Chronic Biologic Therapy: A New Paradigm for Kidney Transplant Immunosuppression
Flavio Vincenti, MD Christian P. Larsen, MD, PhD Mohammed H. Sayegh, MD
Flavio Vincenti, MD: Hello. I'm Dr. Flavio Vincenti, Professor of Clinical Medicine with the kidney transplant service at the University of California at San Francisco. I'd like to welcome you to this Medscape CME Spotlight on "Chronic Biologic Therapy: A New Paradigm for Kidney Transplant Immunosuppression." I'm pleased to be joined by my colleagues Dr. Chris Larsen, Professor of Surgery at Emory University in Atlanta, Georgia, and Dr. Mohammed Sayegh, Professor of Medicine at the Harvard Medical School in Boston.
The learning objectives for this program are to:
Dr. Sayegh, will you review the results of the published studies on costimulation blockade with belatacept?
Mohammed H. Sayegh, MD: The first trial of T-cell costimulation blockade with belatacept was published in August 2005 in The New England Journal of Medicine.[1]
Dr. Sayegh: This report summarized the results of the phase 2 study of the use of belatacept as a replacement for calcineurin inhibitors (CNIs) in kidney transplantation.
Dr. Sayegh: The study design included a control group and 2 therapeutic arms. In the control group, a CNI was used as the mainstay of immunosuppressive therapy. In the therapeutic arms, 2 protocols that differed by dose and intensity ("less intense" or a "more intense") were used. It is important to remember that belatacept is a biologic agent that has to be given systemically and periodically on a chronic basis; it is not a pill that can be taken orally. The study was an equivalency study; it assessed the equivalence (similar or noninferior results) of 2 treatments, the study drug vs the standard of care -- in this case a CNI.
Dr. Sayegh: This study showed that it is possible to replace CNIs with belatacept. This is a very important observation because it was the first time that a chronic biologic agent was tested in a kidney transplant population or in any transplant population. Another interesting finding of this study is that it appears that the therapy is relatively safe; no major drug-related side effects were reported. As both of you were involved in the study, later I'd like to hear about the occurrence of 3 cases of posttransplant lymphoproliferative disorder (PTLD) during the study. Although there was no statistical difference between the groups, PTLD did occur.
Beneficial effects, in addition to equivalency, were demonstrated in the biopsy studies. CNI-related toxicity was alleviated when belatacept was used, as evidenced by less biopsy-proven chronic allograft nephropathy (CAN) and less adverse effect on the glomerular filtration rate (GFR), a measure of renal function that has implications for long-term outcomes. Overall, this was a very positive study from the standpoint of establishing that a chronic biologic agent targeting T-cell costimulatory pathways, particularly B7, has the potential to replace CNIs and has significant advantages in that it may prevent some of the complications of CNIs.
Dr. Vincenti: Dr. Larsen, will you comment on the cases of PTLD? Because whenever we introduce a new immunosuppressive or biologic agent in transplantation, the question of PTLD comes to the forefront. There were 3 cases in the more intense regimen group. Was this a random cluster or a signal?
Christian P. Larsen, MD, PhD: We'll need to keep our eyes on this. Some of the cases involved primary exposure to the Epstein-Barr virus (EBV) -- an EBV-positive donor organ transplanted into an EBV-negative recipient -- which is a high-risk situation. Another patient had T-cell-depletion therapy for rejection and was subsequently converted to standard of care and then developed PTLD. So in this case, the association is very clear and this is clearly something we need to watch. There has been long-term follow-up of the patients from the initial phase 2 study and we've continued to monitor safety in the phase 3 studies. Thus far, there haven't been any additional signals of concern, although it is something we need to keep our eyes on. At present, this therapy doesn't appear to be associated with a higher prevalence of PTLD. Furthermore, an association between abatacept and PTLD has not been shown in the autoimmune disease experience.
Dr. Vincenti: To summarize what Dr. Sayegh said about the phase 2 study results,[1] differences in the rejection rates among the 3 groups were not statistically significant. There was significant improvement in GFR in the 2 belatacept arms, and there was diminution of biopsy evidence of CAN in patients treated with belatacept compared with cyclosporine. This was a 12-month study and belatacept was administered every 8 weeks or 4 weeks, depending on whether the patients were 3 or 7 months post-transplantation. The question is, can this therapy be sustained on a longer-term basis?
Dr. Larsen: Is this a therapy that can be administered long-term, be it every 8 or 4 weeks? There is an ongoing long-term extension study of the initial phase 2 trial, in which patients were offered the opportunity at 12 months to continue participation. To date, nearly 50 patients have been followed long-term, receiving the original regimen every 4 or 8 weeks with follow-up out to, in some cases, just over 7 years. The experience has been favorable. The original study design didn't allow for a large cohort of belatacept-treated patients to be compared with patients on CNIs, but we do have long-term safety and tolerability experience, which looks very favorable.[2]
Dr. Vincenti: Were there any additional cases of PTLD during those 48 months of follow-up?
Dr. Larsen: There have been no additional cases. You may want to comment on your experience with the long-term therapy.
Dr. Vincenti: We enrolled 20 patients in the long-term extension study. Most of these patients have been followed for 5 years, the longest for more than 7 years. Every year they are asked whether they wish to withdraw from the study and be placed on CNIs. Almost all have consented to remain in the study. Patients overwhelmingly favor not taking a CNI and having to deal with the unavoidable side effects.
Dr. Sayegh: Can you comment on the issue of compliance? One of the concerns that I hear from the transplant community and nephrologists involved in the care of these patients is that the patient has to come back to the clinic to get an injection every few weeks. Some view this as very positive because this way you now know what they are getting, and noncompliance with immunosuppression is not an issue. Others are concerned about whether patients will actually come back and get injections. Since you have patient follow-up for up to several years, what is your experience regarding patient compliance with this therapy? Do you think chronic biologic therapy is a strategy that will ultimately help noncompliance, particularly in children and adolescents?
Dr. Larsen: It has some nice potential advantages. With belatacept we know when patients take their meds and when they don't, based on whether or not they show up for their infusions. Our experience with this has been very good. I'm curious about Dr. Vincenti's thoughts on that point. The phase 2 study[1] included a select group of highly motivated patients who wanted to participate in the trial. Our experience has been great. They have not missed their follow-up and all but 1 of the original subjects have continued on long-term biologic therapy. As a community, we will have to think about how we are going to use this -- assuming it's successful in the phase 3 studies -- because there are some logistical differences to deal with, an upside on the compliance side but some challenges as well.
Dr. Vincenti: The challenge is how to transition patients from a clinical trial, where you have monitors and a research coordinator, to clinical practice, where patients may want to have the drug administered at home or be given it by their local community physician or nephrologist. One of the advantages of belatacept is that it doesn't produce cytokines, so there are no acute side effects and administration is completely safe, which is key in terms of where patients can receive treatment. Patients can receive it at home by a nurse or in a local physician's office, so they don't necessarily have to come to the medical center to receive it. Longer-term however, a practical and cost-effective infrastructure needs to be put in place to accomodate large numbers of patients on belatacept.
Dr. Sayegh: Biologics have been used as chronic therapy in other diseases such that patients have to come in and get an infusion. It's new to our patient population, but it's certainly been done in patients with autoimmune diseases, such as multiple sclerosis and others, and we can learn from those experiences.
Dr. Vincenti, you mentioned a very important point, which is the issue of infrastructure, such as an infusion room and home visits by nurses to give the infusions. This is an exciting strategy because it would allow us to monitor compliance. If a patient doesn't get their infusion, you would know and could follow up right away.
Dr. Larsen: If the phase 3 study shows that there is an improvement in GFR of about 15 mL/min, which is a substantial improvement, and a reduction in scarring, then we'll figure out the infrastructure issues. The fact that the peri-infusion side effects are quite minimal is key, and then there is the potential for a subcutaneous (SC) formulation.
Dr. Vincenti: We need to solve the problem not only for belatacept, but also for a number of biologics in the pipeline, because they will all require the same basic model. For the sake of our transplant patients, we have to come up with a solution. Clearly having a preparation that can be administered SC would make things much easier. CTLA-4Ig, the parent compound of belatacept, is undergoing clinical trials of SC administration in rheumatoid arthritis patients, and belatacept is undergoing pharmacokinetic studies of SC administration in healthy volunteers. At some point, if the pharmacokinetic profile looks feasible, SC administration may be the most ideal and practical strategy for treating patients with this therapy.
Dr. Larsen: Earlier you brought up the trials subsequent to the phase 2 trial that are ongoing. There are 2 ongoing phase 3 trials.[3] The first, which is essentially a larger version of the phase 2 study, is designed for recipients of standard kidneys from living or deceased donors. The second is designed for recipients of extended-criteria donors (high-risk donors and high-risk grafts), where the potential short-term benefits of CNI avoidance (preventing delayed graft function) might be very attractive.
We're looking forward to the results of the phase 3 studies, which should be published later this year. There is also the corticosteroid avoidance study, which uses a rabbit-derived antithymocyte globulin (rATG)-based approach to see if we can use belatacept to not only avoid CNIs, but also to avoid corticosteroids.[4] We're also participating in a study together -- the Immune Tolerance Network (ITN) study[5] -- and maybe you'd like to comment on that.
Dr. Vincenti: The ITN study is designed to minimize immunosuppression by treating patients with a protolerance regimen. At some point, we hope that the maintenance phase of treatment will consist of belatacept and sirolimus. Both of these agents expand Treg cells and do not undermine toleragenic pathways. We also hope to be able to identify a signature in a few patients that will allow us to initially withdraw sirolimus, keep them on monotherapy with belatacept for a while, and with validation of tolerance (the genomic signature), withdraw therapy altogether. But this is in the future. We are moving toward a more simplified way of administering immunosuppression. If we can reach the point of monotherapy, or therapy with a biologic agent plus an oral agent (preferably one that will not need therapeutic drug monitoring), then we will have truly simplified the lives of our patients.
Dr. Vincenti: I have a question for Dr. Sayegh because he's conducted some studies on rATG and its role in Treg cells. The corticosteroid withdrawal study that Dr. Larsen mentioned breaks the usual clinical development pathway of belatacept. Instead of using an anti-interleukin (IL)-2 antibody that has a potential adverse effect on Treg cells up front, we're going to use rATG initially for a few days after transplantation for depletion, and then maintain patients on belatacept. What are the immunologic implications of such an approach?
Dr. Sayegh: The animal studies that we are reporting on at this meeting are based on 2 interesting observations. First, a couple of years ago we published a paper showing that rATG, which is a T-cell-depleting agent, a polyclonal antibody, not only depletes T cells, but causes the expansion and generation of Treg cells.[6] The other observation is from a study done with Dr. Larry Turka from the University of Pennsylvania, showing that after you deplete T cells, the T cells that recover tend to be more of the affector memory phenotype than naive T cells, at least in adults, and tend to be resistant to costimulation blockade.[7]
Dr. Sayegh: We have been developing strategies in animals to determine how to use a T-cell-depleting agent with a costimulation blockade strategy that allows sparing of regulatory and/or expansion of Treg cells and prevents expansion of these "nasty cells" that are resistant to tolerance. We designed a protocol using the T-cell-depleting agent rATG in combination with CTLA4Ig and sirolimus with no CNI or corticosteroids. It is interesting that this is somewhat similar to what is being done in humans. We tested this in a very difficult skin transplant model and demonstrated significant prolongation of graft survival. Now we have biological and experimental evidence that this strategy may make a lot of sense.
Last, we are working on something that may be relevant in the future. If you use lower doses of rATG for maintenance as a chronic biologic agent, you don't deplete T cells, but you expand Treg cells. I envision that in the future we will be able to tailor upcoming therapies with existing biologic agents, which will potentially allow us to significantly minimize and ultimately withdraw all drugs from patients, after maybe 1-3 years. That would be tremendously beneficial. There is a lot of excitement about the use of biologic agents, based on our understanding of the functions of Treg cells. The future looks very promising.
Dr. Vincenti: Dr. Larsen, I have a question about the use of depletion. We have done some work with memory cells. Sometimes costimulation blockade fails. Why does it fail, and does depletion therapy immediately after transplantation help plug this deficiency?
Dr. Larsen: It's apparent that CD28 blockade is not enough to completely control the immune response. In studies that our group, as well as many others, have done, what seems to have emerged is that one of the areas that costimulation blockers are not as effective in as we'd like is when patients have memory T cells that are responsive to the donor. We need other strategies to use together with costimulation blockade. One of the most attractive is T-cell depletion. The rATG-belatacept combination is particularly interesting in this regard. I would point out, though, that there is a residual population of memory cells that resist depletion, so we need to watch that. But at least in clinical practice, it appears that we can use costimulation blockers with either anti-IL-2 receptor antibodies or rATG. The other area that you brought up in the trials is that there is a large number of patients who might benefit -- ie, those with varying degrees of allograft dysfunction and CNI-related side effects. Dr. Vincenti, maybe you could tell us about opportunities for conversion studies.
Dr. Vincenti: There are 2 populations of patients. I'd like to digress a bit to the children. Most of the kids tend to be EBV-negative and receive kidneys from EBV-positive adults. Whenever we have a novel therapy, children come to the forefront because children are going to be on immunosuppressive therapy for the rest of their lives, and a nontoxic therapy like belatacept makes a lot of sense. However, there is the initial period when they are exposed to EBV at the time they are being treated with costimulation blockade, and it could have implications vis-à-vis primary infection, PTLD, and so on.
Conversion studies will help tremendously in 2 groups of patients. First, I think the perfect strategy for children will be conversion to costimulation blockade, maybe after 3 months. And the other group is patients who require CNIs in the early phase of transplantation when the risk of rejection is very high, but beyond 3 months could be converted to belatacept. And then there are patients who have difficulties with CNI therapy (ie, metabolic problems).
One of the most surprising findings during the past 3-5 years is that even though rejection rates have been reduced from 40% to approximately 10%, we have not improved long-term outcome. There are clearly other important factors than acute rejection, such as metabolic issues. New-onset diabetes occurs in 30% of patients, and hypertension, hyperlipidemia, and cardiovascular disease are very important causes of premature death in patients with functioning grafts. So there is a group of patients that could potentially benefit from conversion to a therapy that's not associated with cardiovascular metabolic complications or nephrotoxicity. But, of course, we have to see the efficacy; the drug has to prove itself and that's why the results of the phase 3 studies are going to be so critical.
Dr. Vincenti: A final question to both of you. Looking to the future, where do you see the combination of novel biologics? For example, costimulation blockade combined with antiadhesion or other biologics that have targets either in or outside of the costimulatory pathway but are important in coactivation of T cells.
Dr. Sayegh: If you look at what we have learned from experimental and clinical studies, I would say there are multiple targets for combination therapy. I don't know what the best combination is, but I think we know what the targets are. One is T-cell depletion. Others include rATG, other T-cell-depleting agents (potentially), the costimulatory blocker belatacept, and antiadhesion/costimulation. In addition, there are a couple of biologic agents, including LFA-1 or LFA-3, that are currently being tested in transplantation and other diseases. The other area that we keep forgetting about is targeting B cells. Monoclonal antibodies that deplete B cells are available, and in addition, there are the anti-CD40 agents, which target antigen-presenting cells and B cells.
Some combination therapy to target T-cell-mediated immunity with the first 3, and B-cell immunity, could be very beneficial. I see the future era as one in which we will use less and less nonspecific immunosuppression with 3 or 4 oral drugs daily, to one in which we use more and more novel biologic combinations that specifically target an immune response, with the ultimate goal of giving very few or even no oral drugs on a daily basis.
Dr. Larsen: There are the 2 ways that we can use biologic combinations. First, they can be used as induction agents to prevent early rejection. rATG is the prototypic agent, but the LFA-3 CD2 inhibitor alefacept has potential in this regard. The belatacept trials have really opened up the possibility of changing our paradigm, such that biologic agents are used soley as induction agents. It now appears that biologic agents may be most useful as long-term maintenance drugs. Another target that is particularly attractive is the LFA-1 pathway. There is a lot of experience with the LFA-1 antagonist efalizumab in psoriasis. In this setting it seems to be safe and effective for treating a T-cell-mediated disease. So it may prove useful in transplantation.
Dr. Vincenti: We can begin to think about patients being treated with intermittent parenteral therapy -- and if we had SC formulations -- perhaps with weekly or every other week injections. In summary, the future of transplant therapeutics may belong to biologics. I'd like to thank my colleagues for this informative discussion of chronic biologic therapy, a new paradigm in kidney transplant immunosuppression. I'd also like to thank the audience for joining us today and for your participation in the Medscape continuing education program for physicians and other clinicians who care for solid organ transplant recipients.