rabbit antithymocyte globulin. Recently, alemtuzumab (anti-CD52) also has been used extensively as a depleting strategy in some programs.

10

+-

+-+-

+-


Maintenance ImmunosuppressionMaintenance immunosuppression is designed to suppress the alloimmune response, to provide a safe level of long-term graft survival and function with a very low rejection rate, to give an acceptable rate of side effects, and to lower the incidence of chronic rejection over the long term. In primary maintenance immunosuppressive therapy, many patients continue to receive corticosteroids; however, steroid-free regimens remain an important therapeutic goal. Mycophenolate mofetil (MMF), with or without sirolimus and prednisone, is the most widely employed maintenance immunosuppressive agent in solid organ transplantation, and has replaced the use of AZA, except in the UK and some developing countries.3

Antirejection TreatmentThe need for treatment for acute rejection episodes within 1 year of kidney transplantation has improved from 18% in 2000 to 15% in 2002. Historically, acute rejection was shown to be one of the strongest prognostic factors for long-term graft survival following renal transplantation. As posttransplant immunosuppressive therapy has evolved, there has been a corresponding reduction in the rate of early acute graft-rejection episodes. Factors that may contribute to graft failure during the fi rst year post-transplant include acute rejection, primary nonfunction, graft thrombosis, recurrent kidney disease, or the death of a patient with a functioning graft. Some events in the fi rst year also are associated with a lower probability of long-term graft survival. For example, a recent analysis reemphasized that the functional response of the acute rejection episode to therapy is important with respect to the impact on graft survival. Acute rejection episodes that do not respond well to treatment are possible markers for an increased risk of subsequent late rejection and graft failure.21 T-cell-mediated rejection accounts for most rejection episodes but antibody-mediated rejection is recognized with increasing frequency.3 Antibody-mediated rejection is treated with some of the same strategies as T-cell-mediated rejection because the antibody response requires T-cell help, particularly as it develops. However, it is also treated with plasmapheresis, IVIG, and rituximab. Table 3 details potential therapeutic options.

TYPE OF ACUTE REJECTIONPOTENTIAL IMMUNOSUPPRESSIVE

THERAPY ALTERNATIVES

T-cell-Mediated Rejection

Table 3. Immunosuppressive Agents for Treating Acute Graft Rejections

SteroidsAnti-T-cell Agents (muromonab-CD3, antithymocyte globulins)

Antibody-Mediated Rejection SteroidsAnti-T-cell Agents (muromonab-CD3, antithymocyte globulins)PlasmapheresisIVIGRituximab

Therapy of the acute rejection is tailored toward the type of rejection.

Steroids are the mainstay of initial therapy for acute rejection episodes, although their actions are multiple on macrophages and T cells and are not well understood. The anti-infl ammatory properties of steroids are also believed to be therapeutically benefi cial in these episodes. A typical steroid dose is 3 to 10 mg/kg per day for 3 to 5 days, which is then tapered to a maintenance dose. This strategy is effective in reversing acute rejection in approximately 60% to 75% of episodes.22

Muromonab-CD3 targets the CD3 complex on the surface of mature T cells, thus inhibiting the alloimmune response. In fi rst acute rejection episodes, this agent achieves reversal in approximately 94% of episodes. It is used to treat steroid-resistant rejection and often used as the fi rst-line agent for severe vascular rejections. The development of human anti-murine antibodies by the recipient, however, can potentially reduce the effi cacy of muromonab-CD3. These antibodies may preclude the use of muromonab-CD3 by neutralizing the therapeutic effect.22

11


Antithymocyte globulin binds circulating T and B lymphocytes, which are then removed from the circulation via the reticuloendothelial system. In acute rejection episodes, antithymocyte globulin has effi cacy similar to that of muromonab-CD3 and is also often used for steroid-resistant acute rejections.22 Preferential use of this agent to treat acute rejection as compared with muromonab-CD3 has become more common in recent years.3

Strategies to Refi ne Immunosuppressive Therapy

Corticosteroid-Sparing RegimensThe toxicity of long-term steroid exposure has created a growing interest in steroid avoidance and minimization protocols. Some of the potential benefi ts of the withdrawal or avoidance of steroids include normal growth in children, improved lipid profi les, improved blood pressures, better glycemic control, and lower risk of bone disease. Compared with protocols that discontinue steroids after the initial posttransplant period, a steroid-free protocol may avoid the increased risk of infection, body disfi gurement, and other steroid-induced side effects. It may also avoid the long-term risks of steroid use and the increased risk of rejection when the steroids are withdrawn.23 However, recent data have demonstrated that the risk of rejection is higher in patients withdrawn from steroids on a cyclosporine-plus-steroid protocol. Long-term observation is needed to determine the long-term safety of steroid avoidance and withdrawal.

The availability of tacrolimus has allowed for the development of protocols that have achieved high rates of successful steroid withdrawal after 6 months of therapy. More recently, studies involving rapid steroid withdrawal over 1 to 2 weeks in patients receiving tacrolimus have shown similar graft survival rates compared with patients withdrawn after 3 to 6 months. MMF has also been widely used in steroid-free protocols, although the long-term effects remain to be determined. As the complexity and diversity of current protocols increase, we are likely to see more widespread use of steroid-free protocols; however, it is unlikely that randomized trials of long duration will be undertaken to assess the safety of these protocols.

Calcineurin Inhibitor-Sparing RegimensDue to the risk of both acute and chronic nephrotoxicity occurring with CNI therapy, the development of protocols free of these agents is an ongoing part of the evolution of immunosuppressive therapy in renal transplantation. It is possible that sirolimus in combination with MMF and steroids may potentially offer a regimen that provides good long-term immunosuppression with less nephrotoxicity. The use of a completely CNI-free regimen may prevent or delay the onset and progression of chronic allograft nephropathy (CAN) by minimizing immune injury and drug-induced nephrotoxicity, which in turn may lead to a cycle of tissue injury, interstitial fi brosis, ischemia, and pathologic tissue remodeling. 24

The initial use of sirolimus in CNI-free regimens demonstrated improved kidney function at 1 year, but the overall merits of CNI-free protocols compared with other protocols such as tacrolimus and MMF is not known.25 Similarly, more recently, investigators comparing basiliximab, MMF, and prednisone plus either cyclosporine or sirolimus, found that at 2 years, the sirolimus-treated group had better renal function, less scarring and atrophy, and lower expression of genes associated with injury and fi brogenesis.24 However, the control group was the relatively toxic combination of cyclosporine and sirolimus.

The early withdrawal of cyclosporine from a sirolimus-cyclosporine-steroid regimen has been shown to improve renal function and, ultimately, results in better graft survival—again, as compared with continuation of the relatively toxic combination of cyclosporine and sirolimus.26

Follow-up results at 4 years from a study of 430 eligible patients randomized at 3 months posttransplant to either remain on the sirolimus-cyclosporine-steroid therapy or to have cyclosporine withdrawn demonstrate the feasibility of this strategy. In this trial, differences in acute rejection and mortality were not signifi cant; however, the patients who were withdrawn from cyclosporine had signifi cantly better graft survival, improved calculated GFR and improved mean arterial blood pressure. To be generalized, such studies should include comparison with less toxic control therapies.

12


Depleting RegimensExperimental depleting induction regimens have used alemtuzumab, an anti-CD52 antibody for the protein induction phase, followed by sirolimus and tapering prednisone for maintenance immunosuppression.27 However, the long-term consequences of severe depletion are unknown, and clinical observations suggest a possible increase in antibody-mediated rejection with this regimen. Alemtuzumab can cause more profound depletion of lymphocytes than monocytes. The resultant imbalance of lymphocytes and monocytes after alemtuzumab treatment of a renal-transplant recipient may lead to an acute rejection dominated by monocytes.28

Remaining Issues and Unmet Needs in Immunosuppression in Transplantation

Despite many advances in solid organ transplantation over the last decade, clinical barriers and challenges to optimal immunosuppressive therapy still remain. Although short-term outcomes provided by current approved and available immunosuppressive combination therapies have continued to improve, the consequences of their prolonged administration have become the subject of growing problems, such as drug toxicities, late graft deterioration, and adverse events, which signifi cantly affect both patient and graft survival.

Toxicities of Immunosuppressive Therapy

Immunosuppressive therapy may be accompanied by undesired consequences, including immuno-defi ciency and drug-specifi c, non-immune toxicities.

Immunodefi ciency ToxicitiesSuppression of the transplant recipient’s normal immune functions establishes a state of immunodefi ciency and heightens the risk of severe infections, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), human polyoma virus (BK virus), pneumocystis, and granulomatous infections. In addition, these infections occasionally translate to tumors, such as posttransplant lymphoproliferative disease and skin cancers. Cancers and infections remain common, and their occurrence is signifi cantly increased in transplant recipients compared with the general population.

The use of more immunoselective drugs can reduce these risks. The understanding of the immune cascade and the identifi cation of selective target blockers can be translated to clinical practice. Research efforts continue to focus on selective immunosuppressive agents with specifi c target sites that have minimal risk of immunodefi ciency toxicities. For example, selective inhibitors such as anti-CD25 antibody (signal-3 blocker) or belatacept (signal-2 blocker) have little effect on the risk of infection and post-transplant lymphoproliferative disease and may achieve a better balance of immunosuppression and immunocompetence.

Non-Immune ToxicitiesA wide range of side effects accompany the small-molecule immunosuppressive agents. Five of the most prevalent are the “ABCDN group”: anemia, blood pressure elevation, cholesterol elevation, diabetes, and nephrotoxicity. The goal of immunosuppressive research is not to trade one set of toxicities for another—for example, by exchanging sirolimus hypercholesterolemia and anemia for tacrolimus nephrotoxicity—but to reduce them all. The goal is to achieve a reduction in the total burden of non-immune toxicities.

The non-immune side effects of immunosuppressive therapy have become more serious concerns because they can be indirectly linked to organ or tissue damage and even cardiovascular events and/or death. Non-immune toxicities are agent-specifi c, arising from each drug’s mechanism of action. Immunosuppressive agents target molecules that act both in the immune cascade and in non-immune tissues.1 For example, cyclosporine and tacrolimus therapies are associated with hypertension (HTN), diabetes, and dyslipidemias at 1 year posttransplantation and are seen in as many as 40% of patients undergoing these therapies.29 The majority of non-immune toxic effects of current immunosuppressive therapy are shown in Table 4.

13


Tab

le 4

: Non

-im

mu

ne

Toxi

c E

ffec

ts o

f Im

mu

nos

up

pre

ssiv

e T

her

apy

AG

ENT

I. C

ort

ico

ster

oid

sp

red

nis

on

em

eth

ylp

red

nis

olo

ne

II. S

mal

l Mo

lecu

le D

rug

s

1. I

nh

ibit

ors

of n

ucl

eoti

de

syn

thes

es

b. T

OR

Inh

ibit

orscy

clo

ph

osp

ham

ide

myc

op

hen

ola

te m

ofe

til

(MM

F)m

yco

ph

eno

late

so

diu

m

azat

hio

pri

ne

tacr

olim

us

(or F

K50

6)

cycl

osp

ori

ne

(or

cycl

osp

ori

ne

A)

siro

limu

sev

ero

limu

s

TOX

ICIT

IES

MO

NIT

OR

ING

CO

NSI

DER

ATI

ON

S1

Cat

arac

ts, h

yper

ten

sio

n (H

TN),

hyp

erg

lyce

mia

, ost

eop

oro

sis,

cu

shin

go

id h

abit

us,

hyp

erlip

idem

ia, i

mp

aire

d g

row

th

Leu

kop

enia

, th

rom

bo

cyto

pen

ia, a

lop

ecia

, ski

n ra

shes

, nau

sea,

vo

mit

ing

, ab

do

min

al c

ram

ps,

dia

rrh

ea, o

ral u

lcer

atio

n, i

nfe

ctio

ns,

oth

ers.

30

Dia

rrh

ea, n

ause

a, n

eutr

op

enia

, th

rom

bo

cyto

pen

ia m

ild a

nem

ia, n

ause

a,

dia

rrh

ea1,

9

Seve

re le

uko

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ia a

nd

/or t

hro

mb

ocy

top

enia

, mac

rocy

tic

anem

ia, a

nd

se

vere

bo

ne

mar

row

dep

ress

ion

.7

Nep

hro

toxi

city

, HTN

, neu

roto

xici

ty, h

epat

oto

xici

ty, h

yper

lipid

emia

, h

yper

gly

cem

ia, p

ost

tran

spla

nt

dia

bet

es10

Nep

hro

toxi

city

, HTN

, neu

roto

xici

ty, h

epat

oto

xici

ty, h

yper

lipid

emia

, g

ing

ival

hyp

erp

lasi

a, h

yper

gly

cem

ia, p

ost

tran

spla

nt

dia

bet

es, g

ou

t32

Hyp

erlip

idem

ia, i

ncr

ease

d C

NI t

oxi

city

at

full

do

se o

f CN

I, th

rom

bo

cyto

pen

ia, d

elay

ed w

ou

nd

hea

ling

, in

ters

titi

al lu

ng

dis

ease

, le

g e

dem

a.1,

12

Use

for 3

–10

day

s h

as b

een

rep

ort

ed t

o p

rod

uce

a

pro

fou

nd

an

d d

ura

ble

lym

ph

op

enia

last

ing

gre

ater

th

an 1

yea

r.33

a. C

alci

neu

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Inh

ibit

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As

a cl

ass,

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Is e

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dm

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15

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eple

tin

g A

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die

s (a

gai

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, B c

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, or

bo

th)

a. P

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clo

nal

an

tib

od

ies

anti

thym

ocy

te

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bu

lin (r

abb

it)

anti

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(e

qu

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b. M

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ia, i

dio

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o m

on

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rin

g re

qu

ired

1


In addition to individual agent toxicities, combination therapy can potentiate non-immune toxicity. For example, sirolimus combined with cyclosporine or tacrolimus potentiates nephrotoxicity. Thus, one strategy is to investigate combinations in attempts to avoid the toxicities seen with CNIs.35 One trial indicated that sirolimus potentiates tacrolimus nephrotoxicity and the sirolimus combination produced greater renal dysfunction and hypertension than did MMF plus tacrolimus.36 In clinical practice, the toxicity of a target-of-rapamycin (TOR) inhibitor and calcineurin inhibitor combination can be reduced by withdrawing 1 of the drugs,37 but long-term safety and effi cacy of such protocols remains to be established. Similarly, increased GI toxicity has been noted with MMF and tacrolimus combination therapy.

Calcineurin Inhibitor (CNI) NephrotoxicityNephrotoxicity as a result of the use of CNIs is seen in most renal transplant cases on long-term follow-up.31 After 2 years of CNI treatment, structural changes of tubular atrophy and interstitial fi brosis have been documented in 75% to 90% of CNI-treated patients;24,38 and in all cases by 10 years posttransplant. These pathologic renal changes exacerbate scarring and atrophy and contribute to loss of function.38

Among recipients of non-renal transplants, renal insuffi ciency and permanent renal failure are prevalent among patients who receive continuous CNI therapy. The mechanism of CNI nephrotoxicity may be due to an impact of calcineurin on the renal vasculature, manifested early as increased vascular resistance and later by structural changes such as arteriolar nodular hyalinosis.24,38

A randomized prospective trial comparing CNI-free to CNI-based immunosuppression found that the CNI-free group had better renal function, a diminished prevalence of atrophy and fi brosis, and down-regulated expression of genes associated with fi brogenesis. The investigators in this trial concluded that in terms of renal function and histologic integrity of renal allografts at 2 years posttransplant, superior results were achieved with the CNI-free regimen (sirolimus plus MMF plus steroids) than with continuous use of cyclosporine with MMF and steroids.24 However, this was a small study and requires confi rmation.

The ongoing evolution of immunosuppressive therapy will include options for reducing these and other non-immune toxicities of CNIs, such as posttransplant diabetes, hyperlipidemia, hypertension, and anemia. Options include choosing more selective drugs, avoiding toxic combinations, and maintaining vigilance for toxic effects and reacting to reduce them.1 Special efforts should be made to identify specifi c patient populations who are at heightened risks; for example, the older obese patient at risk of diabetes.

Immunosuppressive Strategies for Specifi c Patient Populations

High-risk patients need to be identifi ed prior to renal transplantation in order to implement the most appropriate immunosuppressive regimens individualized for a given patient. These risks can be either immunologic or medical, both of which require special management.

High Immunologic Risk Patients who are younger and female, and those with African-American heritage have a higher immunologic risk, which impacts treatment decisions. In addition, numerous transplant-related and posttransplant variables elevate immunologic risk and affect the immunosuppressive strategy selected. The graft-related risks include the use of grafts from deceased donors or from donors over 55 years of age. The recipient risk factors include patients undergoing retransplant, or who have a high number of panel reactive antibodies (PRAs) or positive B- and T-cell cross matches, and those who experience delayed graft function posttransplant.39

Based on clinical observations, immunosuppressive protocols for African-American recipients, recipients of secondary grafts, and recipients with high PRA levels should be tailored to be more intensive and given in higher doses. Similarly, children’s immune systems are relatively aggressive, and they require higher-dose immunosuppression compared with elderly patients. Patients requiring a more aggressive approach may receive standard triple immunosuppressive therapy, including CNI, steroids, and antimetabolites.

16


Conversely, some patients may require lower levels of immunosuppression; individualized approaches for those at specifi c risks may include steroid avoidance and CNI-elimination protocols. Some of the specifi c strategies used for different patient populations are summarized in Table 5.

Immunosuppressive protocols are tailored based on an individual patient’s immunologic and medical risks.

High Medical RiskRenal transplant patients can either present with or develop a number of concomitant medical conditions that will impact immunotherapy decisions. Beyond the fi rst year posttransplant, infections and malignancy account for approximately 10% to 12% of all deaths in renal graft recipients, while cardiovascular disease accounts for approximately 30% of deaths.40 In fact, renal dysfunction itself is a cardiovascular risk factor, given its association with hypertension, anemia, and lipid disorders. Similarly, diabetes, which is present in 40% to 50% of renal transplant patients, is also an important clinical issue that contributes to the risk of cardiovascular disease and hypertension. Older patients present with a number of concurrent medical conditions, possible reduced performance status, and additional cardiovascular and circulatory issues. Patients with more medical risk factors also require tailored immunosuppressive regimens; for example, for patients with vascular disease, steroids may be withdrawn or avoided.

Issues of Chronic RejectionNewer immunosuppressive therapy regimens in renal transplantation have reduced the incidence of acute rejection. However, long-term graft survival has not improved. While 1-year graft survival rates now exceed 90%, this falls to 65% to 70% at 5 years and to under 50% at 10 years.39 The clinical challenge is to prevent and treat the long-term complications of renal transplantation, including suboptimal allograft function, premature death, cardiovascular disease, and bone disease.

Several different causes can be identifi ed for progressive loss of graft function. The development of antibodies specifi c for donor MHC molecules is hypothesized as a factor contributing to chronic rejection. Other factors include transplant glomerulopathy, recurrent or persistent renal disease, hypertension, proteinuria, and infection, as well as CNI toxicity. Long-term graft survival may be negatively impacted by such factors as older recipients and donors, prolonged wait times, by uncontrolled, late, silent rejections, or by over-immunosuppression (leading to infections such as BK virus), or by a combination of these factors. Changes in the immunosuppressive therapy may slow the progression of chronic allograft

17

High Medical Risk

RISK FACTOR CONSIDERATIONS OR ALTERATIONS TO IMMUNOTHERAPY

Table 5. Immunosuppressive Strategies for Specifi c Patient Populations

High Immunologic Risk

African Americans Standard triple immunosuppressive therapy, including CNI, steroids, and antimetabolites

High Panel-Reactive Antibodies Standard triple immunosuppressive therapy, including CNI, steroids, and antimetabolites

Positive Cross Match Induction antibody therapy with thymoglobulin, MMF, and tacrolimus, plasmapheresis, rituximab, and IVIG

Diabetes Avoid steroids, CNIs, or sirolimus

Hyperlipidemia Avoid steroids, CNIs, or sirolimus

Vascular Disease Steroid withdrawal or avoidance

Older Donor CNI withdrawal or avoidance


nephropathy (CAN) if such changes are able to halt an ongoing immune response or, when CNI toxicity is a signifi cant contributor to the process, when CNIs are withdrawn. The mainstays of treatment for graft preservation, however, include control of blood pressure, treatment of hyperlipidemia, and management of diabetes.22 Specifi c clinical situations and posttransplant complications create a need to further individualize therapy; some of these options are reviewed in Table 6.

Specifi c graft situations and posttransplant complications create a need to further individualize therapy.

POSTTRANSPLANT SITUATION POTENTIAL MANAGEMENT STRATEGIES

Chronic Rejection

Table 6: Modifi cation of Immunosuppressive Therapies

Blood pressure control, ACE-I, ARB

Posttransplant Complications:

Diabetes

Hyperlipidemia

CMV Infection

BKV Nephritis

EBV (PTLD)

Avoid / decrease steroids or CNIs

Avoid / decrease steroids, CNIs, or sirolimus

Reduce dose intensity, decrease antiproliferative agents

Reduce dose intensity

Reduce dose intensity, rituximab, chemotherapy

Deteriorating Graft Blood pressure control, ACE-I, ARB, Non-CNI immunosuppressive regimen

Optimizing outcomes requires long-term follow-up by knowledgeable caregivers who recognize and react to change.1 Identifying progression of renal injury is best conducted using serial assessment of renal function and histology, as graft injury is likely a dynamic process with a limited ability for recovery from irreversible changes.41 A major challenge regarding long-term immunosuppression is the need for the development of inexpensive and noninvasive tools to defi ne and monitor responses along the spectrum of immunity.40 For example, tests such as microarray analysis of gene expression in biopsy specimens could be used to more precisely determine the immunologic basis of rejection in a particular patient. This ability would change clinical management as well as the design of clinical trials.

New biologic agents, including monoclonal antibodies and fusion proteins, have been developed to address many of these problems. These precisely targeted, selective immunosuppressive agents are not immunogenic, have long half-lives and prolonged biologic effects allowing intermittent administration, and have a favorable safety profi le with minimal non-immune toxicities. These agents exploit normal mechanisms of T-cell activation; for example, by inhibiting costimulatory signals to block T-cell activation. They may replace the drugs associated with most of the long-term non-immune toxicities, such as the corticosteroids and CNIs.

Investigational Immunosuppressive Agents in Clinical Trials in Renal Transplantation

Research continues to focus not only on the development of new immunosuppressive agents, but also on individualizing immunosuppression based on genotyping (or pharmacogenomics), on establishing new biomarkers, and on gaining better understanding of immune regulation in transplant rejection. The ultimate objective is to develop clinically applicable immunologic tolerance protocols. Several clinical trials currently under way include protocols for extensive sample collection and analysis in order to develop predictive biomarkers and incorporate them into clinical practice.

The adverse side effects of available immunosuppressive therapeutics are due in large part to their nonselective mechanisms of action, as most clinically approved immunosuppressive maintenance drugs target signaling pathways and/or enzymes with wide-ranging cellular distribution.42 To refi ne immunosuppressive therapy, research is being focused on the development of more selective agents with unique or novel mechanisms of action. A number of products in the pipeline for immunosuppressive therapy, including both small molecules and biologics, are summarized in Table 7.

18


Table 7: Investigational Agents in Clinical Trials in Transplantation

A number of small molecule and biologic agents, designed to be used in short courses for induction, for treatment of acute rejection, or for prolonged immunosuppression, are in clinical trials.

AGENT CURRENT STATUS MECHANISM OF ACTION

Biologics

LEA29Y (belatacept)

Bristol-Myers SquibbOne Phase 2 trial completed: Effi cacy and Safety as Part of a Quadruple Drug Regimen in First Renal Transplant Recipients43; two Phase 3 trials ongoing: BENEFIT including recipients of cadaveric or living donor kidneys and BENEFIT-EXT including recipients of kidneys from extended criteria donors44

Inhibition of T-cell costimulation pathway by blocking CD28, its homologue CTLA4, and their ligands CD80 and CD86. Infusion.

Efalizumab (anti-CD11a)

Genentech Phase 2 trial in renal transplantation; islet trial ongoing

Anti-CD11, a monoclonal antibody, blocking T-cell adhesion, traffi cking, and activation. Subcutaneous injection.

Non-Biologics / Small Molecules

FTY720 (fi ngolimod)

NovartisPhases 2 and 3 ongoing; Completed two Phase 1 and two Phase 2 trials45

Induces rapid and reversible sequestration of lymphocytes into secondary lymphoid organs, thereby preventing their migration to sites of infl ammation. Oral agent.45,46

FK778 Astellas Pharma US, Inc.Phase 2 ongoing

Inhibits pyrimidine synthesis, blocking proliferation of T and B cells. Oral agent.

Pfi zerPhase 2 trial in kidney transplantation; Phase 2 trial in rheumatoid arthritis

Tyrosine kinase JAK3 inhibitor, inhibiting cytokine-induced signaling and proliferation. Oral agent.

CP-690,550

Figure 2. Sites of Action of Experimental Immunosuppressants

The development of an immune response and full activation of T cells requires 2 distinct but synergistic signals. The investigational agent belatacept (LEA29Y) inhibits signal 2 in the immunologic cascade. Other new agents block or stimulate different receptors involved in the immune response: FTY720 is an S1P-R agonist; FK778 inhibits pyrimidine synthesis; CP-690,550 blocks cytokine-induced proliferation at JAK3. Adapted from Halloran PF.1 © 2004 Massachusetts Medical Society. Used with permission.

19

Belatacept(LEA29Y)

CP-690,550

FTY720

FK778


Biologic Products

Belatacept (LEA29Y)The development of an immune response and full activation of T cells requires 2 distinct but synergistic signals, as demonstrated in Figure 2. The fi rst signal, delivered through the T-cell antigen receptor, is provided by the antigen itself and is responsible for the specifi city of the immune response. The second, or costimulatory, signal is not antigen-specifi c, and many T-cell molecules may serve as receptors for costimulatory signals. The best characterized costimulatory pathway includes CD28, its homologue CTLA4, and their B7 ligands CD80 and CD86.47, 48

Initial immunosuppressive drug development in this area focused on a recombinant fusion protein CTLA-4-Ig, which has shown promise in the treatment of autoimmune diseases, such as rheumatoid arthritis.49 When tested in transplantation, this compound suppressed rejection and induced tolerance in rodents but was less effective in primates. A rational design concept was used to create a modifi ed version of CTLA4-Ig, which produced LEA29Y (belatacept). The restricted distribution of belatacept’s target (the B7 ligands, CD80 and CD86) makes the drug highly immunoselective, thus allowing effective maintenance immunosuppression with little morbidity or toxicity.47

Belatacept is designed for use as an agent of chronic maintenance immunosuppression because it acts extracellularly on a specifi c target, which may limit systemic non-specifi c toxicities.47 This strategy aims to protect the transplanted organ against acute and chronic rejection and to sustain better long-term function, with more favorable effects on lipids, CV end points, and diabetes as compared with corticosteroids and calcineurin inhibitors. Belatacept may also allow the minimization and/or avoidance of those drugs.

Another important property of belatacept is its ability to inhibit T-cell-dependent antibody responses, especially since the development of anti-donor antibodies contributes to late kidney transplant deterioration, including some cases of transplant glomerulopathy, and constitutes a major barrier to retransplantation.47 Belatacept may have the potential to reduce the incidence of sensitization in recipients whose grafts do fail, and permit them to receive another transplant.

Figure 3. Trial Design and Belatacept Dosing Regimen

A study of 218 renal transplant recipients compared 2 LEA29Y-based CNI-free maintenance regimens to a cyclosporine-based regimen.47

20

Consent/enroll

Identify ‘higher’ or ‘lower’ risk patient

‘Low-risk group’Patients receiving fi rst renal transplant

History of panel-reactive antibodies <20%Low risk of AR (investigator determined)

‘Higher risk group’Patients receiving > 2nd renal transplant

History of panel-reactive antibodies >20%Higher risk of AR (investigator determined)

Randomize to treatment arm (1:1:1)(High-risk patients limited to 10% of total number of patients)

LEA29Y‘More intensive’ regimen

0—3 months10 mg/kg on Days

1, 5, 15, 29, 43, 57, 71, 854—6 months

10 mg/kg on Days 113, 141, 1697—12 months

5 mg/kg every 4 or 8 weeks

LEA29Y‘Less intensive’ regimen

0—1 month10 mg/kg on Days 1, 15, 29

2—3 months10 mg/kg on Days 57, 85

4—12 months5 mg/kg every 4 or 8 weeks

CsA(dosed as per protocol)

Initial daily dose7 ± 3 mg/kg0—1 month

Adjusted to 150-400 ng/mL1—12 months

Adjusted to 150-300 ng/mL


A recently published randomized study of 218 renal transplant recipients compared 2 belatacept-based, CNI-free maintenance regimens to a cyclosporine A-based maintenance regimen, as shown in Figure 3.43 This evaluation demonstrated that the belatacept-based CNI-free regimens were equivalent to the cyclosporine-based regimen in terms of effi cacy for acute rejection prophylaxis at 6 months’ follow-up. The observed acute rejection rates of 6% to 7% with belatacept, mycophenolate, steroids, and basiliximab in this trial compare favorably to reported rates of 8% to 17% in clinical trials of cyclosporine, mycophenolate mofetil, steroids, and basiliximab, and are lower than the reported rate of 47% in a clinical trial using mycophenolate mofetil, steroids, and basiliximab alone in low-risk transplant recipients.

At 12 months’ follow-up, patient cardiovascular metabolic profi les were favorable with belatacept treatment as compared to cyclosporine therapy, and renal function, as measured by GFR, was signifi cantly higher in patients receiving the belatacept regimens. Measured GFR was approximately 9 to 13 mL/minute higher in recipients of belatacept as compared with recipients of cyclosporine. Underscoring the potential benefi t of non-nephrotoxic therapy, differences in measured GFR favoring belatacept were also observed in patients with impaired function with tubular atrophy and interstitial fi brosis (commonly known as chronic allograft nephropathy).43 These early results suggest that belatacept will allow patients to avoid the renal, cardiovascular, and metabolic toxicities of cyclosporine. Thus, costimulation blockade offered by belatacept may offer a new, CNI-free paradigm for improving long-term outcomes in renal transplant maintenance immunosuppression.

Anti-CD11a (efalizumab)Efalizumab, already approved for use in the treatment of psoriasis, is a humanized IgG1 monoclonal antibody that targets the CD11 chain of LFA1, which has been shown to block T-cell adhesion, traffi cking, and activation. In a Phase 1/2, open-label, dose-ranging, multicenter trial, efalizumab was administered weekly for 12 weeks’ posttransplantation and used as chronic induction with a maintenance regimen of full-dose or half-dose cyclosporine. At 3 months, 7.8% of patients had reversible rejection episodes and at 6 months, 1 additional rejection episode occurred for a cumulative rejection rate of 10.4%. In a subset of 10 patients who received the high-dose efalizumab (2 mg/kg) with full-dose cyclosporine, MMF, and steroids, 3 patients developed posttransplant lymphoproliferative disease. The authors concluded that while efalizumab appears to be an effective immunosuppressive agent, it should be used in a lower dose (0.5 mg/kg) and with an immunosuppressive regimen that spares calcineurin inhibitors.44

Non-biologics/Small Molecules

FTY720 (fi ngolimod)FTY720 is a synthetic structural analogue of myriocin, a metabolite of an ascomycete, with a novel mechanism of action. FTY720 acts as an agonist of the S1P-R receptors, which in turn reduces the recirculation of lymphocytes by sequestering them into secondary lymphoid organs without affecting their function or properties. This reduces migration of effector cells to infl ammatory tissues and graft sites.45,46

In clinical trials to date, 2 Phase 2 trials in combination with cyclosporine have been completed with FTY720, as well as 2 randomized, placebo-controlled Phase 1 trials in maintenance therapy.45,46,50 The recently published fi rst Phase 2A study of FTY720 in de novo renal transplantation47 found that at a dose of 2.5 mg, FTY720 was as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation, with the incidence of the composite end point of biopsy-confi rmed acute rejection, graft loss, or death to be 14.6% at Month 3 in these FTY720-treated patients. In addition, FTY720 was observed to be well tolerated and not associated with the side effects commonly observed with immunosuppressive therapies—the main difference in tolerability being a transient asymptomatic bradycardia and an expected decrease in peripheral lymphocytes, which was reversible after treatment discontinuation.44-46 The possible occurrence of retinal edema due to FTY720 is being investigated.46

21


FK778 FK778 is a synthetic malononitrilamide, derived from lefl unomide, with both immunosuppressive and anti-proliferative effects. FK778 inhibits both T-cell and B-cell functions by blocking pyrimidine synthesis. Single- and repeat-dose Phase 1 studies have indicated oral bioavailability and no dose-limiting effects at the levels tested. In a double-blind randomized Phase 2 study, 149 patients were given either high- or low-level FK778 or placebo combined with tacrolimus and steroids. In this evaluation, both active treatment arms showed effi cacy of FK778 to reduce acute graft rejection. Anemia was the most commonly reported adverse event and was dose-related. Currently, additional clinical studies of FK778 are under way in Europe and in the United States in liver and renal transplantation patients.51,52 Data from preclinical and clinical trials to date indicate the potential for improvement in transplant outcomes based on the ability of FK778 to prevent acute and chronic allograft rejection in organ transplant models, its favorable myocardial profi le, and its potential anti-viral activity.52 However, its relatively narrow window between effi cacy and toxicity has been a concern.53

CP-690,550The tyrosine kinase JAK3 is required for the transduction of immune cell proliferative signals, and inhibition of this signaling provides an opportunity to disrupt proliferation. JAK3, unlike other members of this family, is expressed at high levels in natural killer cells and thymocytes and is inducible in T cells, B cells, and myeloid cells but is not expressed in resting T cells.

In preclinical models, the JAK3 inhibitor CP-690,550 has resulted in strong immunosuppression and signifi cant improvement in allograft survival. Of note, this agent has activity beyond JAK3; it also affects JAK2,54 which is required for signaling by erythropoietin receptors, thus creating the potential for anemia. It may also be capable of over-immunosuppression similar to that seen with currently used clinical immunosuppressants. The JAK3 inhibitor CP-690,550 is in Phase 2 trials.

Other Investigational Immunosuppressive TherapiesA number of additional agents already in use or under investigation for other indications also have potential for use in renal transplantation. For example, 2 monoclonal antibodies, an anti-CD40 antibody being investigated in Phase 1 trials for the treatment of non-Hodgkin’s lymphoma (Chiron/Xoma) and an anti-IL-15 antibody being developed for the treatment of rheumatoid arthritis (Amgen) are potential candidates for use in transplantation, as well. In addition, Thios Pharmaceuticals has planned to move TSI (rPSGL-Ig), an agent previously evaluated in re-vascularization, into Phase 2 trials to prevent delayed graft function (DGF) in renal transplantation.

PharmacogenomicsIn the future, pharmacogenomics may provide the information necessary to tailor individualized immunosuppressive regimens, based on genotyping. This may prove especially relevant for the use of drugs with high toxicities and narrow therapeutic indexes.55,56 For example, the CYP3A (cytochrome P-450-3A) allele CYP3A5*1 is associated with increased CYP3A5 levels and is present in 70% to 80% of African Americans but in only 5% to 10% of whites.57 African-American patients with this genotype may metabolize drugs faster and require higher doses to achieve target blood concentrations than other ethnic groups. There is also signifi cant variability within ethnic groups, which makes the planning of initial dosing diffi cult for drugs with a narrow therapeutic range.57 For example, CYP3A5 genotyping can predict which patients may experience a delayed time to reach target levels of tacrolimus, which is associated with earlier transplant rejection. Thus, genotyping for this allele could help reduce graft rejection in the high-risk group of African-American patients.58

22


Assessing the Effi cacy of Immunosuppressive Strategies

The evolution of immunosuppressive therapy in renal transplantation has resulted in a steady decline in acute rejection rates and substantial improvements in short-term renal transplant survival.59 This has created a paradox for investigators attempting to assess the effi cacy of newer immunosuppressive agents, as these traditional end points are becoming impractical due to fewer such events. Innovative approaches for assessing the effi cacy of new strategies are emerging in which alternative surrogate markers, such as renal function, histologic fi ndings, and immunologic markers in urine are being used or considered to assess outcomes.59

As shown in Figure 4, benefi ts of agents developed in the 1980s, such as cyclosporine, were detected by assessment of 1-year graft survival. In the 1990s, evaluation of novel immunosuppressants shifted from graft failure to acute rejection, and agents such as MMF, tacrolimus, and sirolimus were evaluated on end points surrounding 1-year acute rejection rates.59 As immunosuppressive therapies continue to evolve, surrogate markers may play an increasingly important role as study end points.

Figure 4: Timeline and potential future end points in renal transplantation adapted from Hariharan et al., 200359

YEAR 1970 1975 1980 1985 1990 1995 2000 2005 FUTURE

Renal Function

Histology

Immune Markers

Composite End Point

Earlier agents were assessed based on 1-year graft survival. Subsequently, evaluation of immunosuppressantsshifted from graft failure to acute rejection, and most recently to end points surrounding 1-year acute rejection rates. Agents currently in clinical trials, such as belatacept, rely on objective assessments of renal function such as measured GFR .

Graft Loss

Death

Acute Rejection (Bx proven)

Rx Failure

ORIGINAL END POINTS:

RECENT ALTERNATIVE END POINTS:

FUTURE END POINTS:

MEASURED GFR

CsAAZATHIOPRINE,PREDNISONE

AGENTS MMF SIROLIMUS

TACROLIMUS BELATACEPT

Posttransplantation MonitoringThe identifi cation of markers that, within a few months’ posttransplant, could predict long-term survival would permit individualization of immunosuppressive therapy. These end points fall into 3 categories: clinical, histologic, and immunologic, and should be combined with strategic monitoring of the recipient’s general health.59

23


Clinical End PointsSerum creatinine – Short-term postttransplant renal function has been correlated with long-term survival, and renal function can be estimated by the serum creatinine level. Serum creatinine at 6 and 12 months after renal transplantation has been shown to correlate with long-term graft survival.59

Calculated creatinine clearance – GFR is considered the best overall index of renal function in health and disease. Because GFR is diffi cult to measure in clinical practice, most clinicians estimate the GFR from the serum creatinine concentration. However, the accuracy of this estimate is limited because the serum creatinine concentration is affected by factors other than creatinine fi ltration such as age, gender, and body size. To circumvent these limitations, several formulas have been developed to estimate creatinine clearance from serum creatinine concentration, and including age, sex, and body size variables. However, these equations based on measured or estimated creatinine clearance systematically overestimate GFR.60

Measured Glomerular Filtration Rate (GFR) - GFR is recognized as the more accurate assessment of renal function and, despite the diffi culty of obtaining this measure, it is emerging as an important endpoint in clinical trials.41

Histologic End PointsRenal histologic fi ndings can be observed before renal dysfunction, and as a result, this assessment has become an attractive short-term end point. Until recently, renal histologic evaluation was practical only in patients experiencing renal dysfunction.59 However, scheduled protocol renal biopsies, which can detect silent tubulitis, have also recently been performed in recipients with stable renal function.61 However, the signifi cance of silent tubulitis is not clear. Although the additional costs associated with detecting silent acute rejection and logistic issues present challenges to use of this end point, future studies should consider incorporation of this evaluation.59

Non-specifi c atrophy and fi brosis – Some kidneys are lost with a slowly progressive but non-specifi c phenotype, where extensive tubular atrophy and interstitial fi brosis occur. In effect, this represents loss of nephrons. In some cases, this is related to a specifi c disease entity, such as recurrent glomerulonephritis. In others, it is attributable to transplant glomerulopathy arising from alloantibody injury, and in some cases, no specifi c disease entity can be identifi ed, and the nephron loss probably refl ects the cumulative effect of multiple insults—donor age, brain death, ischemic damage at the time of transplant, T-cell- mediated rejection, and toxicity from drugs. In such cases, the term “chronic allograft nephropathy” (CAN) has been applied. The heterogeneity and non-specifi city of CAN make it unsuitable as an end point to evaluate new immunosuppressive agents. However, CNIs do produce tubular atrophy and interstitial fi brosis, and protocols that avoid CNIs can develop objective assessments of these changes. Quantifi cation is facilitated by the use of indices such as the Banff Score Index.62

Immunologic MarkersIdentifi cation of reliable immunologic markers that could be detected before the development of renal dysfunction would be a valuable addition to posttransplant monitoring.59 Potential options are as follows:

Anti-HLA antibodies – The detection of anti-donor antibodies early after transplantation has been correlated with immunologic injury and renal dysfunction, making this a potential marker to be evaluated for measuring transplant outcome.59

T-cell responses to donor antigen – Measuring T-cell reactivity to donor cells or HLA peptides has been successfully correlated with risks of acute and chronic rejection.63 These studies are also important to incorporate in future clinical trials to minimize or withdraw immunosuppression. Tissue, blood, and urine immune molecules – The immunologic acceptance of a graft can also be evaluated using molecular markers of rejection/acceptance in blood, tissue, and urine cytokines. Although the reproducibility and availability of such markers in clinical trials and practice remains a challenge, they are attractive future end points due to their non-invasive nature.59

24


General HealthScreening for potential toxicities of immunodefi ciency, including infections such as CMV, EBV, Pneumocystis Carinii, BK virus, and malignancies (most commonly lymphomas and skin cancers), requires routine posttransplant patient monitoring. Similarly, non-immune morbidities, such as cardiovascular risk factors (hypertension, diabetes, and hyperlipidemia), are relevant events that adversely affect long-term outcomes. As the rates of acute rejection and late graft failure decline, morbidity and assessments of the recipient’s general health are becoming increasingly relevant to clinical practice.59

Immunosuppressive Therapy Compliance

Another issue in immunosuppressive therapy in renal transplantation is non-compliance with the prescribed posttransplant medication. Risk factors for non-compliance include direct side effects (cosmetic and others), inconvenient or burdensome regimens, fi nancial concerns, the complexity of the regimen, and the “pill burden” felt by some patients. Non-compliance models have found that age, occupation, time since transplant, and certain medication-related beliefs to be predictive of the likelihood of compliance. Donor type and history of diabetes and of infection also may affect compliance.64 Immunosuppressive regimens associated with improved compliance may improve long-term outcomes. Parenteral administration of protein drugs could have advantages: supervised administration in clinics could eliminate some forms of non-compliance. In addition, lack of side effects may make these drugs more acceptable.

High-tech Immune Monitoring

A major challenge remains in the development of inexpensive and noninvasive tools to defi ne and monitor responses along the spectrum of immunity that ultimately lead to immune tolerance.65 Specifi cally, new biomarkers that allow early diagnosis of rejection at the molecular level must be developed to enable treatment to be individualized rather than using set immunosuppressive protocols. Furthermore, developing assays that defi ne the phenotype of a potentially tolerant recipient is critical to the success of immunosuppressive withdrawal. These assays will include T-cell alloreactivity assays, humoral immune responses, and molecular profi ling of intragraft events.

Immune Tolerance Strategies

In a sense, all transplantation is based on a form of adaptive tolerance, because the persistence of the organ in the presence of immunosuppressive drugs induces partial unresponsiveness in most patients. Thus, immunosuppressive drugs really only prevent graft injury for long enough that adaptations can occur. Lower doses of immunosuppressants are then needed for life in most persons to stabilize these adaptations.

Immunologic tolerance is defi ned as unresponsiveness to a specifi c antigen in an immunocompetent person, usually induced by exposure to the antigen under special circumstances. In other words, immunologic tolerance of the antigens of the graft would be achieved while retaining immune responses against all other antigens. The hope is that patients can achieve “lifelong tolerance” to the transplanted organ via manipulation of the recipient’s immunity during the very fi rst weeks after transplantation. In practice, proposed tolerance strategies often use conventional immunosuppressive therapies.66

To pursue this objective, the National Institutes of Health Immune Tolerance Network (www.immunetol-erance.org) was established in 1999. Recently, various pilot clinical trials in transplantation, autoimmunity, and allergies—designed to explore the biology of tolerance in humans—have been approved through this venue, and these studies may shed light on how to achieve the goal of immune tolerance.66, 67

At present, however, no practical therapies are ready for the clinic, and it is by no means clear that they ever will be. The human immune response is complex, and human genetic diversity is extensive. Even the tolerance strategies that do exist make extensive use of immunosuppressive drugs. For the

25


present, immunosuppression is here to stay. However, withdrawal of immunosuppressive drugs may be acceptable in selected patients who are well adapted to their graft, if assays to detect T-cell responses and alloantibody responses at an early treatable stage could be developed.

Successful allogeneic stem cell transplantation (bone marrow transplantation) can achieve true tolerance. However, this is a diffi cult and dangerous treatment across HLA differences, and it is not yet ready for widespread use as a strategy to prepare patients for organ transplantation.

Conclusion

Advances in the understanding of the refi ned details of immunologic mechanisms have fostered the development of new biologic agents that selectively intervene in this complex cascade. New agents with favorable safety profi les and targeted mechanisms of inhibition reduce the non-immune toxicities associated with earlier drugs and contribute to improved acute and chronic graft survival. As a result of selective targeting, such as blocking costimulatory signals, these agents show a promising ability to achieve a balance between immunosuppression and its complications. These agents are not immunogenic, have long half-lives and prolonged biologic effects, allowing intermittent administration, and have minimal non-immune toxicity. The equivalent potency with greater specifi city and selectivity of the new biologic agents render them less toxic than earlier immunosuppressive drugs. This evolution toward individualized immunomodulation offers hope for continued improvements in acute and chronic rejection. For patients who endure long waiting periods before transplantation, new agents promise to improve their quality of life and protect the survival of graft and patient.

26


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Notes


Post-TestACCELMED® Monograph

The Evolution of Immunosuppression in Renal Transplantation

1) The overall objective of successful immunosuppressive therapy is: a. immunosuppression: preventing immune rejection of the allograft b. maintaining immunocompetence: minimizing the risk of undesired consequences of immunosuppression such as certain infections and cancers c. maintaining a balance of A and B d. neither A nor B 2) Three different elements in immunosuppressive therapy in renal transplantation are: a. Antibody induction therapy, maintenance immunosuppression, treatment of graft rejection b. Antibody induction therapy, graft enhancement, maintenance immunosuppression c. Primary and secondary maintenance immunosuppression, treatment of graft rejection d. Antibody induction therapy, management of CNI toxicity, maintenance immunosuppression e. None of the above

3) Agents in the class of calcineurin inhibitors are: a. Muromonab-CD3 b. Mycophenolate mofetil (MMF) c. Cyclosporine and tacrolimus d. Rituximab e. None of the above

4) Antibody induction immunosuppressive therapy in current use includes: a. Polyclonal anti-lymphocyte antibodies and anti-CD3 monoclonal antibodies b. Daclizumab or basiliximab c. Alemtuzumab d. A and B e. A, B, and C

5) Maintenance immunosuppressive therapy may include: a. Cyclosporine or tacrolimus b. Adjunctive maintenance therapy with glucocorticosteroids plus mycophenolate mofetil c. Adjunctive maintenance therapy with azathioprine or sirolimus d. All of the above e. None of the above

6) Some strategies to reduce non-immune toxicities of current immunosuppressive therapy include: a. The growing use of corticosteroid-sparing regimens b. The growing use of CNI-sparing regimens c. The anticipation of diabetes risks and choice of less diabetogenic agents d. A shift away from the use of cyclosporine plus sirolimus e. All of the above

7) Basic toxicity problems with current immunosuppressive strategies are: a. The growing use of corticosteroid- sparing regimens b. The growing use of CNI-sparing regimens c. Immune and non-immune toxicities of common immunosuppressive regimens d. A shift away from muromonab-CD3 and equine antithymocyte globulin to rabbit antithymocyte globulin

8) An investigational agent in clinical trials in transplantation immunosuppression that provides selective costimulation blockade is: a. XL-880 b. sorafenib c. efalizumab d. belatacept e. None of the above

9) Potential surrogate markers for immunosuppressive therapy in renal transplantation include: a. Posttransplant monitoring of serum creatinine and creatinine clearance b. Glomerular fi ltration rate (GFR) c. Cystatin C d. Renal histologic end points e. All of the above

10) Immune tolerance strategies a. Have been proven successful and are in routine clinical practice b. Exhibit signifi cant drug-related toxicities c. Have started pilot trials through the National Institutes of Health Immune Tolerance Network d. None of the above e. All of the above

30


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