Belatacept-treated Patients Research Articles

Conversion from calcineurin inhibitors to belatacept-based immunosuppressive therapy skews terminal proliferation of non-classical monocytes and lowers lymphocyte counts

Belatacept, a modified form of CTLA-Ig that blocks CD28-mediated co-stimulation of T cells, is an immune-suppressant that can be used as an alternative to calcineurin inhibitors (CNIs). In kidney transplant recipients, belatacept has been associated with improved renal function and reduced cardiovascular toxicity. Monocytes as well as T-lymphocytes play causal roles in the pathophysiology of atherosclerotic disease. We hypothesized that the beneficial impact of the use of belatacept over CNIs on cardiovascular risk could be partly explained by the impact of belatacept therapy on these circulating leukocytes. Hence, we phenotyped circulating leukocytes in transplanted patients with a stable renal function that were randomized between either continuation of CNI or conversion to belatacept in two international studies in which we participated. In 41 patients, we found that belatacept-treated patients consistently showed lower numbers of B-lymphocytes, T-lymphocytes as well as CD14-negative monocytes (CD14NM), especially in non-diabetic patients. Our observation that this decrease was associated to plasma concentrations of TNFα is consistent with a model where CD14NM-production of TNFα is diminished by belatacept-treatment, due to effects on the antigen-presenting cell compartment.

CD86 occupancy in belatacept-treated kidney transplant patients is not associated with clinical and infectious outcomes

The CD86 occupancy assay has been developed to measure the number of CD86molecules unbound to belatacept, but its association with clinical outcomes has not been assessed yet. All kidney transplant patients switched to belatacept in our center between 2016 and 2018 were included. Blood samples were collected before each infusion for 1year to assess CD86 occupancy by CD86 antibody cytometry staining on the surface of CD14+ monocytes. Results were expressed as the median fluorescence intensity (MFI) value of CD86staining. At each infusion, the MFIDay of infusion /MFIDay 0 ratio was calculated. Forty-one patients were consecutively included. After every 2-week infusion period, CD86MFI ratio dropped from 1.00 to 0.73 [0.57-0.98], p=.07. However, this ratio progressively increased to 0.78 [0.53-1.13] at 1year, which was not statistically different from pre-switch ratio, p=.4. Over the first year, the MFI ratio coefficient of variation was 31.58% [23.75-38.31]. MFI ratio was not different between patients with or without opportunistic infections: 0.73 [0.60-0.88] versus 0.80 [0.71-1.00], p=.2, or between patients with or without EBV DNAemia, p=.2. Despite previous in vitro results, the CD86 occupancy assay suffers from a high intra-individual variability and does not appear to be relevant to clinical outcomes.

Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients.

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor–treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses, counts and relative frequencies of spike receptor binding domain–specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo–activated programmed cell death 1–positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients.

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients.

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination.

Humoral and Cellular Immune Responses of Solid Organ Transplant Patients on Belatacept to Three Doses of mRNA-Based Anti-SARS-CoV-2 Vaccine.

Background: Two doses of anti-SARS-CoV-2 mRNA-based vaccines are poorly immunogenic in solid organ transplant recipients (SOT). Methods: In total, 68 belatacept-treated SOT recipients followed at the Toulouse University Hospital were investigated. They were given three injections of the BNT162b2 mRNA COVID-19 vaccine. Their humoral response was assessed by determining anti-spike antibodies and neutralizing antibodies. The T-cell responses were assessed using an enzyme-linked immunospot assay that measured the interferon-γ produced by specific SARS-CoV-2 T-cells in a subgroup of 17 patients. Results: Only 23.5% of these patients developed a detectable anti-spike response. Moreover, the cellular and the humoral responses were well correlated. Patients with no humoral response were also without a detectable cellular response. Those belatacept-treated patients who developed an Anti-SARS-CoV-2 humoral response were younger, had been transplanted for longer, and had a higher lymphocyte count and a better glomerular filtration rate than those with no response. Finally, patients on tacrolimus plus belatacept produced a lower immune response. Conclusions: Belatacept-treated SOT recipients have a reduced immune response to anti-SARS-CoV-2 mRNA vaccination. The vaccine should be given quite separately from the belatacept infusion to improve immunogenicity. Studies to assess whether switching to another immunosuppressive regimen can improve the post-vaccination immune response would be useful.

SARS-CoV-2 Vaccination, Immune Responses, and Antibody Testing in Immunosuppressed Populations: Tip of the Iceberg.

SARS-CoV-2 Vaccination, Immune Responses, and Antibody Testing in Immunosuppressed Populations: Tip of the Iceberg.

Anti-SARS-CoV-2 T-cell Responses After mRNA Vaccination in Belatacept-treated Renal Transplant Patients.

Dear Editor, We read with interest the recent letter by Chavarot et al1 on the humoral and T-cell responses after 2 injections of mRNA vaccine in kidney transplant recipients. The authors reported a low sero-conversion rate at day 60 and a T-cell response in only 30.4% of the patients measured. Importantly, the T-cell response was measured by IFNγ-EliSpot after stimulation with overlapping peptide pools for SARS-CoV-2 spike protein. We would like to further discuss the determination of the T-cell response, as it has important implications for the interpretation of the findings. The safety and efficacy of mRNA vaccines have been demonstrated in numerous clinical studies, and, in most of these studies, vaccine-specific T-cell responses were reported.2-4 In these studies, next to IFNγ EliSpot, T cells were detected in addition by flow cytometry to characterize the cytokine profile. Sahin et al3 found in a phase I/II study that BNT161b1 elicited a strong Th1 response. In most of the experimental groups, IL-2 producing T-cells dominated over IFNγ producing T-cells or even IFNγ+IL-2+ T cells. A similar observation was made in a phase I/II trial on BNT162b2 as reported in preprint by Sahin et al.4 In a phase I study on the mRNA-1273 vaccine, Anderson et al2 demonstrated that vaccine-specific T-helper-cell responses measured on day 43 were of the Th1 type. However, the IL-2 response by T helper cells was greater than the IFNγ response but lower than the TNFα response.2 This effect was consistent over 2 different age groups ranging from 56 to 70 y of age and ≥71 y of age. Thus, vaccine-specific T-cell responses are not restricted to IFNγ producing Th1 cells. We would like to point out that the lack of T-cell response reported by Chavarot et al may not give a comprehensive information on the overall T-cell response to vaccination in renal transplant patients as an IFNγ EliSpot was the only readout.1 IL-2 or TNFα single positive T helper cells are not detected in this assay but usually evolve after vaccination in healthy people. Thus, renal transplant patients may well harbor vaccine-specific T-cell immunity upon vaccination. Additionally, it remains unclear whether the impaired Th1 response is a mainly belatacept-dependent effect as suggested by the authors. From our point of view, this is not exclusively related to the inhibition of costimulation but to the high-grade immunosuppressive regimen after kidney transplantation. In summary, the measurement of vaccine-specific T-cell responses is complex and a comprehensive characterization of vaccine-specific T-cell responses is necessary to draw conclusions on the immunogenicity of BNT162b2 in renal transplant patients. Nevertheless, the present study provides substantial evidence that vaccine responses in kidney transplant patients should be monitored and individualized vaccination strategies might be needed in this vulnerable cohort.

The impact of belatacept on the phenotypic heterogeneity of renal T cell–mediated alloimmune response: The critical role of maintenance treatment and inflammatory load

Belatacept offers superior long-term outcome relative to calcineurin inhibitor (CNI)-based immunosuppression. However, the higher frequency of early T cell-mediated rejection (TCMR) in belatacept-treated patients hampered the widespread adoption of costimulation blockade. Here, we applied gene expression analysis and whole-slide inflammatory cell quantification to assess the impact of belatacept on intragraft immune signature. We studied formalin-fixed, paraffin-embedded renal biopsies from 92 patients stratified by histopathologic diagnosis (TCMR, borderline changes, or normal) and immunosuppression regimen (belatacept, CNI). An interaction model was built to explore maintenance treatment-dependent expression level changes of immune response-related genes across diagnostic categories of normal, borderline changes, and TCMR. Ninety-one percent of genes overexpressed in TCMR showed significant correlation with whole section inflammatory load. There were 27 genes that had a positive association with belatacept treatment. These were mostly related to myeloid cells and innate immunity. Genes negatively associated with costimulation blockade (n=14) could be linked to B-cell differentiation and proliferation. We concluded that expression levels of genes characteristic of TCMR are strongly interconnected with quantitative changes of the biopsy inflammatory load. Our results might suggest differential involvement of the innate immune system, and an altered B-cell engagement during TCMR in belatacept-treated patients relative to CNI-treated referents.

CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept.

Cytomegalovirus (CMV) remains associated with poor outcomes after kidney transplantation (kTx). The impact of belatacept on CMV infection remains understudied. In this study, we assessed the impact of belatacept on patient and graft survivals. CMV seronegative kTx recipients were included. Patient and graft survival were studied using Kaplan-Meier method, log-rank test. Cox models were used to compare outcomes by CMV risk and immunosuppressive regimen. Incidence and persistence of CMV viremia under belatacept vs tacrolimus were compared. Among 308 CMV seronegative recipients, 168 CMV high-risk and 203 belatacept-treated patients were included. High-risk CMV status was associated with lower patient survival and graft survival. Among the CMV high-risk group, patients treated with belatacept presented a higher incidence of CMV viremia, a higher rate of first-line treatment failure and a longer time to virus clearance. They had a nonsignificant trend toward a lower graft survival. Belatacept-based maintenance immunosuppression is associated with an increased risk of CMV primary-infection and a prolonged course of viral replication in CMV high-risk patients. Further studies are needed to confirm the nonsignificant trend towards a lower graft survival in CMV high-risk patients treated with belatacept and whether it is explained by the higher risk of CMV reactivation and infection.

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial.

Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept-based CNIA/ESW regimens with a tacrolimus-based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti-thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease-calculated eGFR of <45mL/min/1.73m2 at 12months. Results are reported by treatment group (alemtuzumab/belatacept, rATG/belatacept, and rATG/tacrolimus). Superiority was not observed at 1year for the primary endpoint (9/107 [8.4%], 15/104 [14.4%], and 14/105 [13.3%], respectively; P=NS) for either belatacept-based regimen. Differences were not observed for secondary endpoints (death, death-censored graft loss, or estimated glomerular filtration rates<45mL/min/1.73m2 ). Differences were observed in biopsy-proved acute cellular rejection (10.3%, 18.3%, and 1.9%, respectively) (P<.001), but not in antibody-mediated rejection, mixed acute rejection, or de novo donor-specific anti-HLA antibodies. Neurologic and electrolyte abnormality adverse events were less frequent under belatacept. Belatacept-based CNIA/ESW regimens did not prove to be superior for the primary or secondary endpoints. Belatacept-treated patients demonstrated an increase in biopsy-proved acute cellular rejection and reduced neurologic and metabolic adverse events. These results demonstrate that simultaneous CNIA/ESW is feasible without excessive acute rejection.

Ex vivo expansion of regulatory T cells from long-term Belatacept-treated kidney transplant patients restores their phenotype and suppressive function but not their FOXP3 TSDR demethylation status

We recently reported that Tregs from long-term Belatacept-treated kidney transplant patients displayed an altered phenotype and impaired suppressive function compared to Tregs from healthy controls. However, it remains unknown whether ex vivo expansion of Tregs from patients who underwent long-term immunosuppression may be feasible to be used in their treatment. In this work, Tregs from Belatacept-treated patients were polyclonally expanded in vitro in the presence of rapamycin and IL-2. After four weeks of expansion, Tregs from patients expressed high levels of FOXP3, CD25, CTLA-4, Helios and CCR7, and showed strong suppressive activity, even in the presence of pro-inflammatory cytokines. However, FOXP3 TSDR demethylation remained lower in expanded Tregs from Belatacept-treated patients compared to healthy control Tregs. These data suggest that ex vivo expansion of Tregs from patients undergoing long-term immunosuppression may require the use of epigenetic modifying agents to stabilize FOXP3 expression to be considered as treatment in kidney transplant patients.

The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients.

Recent evidence suggests that belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ≥98% to 100%, the impact of belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on belatacept consecutively for at least 6months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in belatacept-treated patients compared to controls who did not receive belatacept. Specifically, significant HLA antibody reduction was evident for class I (P<.0009). Posttransplant belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P<.01). Collectively, these findings suggest belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.

Targeted Proteomic Analysis Detects Acute T Cell-Mediated Kidney Allograft Rejection in Belatacept-Treated Patients.

There is an unmet need for reliable minimally invasive diagnostic biomarkers for immunological allograft monitoring and for the detection of acute kidney transplant rejection. Here, targeted proteomic analysis was applied to compare 92 proteins in sera of belatacept-treated patients who had biopsy-proven, acute T-cell-mediated rejection (aTCMR) with patients without aTCMR. Proximity extension immunoassay was used to measure 92 inflammation-related protein concentrations in the prerejection and rejection sera of 11 patients with aTCMR and 9 patients without aTCMR. This assay uses 2 matched oligonucleotide-labeled antibody probes for each protein and polymerase chain reaction to measure normalized protein expression values. Five proteins (CD5, CD8A, NCR1, TNFRSF4, and TNFRSF9) were expressed significantly higher in samples with aTCMR compared with samples without aTCMR (adjusted P-value < 0.014) and had a good predictive capacity for aTCMR [area under the curve in a receiver-operator curve ranged from 0.83 to 0.91 (P < 0.014)]. These proteins are associated with CD8 cytotoxic T-cell and NK cell functions. Nonhierarchical clustering analysis showed distinct clustering of samples with aTCMR and samples without aTCMR. This clustering was not found in prerejection samples (1 month after transplantation). In prerejection samples, IFN-γ was expressed at a significantly lower level (normalized protein expression value median -0.15, interquartile range: -0.27 to 0.04) than in samples of patients without rejection (median 0.13, interquartile range: -0.07 to 0.15, adjusted P-value = 0.00367). Targeted proteomic analysis with proximity extension immunoassay is a promising minimally invasive technique to diagnose aTCMR in kidney transplant recipients.

Immunomics of Renal Allograft Acute T Cell-Mediated Rejection Biopsies of Tacrolimus- and Belatacept-Treated Patients.

Belatacept-based therapy in kidney transplant recipient has been shown to increase long-term renal allograft and patient survival compared with calcineurin inhibitor-based therapy, however, with an increased risk of acute T cell-mediated rejection (aTCMR). An improved understanding of costimulation blockade-resistant rejections could lead to a more personalized approach to belatacept therapy. Here, immunomic profiles of aTCMR biopsies of patients treated with either tacrolimus or belatacept were compared. Formalin-fixed paraffin-embedded renal transplant biopsies were used for immunohistochemistry and gene expression analysis using the innovative NanoString technique. To validate NanoString, transcriptomic profiles of patients with and without biopsy-proven aTCMR were compared. Biopsies from 31 patients were studied: 14 tacrolimus-treated patients with aTCMR, 11 belatacept-treated patients with aTCMR, and 6 controls without rejection. A distinct pattern was seen in biopsies with aTCMR compared to negative controls: 78 genes had a higher expression in the aTCMR group (false discovery rate P value <.05 to 1.42e-05). The most significant were T cell-associated genes (CD3, CD8, and CD4; P < 1.98e-04), γ-interferon-inducible genes (CCL5, CXCL9, CXCL11, CXCL10, TBX21; P < 1.33e-04) plus effector genes (GNLY, GZMB, ITGAX; P < 2.82e-03). Immunophenotypical analysis of the classic immune markers of the innate and adaptive immune system was comparable between patients treated with either tacrolimus or belatacept. In addition, the transcriptome of both groups was not significantly different. In this small pilot study, no difference was found in immunomics of aTCMR biopsies of tacrolimus- and belatacept-treated patients. This suggests that clinically diagnosed aTCMR reflects a final common pathway of allorecognition which is unaffected by the type of immunosuppressive therapy.

Analysis of NFATc1 amplification in T cells for pharmacodynamic monitoring of tacrolimus in kidney transplant recipients.

BackgroundTherapeutic drug monitoring (TDM) of tacrolimus, based on blood concentrations, shows an imperfect correlation with the occurrence of rejection. Here, we tested whether measuring NFATc1 amplification, a member of the calcineurin pathway, is suitable for TDM of tacrolimus.Materials and methodsNFATc1 amplification was monitored in T cells of kidney transplant recipients who received either tacrolimus- (n = 11) or belatacept-based (n = 10) therapy. Individual drug effects on NFATc1 amplification were studied in vitro, after spiking blood samples of healthy volunteers with either tacrolimus, belatacept or mycophenolate mofetil.ResultsAt day 30 after transplantation, in tacrolimus-treated patients, NFATc1 amplification was inhibited in CD4+ T cells expressing the co-stimulation receptor CD28 (mean inhibition 37%; p = 0.01) and in CD8+CD28+ T cells (29% inhibition; p = 0.02), while this was not observed in CD8+CD28- T cells or belatacept-treated patients. Tacrolimus pre-dose concentrations of these patients correlated inversely with NFATc1 amplification in CD28+ T cells (rs = -0.46; p < 0.01). In vitro experiments revealed that 50 ng/ml tacrolimus affected NFATc1 amplification by 58% (mean; p = 0.02).ConclusionIn conclusion, measuring NFATc1 amplification is a direct tool for monitoring biological effects of tacrolimus on T cells in whole blood samples of kidney transplant recipients. This technique has potential that requires further development before it can be applied in daily practice.

Belatacept and Autoimmune Adverse Events

Belatacept is widely used to prevent rejection in kidney transplants with its excellent tolerability profile. Here, we report a severe psoriasis manifesting in a kidney transplant recipient raising the possibility of belatacept-induced autoimmunity. Our patient was a 42-year-old man with an end-stage renal disease secondary to anti neutrophil cytoplasmic antibody-associated vasculitis. In January 2014, more than 2 years after receiving rituximab as treatment, he underwent primary renal transplantation (with 1 B mismatch). Immunosuppressive induction therapy consisted of anti-IL2R (basiliximab), whereas maintenance therapy consisted of mycophenolic acid and tacrolimus delivered at their standard regular dosages. On day 10 postoperation, a graft biopsy revealed marked thrombotic microangiopathy. Tacrolimus toxicity was suspected and tacrolimus was substituted with belatacept (5 mg/kg monthly) with an excellent result (serum creatinine, 100 μmol/L). In September 2014, physical examination revealed psoriatic plaques, confirmed by skin biopsy. Topical treatment with calcipotriol was introduced. In July 2016, because of a deterioration in his skin condition, we decided to stop mycophenolic acid and commence ciclosporin. Despite an initial improvement, the psoriasis progressively deteriorated (Figure 1). Therapeutic strategies were constrained, because in this transplant recipient, phototherapy and most biologic therapies were contraindicated. In February 2017, we decided to stop belatacept and reintroduce mycophenolic acid. A few weeks after its discontinuation, the plaques progressively disappeared, and complete resolution was finally observed.FIGURE 1: Diffuse well-demarcated psoriasis form plaques.Several factors suggest a casual association between this exposure and the development of the lesions: (i) our patient had neither a personal nor familial history of psoriasis; (ii) its onset at 7 months of costimulation blockade could be plausible (see below); (iii) rapid improvement was observed after its removal; (iv) a biological plausibility to explain this effect can be found. Psoriasis has been reported in patients with rheumatoid arthritis treated with abatacept.1 Regarding the pooled safety data of the BENEFIT trials, a similar frequency of autoimmune-related adverse events (AEs) between belatacept-treated recipients and ciclosporin-treated controls has been observed. However, psoriasis was the most common autoimmune disorder to manifest in belatacept-treated patients, whereas hyperthyroidism was the most frequent to manifest in controls. In the susceptible patient, belatacept could dysregulate immunity in different ways. First, by inhibiting regulatory T (Treg) cells either quantitatively or qualitatively.2 Indeed, abatacept and belatacept are both CTLA4-Ig fusion proteins antagonizing CD80-86, the ligand for CD28 (essential to Treg generation and maintenance) and CTLA-4 (crucial for Treg functions). Second, belatacept blocks the CTLA-4 inhibitory pathway on memory T cells. Belatacept-resistant rejection is thought to be due to alloreactive memory T cells, which are less dependent on CD28 signaling for their activation and are regulated by CTLA-4 intrinsic mechanisms.3 Krummey and Cheeseman4 demonstrated that interleukin 17-secreting T helper (Th17) cells are especially sensitive to CTLA-4 coinhibition and resistant to costimulation blockade. Psoriasis and inflammatory bowel disease, for which a belatacept-induced case has been recently reported,5 are both Th17 mediated. Pharmacovigilance in the “real life” transplant setting often yields new safety concerns about rare drug-related adverse events. Transplant community physicians should be aware that the use of belatacept after kidney transplantation may be implicated in psoriasis occurrence. Patient data were obtained from the DIVAT clinical cohort (divat.fr) ethically approved: N8CNIL 891735 version 2, August 2004.

Increased Pretransplant Frequency of CD28+ CD4+ TEM Predicts Belatacept-Resistant Rejection in Human Renal Transplant Recipients.

While most human T cells express the CD28 costimulatory molecule constitutively, it is well known that age, inflammation, and viral infection can drive the generation of CD28null T cells. In vitro studies have demonstrated that CD28null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28null cells may precipitate costimulation blockade-resistant rejection. However, CD28+ cells possess more proliferative and multifunctional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those who did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28+ CD4+ TEM prior to transplant were more likely to experience acute rejection following treatment with a belatacept-based immunosuppressive regimen. Mechanistically, CD28+ CD4+ TEM contained significantly more IL-2 producers. In contrast, CD28null CD4+ TEM isolated from stable belatacept-treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pretransplant frequencies of CD28+ CD4+ TEM could be used as a biomarker to predict risk of rejection following treatment with belatacept.

A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation.

Belatacept, an inhibitor of the CD28-CD80/86 costimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus far, no biomarker for belatacept-resistant rejection has been validated. In this randomized-controlled trial, acute rejection rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated. Forty kidney transplant recipients were 1:1 randomized to belatacept or tacrolimus combined with basiliximab, mycophenolate mofetil, and prednisolone. The 1-year incidence of biopsy-proven acute rejection was monitored. Potential biomarkers, namely, CD8CD28, CD4CD57PD1, and CD8CD28 end-stage terminally differentiated memory T cells were measured pretransplantation and posttransplantation and correlated to rejection. Pharmacodynamic monitoring of belatacept was performed by measuring free CD86 on monocytes. The rejection incidence was higher in belatacept-treated than tacrolimus-treated patients: 55% versus 10% (P = 0.006). All 3 graft losses, due to rejection, occurred in the belatacept group. Although 4 of 5 belatacept-treated patients with greater than 35 cells CD8CD28 end-stage terminally differentiated memory T cells/μL rejected, median pretransplant values of the biomarkers did not differ between belatacept-treated rejectors and nonrejectors. In univariable Cox regressions, the studied cell subsets were not associated with rejection-risk. CD86 molecules on circulating monocytes in belatacept-treated patients were saturated at all timepoints. Belatacept-based immunosuppressive therapy resulted in higher and more severe acute rejection compared with tacrolimus-based therapy. This trial did not identify cellular biomarkers predictive of rejection. In addition, the CD28-CD80/86 costimulatory pathway appeared to be sufficiently blocked by belatacept and did not predict rejection.

Belatacept in kidney transplantation - past and future perspectives.

Calcineurin inhibitors (CNIs) are used widely for maintenance immunosuppression in renal transplant recipients. However, their side effect profile has led researchers to attempt to find safer alternatives that can maintain effective long-term immunosuppression with less toxicity. Belatacept is a CTLA4-Ig molecule designed to block the costimulatory B7-CD28 signal needed for activation of effector T cells. While it has shown great promise in clinical trials, it has made halting progress towards replacing CNIs in actual clinical practice. The BENEFIT trial revealed some of the advantages of belatacept in terms of maintaining renal function after transplant and reducing some of the metabolic side effects of CNIs related to hypertension and dyslipidemia. Despite that, some cautionary signals have emerged as well, in that belatacept-treated patients experience higher acute rejection rates and greater risk for PTLD. Furthermore, the requirement for monthly intravenous infusions has presented logistical and cost challenges for widespread adoption.

Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial

In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. 36-month follow-up of the intention-to-treat population. CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2). At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect= 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). Exploratory post hoc analysis with a small sample size. Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.