Potential Catalysts in Therapeutics Bruce A. Luxon Division of Gastroenterology-Hepatology, University of Iowa, Iowa City, IA Received July 23, 2014; accepted July 30, 2014.

Key Points: 1. Immunosuppression strategies in liver transplantation are centered on minimizing the known side effects of steroids and calcineurin inhibitors (CNI). 2. Most research studies are designed to determine when and how to withdraw steroids or calcineurin inhibitors, either substituting mammalian target of rapamycin (mTOR) inhibitors or withdrawing an agent completely. 3. A new focus of immunosuppression research takes advantage of a wealth of knowledge about how antigen-presenting cells interact with T cells. 4. Multiple mechanisms have been studied in the costimulatory pathway. This process is required if a T cell is to remain activated. 5. Several medications that block specific costimulatory pathways have already been approved for treating other disease states [such as rheumatoid arthritis (RA) and psoriasis] and are currently being studied for use in liver transplant immunosuppression. Immune suppression in liver transplantation has become fairly standardized over the past decade. This article discusses the objectives outlined in Fig. 1. The use of CNI, steroids, and induction therapy are fairly uniform throughout the country. Individual programs may have differing protocols for the withdrawal of steroids and the desired blood levels of CNI and what to do in specific circumstances [eg, fatty donor liver, hepatitis C virus (HCV) infection, hepatic carcinoma in the recipient]. The drawbacks of the current medications are also well known. CNI have side effects of diabetes mellitus (DM), kidney injury, and hypertension and a possible association with higher rates of malignancy. Steroid side effects of diabetes, osteopo-

rosis, and opportunistic infections have been known for over 30 years in liver transplantation. It has become common to reduce steroid dosage very early in the posttransplant period and to attempt to wean patients off all steroids in a maintenance regimen (Fig. 2).

WHY IS THERE A NEED FOR NEW AGENTS? Given the current state of very successful immunosuppression, it could be argued that there is not a pressing need for novel immunosuppressive agents. This presumption may be partially correct based on the number of new agents that are currently in clinical trials. However, the side-effect profiles of steroids and CNI do suggest that better agents could certainly have a place in the next decade of liver transplantation immunosuppression.

WHAT ARE THE CURRENT TRIALS? There are three categories of trials investigating various aspects of immunosuppression in liver transplantation (Fig. 3). One hundred thirty-five studies listed on the Web site were identified with the key phrases “immunosuppression” and “liver transplant.” The vast majority of these studies were on two main clinical objectives: (1) how to minimize the side effects of CNI most effectively, by ascertaining an optimal timing of steroid use and/or CNI withdrawal and (2) how to incorporate mTOR inhibitors in the immunosuppression regimen. These latter studies focused on certain populations, those with severe

Abbreviations: AP-1, activator protein-1; CDK, cyclin-dependent kinase; CMV, cytomegalovirus; CNI, calcineurin inhibitors; DM, diabetes mellitus; FDA, U.S. Food and Drug Administration; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IKK, I-jB kinase; IL-2, interleukin-2; MAP, mitogen-activated protein; MHC, major histocompatibility complex; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; NFAT, nuclear factor of activated T cells; NF-jB, nuclear factor-jB; PI-3K, phosphoinositide-3 kinase; RA, rheumatoid arthritis; TCR, T-cell receptor. Potential conflict of interest: Nothing to report. Address reprint requests to Bruce A. Luxon, M.D., Ph.D., Division of Gastroenterology-Hepatology, University of Iowa, 200 Hawkins Drive, 4607 JCP, Iowa City, IA 52242. E-mail: [email protected] DOI 10.1002/lt.23971 View this article online at LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2014 American Association for the Study of Liver Diseases. V



Figure 1.

Figure 2.

kidney dysfunction at the time of transplantation or HCV infection and those transplanted who had a hepatocellular carcinoma (HCC) in their native liver. The “big buckets” of immunosuppression are shown

in Fig. 4. Very few new agents are being studied in the categories of CNI, antimetabolites, or mTOR inhibitors. However, considerable innovation has occurred with drugs that are antibodies designed to interact



Figure 3.

Figure 4.

beneficially with T cells. New agents have been found that selectively interfere with T-cell activation or proliferation. Many of these medications have been developed for “nontransplant” indications: RA, sarcoidosis,

psoriasis, or hematological malignancies. If these drugs show promise in some aspect of T-cell inhibition, they often are tried in other disease states, including renal and liver transplantation.



Figure 5.

POTENTIAL TARGETS Considerable knowledge has been developed about how T cells proliferate after they are activated. Newer agents have been developed to block various receptors in one of the pathways that cause T cells to activate and/or proliferate. Three different cascades of signaling molecules are important in this process. A diagram of the various targets is shown in Fig. 5. Considerable evidence has been accumulated suggesting that the T-cell tolerance is regulated by the balance of costimulatory and coinhibitory signals received during T-cell activation. These interactions have been shown to be critical in the development of tolerance and autoimmunity. Blockage of these pathways has become possible in the laboratory, and molecules are now available to target specifically selective pathways to manipulate the immune response after liver transplantation.

CNI Early graft failure from rejection has been very rare since the use of the CNI became widespread. However, late graft loss and the nonhepatic side effects of CNI continue to cause significant morbidity. Many of these adverse events can be managed successfully, but the CNI-associated complications of nephropathy, newonset diabetes, dyslipidemia, and hypertension remain important contributors to the cardiovascular deaths seen after transplantation. No new CNI agents have been publicized. A long-acting tacrolimus with once daily dosing has been developed and was approved by the US Food and Drug Administration

(FDA) in 2013. Large trials compared prolongedrelease tacrolimus to standard tacrolimus and showed that the prolonged-release form had similar efficacy and safety outcomes. Serum tacrolimus levels apparently can be adjusted slightly more slowly in patients using the prolonged-release form. The adverse effects listed above, however, are similar between the prolonged-release form and standard tacrolimus.

Interleukin-2 Inhibitors Interleukin-2 (IL-2) inhibitors have been developed over the past decade but have had considerable difficulty in finding a clinical use in transplantation. They have been used as induction agents, selectively blocking the CD25 site (IL-2 receptor). The only CD25 antibody currently available in the United States is basiliximab. It is specific for the alpha chain of the CD25 receptor (Fig. 6). It is very long acting and remains in the circulation for a considerable time after injection. It was hypothesized that, when basiliximab is used as an induction agent, lower doses of CNI could be used while still preventing acute rejection. Currently there are no clinical trials listed on the Web site that investigate the use of other novel IL-2 blocking antibodies.

mTOR Inhibitors mTOR inhibitors function by binding to the FK506 binding protein and form a complex with and inhibit the mTOR complex 1 (mTORC1). This complex directly affects cell cycle progression and IL-2 signaling to T cells (Fig. 7). The end result of inhibiting mTORC1 is



Figure 6.

Figure 7.

blockade of T-cell progression (but not activation). Neither sirolimus nor everolimus is FDA-approved for use in liver transplantation. Nonetheless, they are effective for maintenance immunosuppression in liver transplantation. There are over 3 dozen trials listed

on investigating their use in liver transplantation. The side effect profile of mTOR inhibitors is different from that of the CNI, mainly increased cholesterol, delayed wound healing, edema, and mouth ulcers.



Figure 8.

One of the best studied uses of sirolimus is in patients with CNI-associated nephrotoxicity (Fig. 8). Multiple trials have suggested that early conversion from a CNI to sirolimus may prevent further deterioration of renal function in patients initially undergoing transplantation with impaired renal function. In addition, both basic science and some clinical evidence indicate that mTOR inhibition may promote tolerance. The hypothesis behind this prediction is that mTOR inhibitors block proliferation but do not stop activation of T cells. A final use of sirolimus is in patients with special circumstances. Besides its use in patients with initial renal dysfunction, patients with liver cancer (HCC) also may benefit from early conversion to sirolimus. mTOR inhibitors slow cell growth, tumor growth, and angiogenesis, so sirolimus may be a viable candidate for immunosuppression in transplant patients with HCC. Several trials have suggested that sirolimus may increase survival in patients undergoing transplantation for HCC, but no randomized trials have been conducted to confirm this speculation. Although many trials are listed on studying sirolimus and everolimus (it has a more favorable pharmacokinetic profile than sirolimus), none is investigating a new mTOR inhibitor.

JAK3 Inhibitors Blockade of the JAK3 pathway interferes with IL-2 signaling and decreases T-cell proliferation. Tofacitinib, a selective kinase inhibitor of JAK, was FDA approved to treat moderate to severe RA in 2012

(Fig. 9). It was initially tried as an immunosuppressive agent in kidney transplants. In 2 small Phase 2 trials, tofacitinib was used at 2 doses and compared with tacrolimus. Biopsy-proven acute rejection was similar in both the tofacitinib and the tacrolimus groups. Renal function was well preserved, with JAK3 blockade showing better preservation of renal function compared with CNI. However, there was a high incidence of BK virus in the tofacitinib group and a substantially higher rate of cytomegalovirus (CMV) infection. There was also a statistically significant increase in lymphoproliferative disorders in the tofacitinib-treated groups. There have been no reported trials of tofacitinib use in liver transplantation, and it is likely that this agent will no longer be studied in transplantation because of its hematologic toxicity and risk of serious infection.

CD28 Inhibitors The best studied pathways in the immunoglobulin super family are the CD28 (Fig. 10) and the CD80/ CD86 pathways. Not surprisingly, several novel molecules have been developed to interact with these pathways. In 2005, abatacept was approved by the FDA for treatment of RA. In this context it improved symptoms and had an excellent safety profile. The drug also showed promise in type 1 diabetes and in some types of airway inflammation. Trials in kidney transplantation were also carried out; however, the results were not as promising. Patients given abatacept had more graft loss from rejection (Fig. 11). It was thought that abatacept provided incomplete blockage of the



Figure 9.

Figure 10.

CD28 pathway because of its poor affinity for the receptor. A modified drug, belatacept, was developed and is a second-generation costimulation CD28 inhibitor. It was approved for use in kidney transplantation in 2011. It is used early after renal transplantation,

being administered at day 0, at day 5, and at the end of weeks 2, 4, 8, and 12. Continued infusion is also used for prevention of chronic rejection. However, belatacept has been associated with a high incidence of posttransplant immunoproliferative disorders and



Figure 11.

Figure 12.

is contraindicated in Epstein–Barr-negative kidney recipients. The use of belatacept was subsequently considered in liver transplant patients. However, in a group of 250 liver transplant patients who received belatacept

as part of their immunosuppression, there was an increased rate of graft loss and death compared with the groups who did not. Hence the FDA required a warning against the use of belatacept in liver transplant recipients. There have been small, uncontrolled



Figure 13.

Figure 14.

trials of belatacept in patients who had significant renal dysfunction prior to undergoing transplant. In a small group of 7 patients with hepatitis C and very severe kidney disease, belatacept seemed to provide adequate immunosuppression.

CD40/CD154 Pathway Inhibitors The final pathway to be discussed is the CD40/ CD154 pathway (Figs. 12 and 13). Previous work with antibodies targeting CD154 was not particularly


successful either in animal models or in early studies in human kidney recipients. Initial studies were complicated by cytotoxicity, thought to be secondary to the chimeric nature of the antibody. A new agent, containing a humanized anti-CD40 antibody, has been developed (ASKP1240). It has been used in human kidney transplant patients with good results. It has not been associated with cytotoxicity or thromboembolic events. In addition, it has not increased the risk of BK or CMV infection in kidney recipients. It is now being used in a Phase 2a study in kidney recipients, which is open but not recruiting. Given its success in primate models of liver transplantation, it is likely that preliminary studies will also be carried out with humans after liver transplantation.

SUMMARY After years of expecting new advances in immunosuppression, we have not seen a newly developed drug in the past decade. Recent efforts have been centered on minimizing the known side effects of steroids and CNI. It is unlikely that a new CNI will be developed; however, extended-release tacrolimus is available. Most clinical research trials are designed to determine when and how to withdraw steroids or CNI, either substituting mTOR inhibitors or withdrawing an agent completely. As with CNI, there is little evidence that new mTOR inhibitors are in the “publicly viewable” pharmaceutical pipeline. New antibodies that block costimulatory pathways currently have been approved or are being studied in both kidney and liver transplantation (Fig. 14). Most studies are initially performed with other diseases requiring immune modulation such as RA or psoria-


sis. Other blocking antibodies are being studied in kidney transplantation. It is unlikely that these newer agents will be generally available in the next 2 to 3 years. It seems likely that they may find specialized use in specific populations of patients (HCC or HCV infection) for whom the risk of side effects is adequately balanced by the beneficial effects of immunosuppression and prevention of infection or cancer progression.

REFERENCES 1. LaMattina JC, Jason MP, Hanish SI, Ottmann SE, Klassen DK, Potosky D, et al. Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction. Transplantation 2014;97:133-137. 2. Klintmalm GB, Nashan B. The role of mTOR inhibitors in liver transplantation: reviewing the evidence. J Transplant 2014;2014:845438. 3. Zarrinpar A, Busuttil RW. Immunomodulating options for liver transplant patients. Expert Rev Clin Immunol 2012; 8:565-578. 4. Crispe IN. Immune tolerance in liver disease. Hepatology; doi: 10.1002/hep.27254. 5. Dhesi S, Boland B, Colquhoun S. Alemtuzumab and liver transplantation: a review. Curr Opin Organ Transplant 2009;14:245-249. 6. Oura T, Yamashita K, Suzuki T, Fukumori D, Watanabe M, Hirokata G, et al. Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates. Am J Transplant 2012;12:1740-1754. 7. Ford ML, Adams AB, Pearson TC. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nat Rev Nephrol 2014;10:14-24. 8. Gotthardt DN, Bruns H, Weiss KH, Schemmer P. Current strategies for immunosuppression following liver transplantation. Langenbecks Arch Surg (in press). 9. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-2729.

Potential catalysts in therapeutics.

After years of expecting new advances in immunosuppression, we have not seen a newly developed drug in the past decade. Recent efforts have been cente...
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