Nephrology Dialysis Transplantation 2007 22(5):1293-1296; doi:10.1093/ndt/gfl830
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Costimulation blockade—what will the future bring?
Flavio Vincenti
University of California, San Francisco, Kidney Transplant Service, San Francisco, California
Correspondence and offprint requests to: Flavio Vincenti, MD, Professor of Clinical Medicine and Surgery, University of California, San Francisco, Kidney Transplant Service, 505 Parnassus Avenue, Room 884M, San Francisco, CA 94143-0780. Email: vincentif{at}surgery.ucsf.edu
Keywords: belatacept; costimulation blockade; fusion receptor proteins
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Introduction
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The long and torturous road in the clinical development of costimulation
blockade came to fruition in 2005, with the approval of CTLA4Ig
(abatacept) for rheumatoid arthritis and the publication of
the promising results of the phase II trial in kidney transplantation
of belatacept (previously referred to as LEA29Y) [
1–3].
Harnessing the therapeutic potential of costimulation blockade,
an essential signal for T-cell activation, has been the focus
of translational research for the past 25 years [
1]. However,
the promising early results of either prolongation graft survival
or induction of tolerance using costimulation blockade in transplantation
experiments in rodents could not be reproduced in non-human
primates (NHP) [
4,
5]. While the discrepancies between the outcome
of transplantation in rodents and NHP treated with CTLA4Ig are
complex and multifactorial (i.e. differences in immune systems,
repertoire of memory T cells and environmental exposure), it
also became apparent that CTLA4Ig did not achieve as good an
affinity to CD86, as compared with CD80, and thus was not as
effective in a more stringent animal model such as the NHP [
5].
Belatacept, a re-engineered CTLA4Ig with two aminoacid substitutions
in the CTLA4 binding domains, bound CD80 2-fold better than
CTLA4Ig and CD86, 4-fold better than CTLA4Ig. The
in vitro superiority
of belatacept in blocking T-cell responses was soon confirmed
in better survival of renal allografts in NHP [
5]. In these
experiments, a CNI-free regimen with belatacept and a combination
of an anti-interleukin-2 receptor antibody (IL-2 mAb) and maintenance
therapy with mycophenolate mofetil (MMF) and steroids resulted
in marked prolongation of the survival of renal allografts.
Clearly however, these regimens did not induce tolerance.
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Chronic protein therapy—a novel delivery of immunosuppression
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The phase II trial of belatacept explored a novel approach in
the delivery of immunosuppression therapy with a regimen designed
for chronic biologic administrations [
6]. In this trial published
in the New England Journal in 2005, 218 patients were randomized
to either two belatacept treatment arms or ciclosporin and all
patients were treated with a similar regimen of basiliximab
induction (two doses of 20 mg) and maintenance therapy with
MMF and prednisone [
3]. Patients in the two belatacept arms
(less or intense or more intense treatments) were initially
treated with different frequency and dosage of belatacept, but
after 7 months of transplantation, were placed on the same regimen.
The primary endpoint was to demonstrate the non-inferiority
of belatacept over ciclosporin in the incidence of acute rejection
at 6 months. Secondary endpoints included differences in measured
glomerular filtration rate (GFR) and chronic allograft nephropathy
(CAN) at 12 months. At 6 months, the incidence of acute rejection
was similar between the two belatacept and the ciclosporin arms,
and the secondary endpoints at 12 months showed a significantly
higher GFR in patients treated with belatacept, as compared
with ciclosporin and CAN was less common in patients treated
with belatacept than with ciclosporin. In addition, patients
treated with belatacept had a more favourable metabolic profile.
An important concern with chronic biologic therapy is whether
it can be sustained over a prolonged period of time (>1 year).
As of August 2006, over 70 patients enrolled in the long-term
trial beyond 1 year have been treated with belatacept for
3
years.
Figure 1 shows the follow-up of 20 patients transplanted
at the University of California, San Francisco (UCSF), who enrolled
in the long-term belatacept trial and have been receiving this
therapy for over 3 years. Three patients discontinued the study
due to patient death (
n = 1), rejection following non-compliance
(
n = 1) and a successful conversion to tacrolimus because of
lack of transportation to the medical centre (
n = 1). All the
other patients continue to be on therapy, are doing well and
have had stable renal function. In the phase II trial, post-transplant
lymphoproliferative disease was reported in 3 patients, but
no other malignancies have been reported in the 3-year follow-up.
Currently, two large phase III trials are enrolling patients
to assess more definitively the efficacy and safety of belatacept.
The first trial is enrolling recipients of extended criteria
kidney donors. The second trial is designed for recipients of
standard kidneys from living or deceased donors. The immunosuppression
regimen in these phase III trials is similar to the one used
in the phase II trial, except that longterm all patients are
maintained on belatacept infusions every 4 weeks (in the phase
II trial, the 8 week regimen was associated with a higher incidence
of subclinical rejection). While the phase II study demonstrated
the efficacy of belatacept in preventing acute rejection, the
therapeutic potential of costimulation blockade should be ultimately
aimed beyond providing immunosuppression to actually inducing
tolerance. Costimulation blockade faces several challenges before
it can achieve its full therapeutic potential. At the present
time, it is unclear what is the best adjunct therapy with belatacept.
Ideally, both calcineurin inhibitors and steroids should be
avoided in tolerance-inducing regimens. In contrast, sirolimus
has been shown to have synergy when used with costimulation
blockade and has the added advantage of promoting growth of
T regulatory cells [
7]. In a NHP model of islet transplantation,
belatacept and sirolimus in the absence of calcineurin inhibitors
and steroids provided excellent immunosuppression [
8]. We are
exploring a similar protocol in a proof-of-concept trial supported
by the Immune Tolerance Network, combining belatacept therapy
with sirolimus in patients who receive kidneys from living donors
(
Figure 2). Patients without rejection and no evidence of anti-donor
alloreactivity (cellular or humoral) may be withdrawn from sirolimus
at 1 year and from belatacept at 2 years (the latter step only
if we are convinced that the patients exhibit a convincing molecular
signature for tolerance).
A strategy that may facilitate the tolerogenic potential of
costimulation blockade is the use of donor-specific transfusions.
Donor-specific transfusions prior to transplantation under the
umbrella of costimulation blockade can induce a state of anergy
and tolerance in rodent transplantation [
9–11].
Since strategies with one agent blocking a single costimulation pathway have been insufficient to induce tolerance, combination therapies targeting different pathways may prove more successful (Table 1). Several novel receptors and ligands in the costimulatory pathway are being characterized and may prove useful in tolerance-inducing strategies [12]. The list includes antagonists of T-cell activation pathway and agonists of inhibitory T-cell pathways [13]. However, as all these biologics are still experimental, their combined use faces regulatory challenges in designing clinical trials and intellectual property conflicts from the pharmaceutical/biotech companies. The most intriguing and realistic combination is belatacept with antagonists of the CD40-CD154 pathway [5,13]. Therapeutic targeting of the CD40-CD154 pathway has been of great interest to the transplant community, following the publication of the remarkable effects of anti-CD154 antibodies in prolonging allograft survival in rodents and NHP [14]. The combination of anti-CD154 and CTLA4Ig resulted in durable tolerance in experimental transplantation [5,13]. Unfortunately, the first human renal transplant trial using a humanized anti-CD154 mAb was associated with thromboembolic complications, which do not appear to be epitope-specific but are likely shared by all anti-CD154 antibodies [15,16]. Antibodies targeting CD154 are unlikely to be used clinically. Agonist and non-agonist antibodies to CD40 are currently being investigated in pre-clinical models of transplantation, as well as in clinical trials outside of transplantation. Chi220, a chimeric human anti-CD40 mAb, was particularly effective when combined with belatacept in renal allograft transplantation in rhesus monkeys [17]. Whether a combination of anti-CD40 and belatacept in combination with sirolimus can in fact induce tolerance or facilitate drug withdrawal remains to be determined.
Finally the combination of efazilumab, a humanized anti-LFA1
which appears to be promising in a phase I/II renal transplant
trial (and is available since it is marketed for psoriasis)
and costimulation blockade is being considered in investigator-initiated
trials in islet transplantation [
18].
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Costimulation blockade and T regulatory cells
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A potential concern of belatacept therapy is the adverse effect
of chronic CD28 blockade on T regulatory cells. Normal function
and homeostasis of T regulatory cells requires signalling through
CD28 [
19]. Prolonged depletion of T regulatory cells by costimulation
blockade could lead to chronic rejection and/or autoimmune diseases.
We have reported that patients treated with belatacept for 6
months to 3 years after transplantation had comparable levels
of T regulatory cells (CD4+CD25+) to controls (transplant patients
on calcineurin inhibitors and normal volunteers) [
20]. In these
preliminary studies, the suppressor function of T regulatory
cells in belatacept-treated patients appeared normal. Whether
these are generic or allloantigen-specific T regulatory cells
remains to be determined. Furthermore, we have found that belatacept-treated
patients had a significantly higher percentage of T regulatory
cells (detected by immunostaining for FoxP3) in their kidney
biopsies during acute rejection, as compared to CNI-treated
patients with rejection [
21]. Higher expression of FoxP3 mRNA
in the urine of patients with acute rejection has been reported
to be associated with improved outcome [
22].
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Conclusion
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The field of renal transplantation has reached a plateau in
terms of reduction of acute rejection and improvement in short-term
graft survival, but these gains have not been extended to long-term
graft survival. A new paradigm for immunosuppression, that provides
effective protection from acute and chronic rejection through
inhibition of selective pathways in T/B-cell activation without
the requirement of nephrotoxic agents (i.e. CNI) or drugs that
worsen cardiovascular risk factors (CNI and steroids), may be
required to finally improve long-term outcome. The promising
results of the phase II clinical trial in renal transplantation
with costimulation blockade, if confirmed by the ongoing two
phase III trials, will spur transplant physicians to explore
additional strategies to maximize the therapeutic potential
of costimulation blockade. Whether tolerance can be achieved
remains to be determined. It is clear though that a new era
of immunosuppression is emerging in transplantation.
Conflict of interest statement. Dr Vincenti received research grants from Bristol-Myers Squibb.
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Disclosure
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The results presented in this paper have not been published
previously in whole or part, except in abstract format.
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References
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- Vincenti F and Luggen M. (2007) T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. Annu Rev Med 58:23.
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Received for publication: 29.11.06
Accepted in revised form: 20.12.06
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