Interleukin-2 Receptor Antagonist Research Articles

Abstract 4079: EGL-001 is a novel immunocytokine designed to specifically target and disarm T regulatory cells in the tumor microenvironment

Abstract Introduction Immune checkpoint blockade (ICB) therapies targeting PD-1/PD-L1 or CTLA-4 have greatly improved clinical outcome in many cancers. However, multiple mechanisms of resistance to ICB severely limit the number of patients experiencing long-term survival benefits. Overcoming resistance to ICB represents a significant challenge for drug development. Regulatory T cells (Tregs) in the tumor microenvironment (TME) prevent effector T cells (Teffs) from mounting a productive immune response and have been implicated in ICB resistance. Novel therapeutic strategies aimed at disarming Tregs in the TME could restore anti-tumor responses and sensitize patients to ICB therapy. Treg survival is dependent on interleukin-2 (IL-2), which signals in Tregs via the high affinity IL-2 receptor (IL-2R). Tumor-associated Tregs differentiate from tumor-associated Teffs and from peripheral Tregs by higher expression of CD25, the IL-2R alpha chain. Tregs in the TME also express higher surface levels of CTLA-4 as compared to peripheral Tregs. Thus, CD25 and CTLA-4 overexpression could allow preferential targeting of tumor-associated Tregs. Methods and Results We used single-cell RNA sequencing data from cancer patients and flow cytometry analysis of human tumor samples to verify that CD25 and CTLA-4 are selectively overexpressed in tumor-associated Tregs as compared with peripheral Tregs or other T cells. Based on these findings, we developed EGL-001, a novel immunocytokine (ICK) comprising a humanized IgG1 directed against CTLA-4 fused to a Treg-specific IL-2R antagonist IL-2 mutein, to selectively target tumor infiltrating Tregs. EGL-001 IgG1 moiety binds membrane CTLA-4, as demonstrated by flow cytometry, and competes with CTLA-4-CD80/86 interaction, as evaluated by ELISA. EGL-001 IL-2 mutein moiety binds to CD25, as demonstrated by bio-layer interferometry, and specifically blocks high-affinity IL-2R signaling in Tregs. Signaling blockade is further potentiated by a CTLA-4 dependent CD25 downmodulation process evidenced by confocal microscopy and flow cytometry. We demonstrate that EGL-001 unique tumor-associated Treg-targeted dual mechanism of action results in increased Treg apoptosis and decreased Treg frequencies in multiple in vitro, ex vivo and in vivo systems. Importantly, EGL-001 only minimally affects IL-2 signaling and survival of Teffs, which are then expected to be unleashed from Treg cell-mediated suppression. Accordingly, EGL-001 induces anti-tumor responses in mice in combination with anti-PD1 therapy. Conclusions EGL-001 is an ICK with a novel and unique mechanism of action combining ICB and Treg selective IL-2 starvation, designed to specifically disarm and deplete tumor-associated Tregs. Based on our preclinical data, EGL-001 is being developed as a cancer immunotherapeutic to improve patients’ response to ICB and counteract ICB resistance. Citation Format: Fiorella Kotsias, Caroline Janot-Sardet, Pamela Pamela Caudana, Erica Russo, Marine Dubois, Andres Zucchetti, Mercedes Tkach, Sebastien Lemoine, Ilgar Z. Mamedov, Alvaro Lladser, Jordan Denizeau, Annalisa Meola, Christine Sedlik, Edith Borcoman, Felix Rey, Pablo Guardado-Calvo, Bernard Vanhove, Monica Gostissa, Eliane PIaggio. EGL-001 is a novel immunocytokine designed to specifically target and disarm T regulatory cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4079.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0–5%; PRA-0) and intermediately sensitized (PRA 6–84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

Induction immunosuppression and post-transplant diabetes mellitus: a propensity-matched cohort study.

Post-transplant diabetes mellitus (PTDM) is a common complication among cardiac transplant recipients, causing diabetes-related complications and death. While certain maintenance immunosuppressive drugs increase PTDM risk, it is unclear whether induction immunosuppression can do the same. Therefore, we evaluated whether induction immunosuppression with IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, or Alemtuzumab given in the peri-transplant period is associated with PTDM. We used the Scientific Registry of Transplant Recipients database to conduct a cohort study of US adults who received cardiac transplants between January 2008-December 2018. We excluded patients with prior or multiple organ transplants and those with a history of diabetes, resulting in 17,142 recipients. We created propensity-matched cohorts (n=7,412) using predictors of induction immunosuppression and examined the association between post-transplant diabetes and induction immunosuppression by estimating hazard ratios using Cox proportional-hazards models. In the propensity-matched cohort, the average age was 52.5 (SD=13.2) years, 28.7% were female and 3,706 received induction immunosuppression. There were 867 incident cases of PTDM during 26,710 person-years of follow-up (32.5 cases/1,000 person-years). There was no association between induction immunosuppression and post-transplant diabetes (Hazard Ratio= 1.04, 95% confidence interval 0.91 - 1.19). Similarly, no associations were observed for each class of induction immunosuppression agents and post-transplant diabetes. The use of contemporary induction immunosuppression in cardiac transplant patients was not associated with post-transplant diabetes.

Impact of Induction Immunosuppressants on T Lymphocyte Subsets after Kidney Transplantation: A Prospective Observational Study with Focus on Anti-Thymocyte Globulin and Basiliximab Induction Therapies.

Induction immunosuppressive therapy for kidney transplant recipients (KTRs) primarily includes interleukin-2 receptor antagonists, such as basiliximab (BXM) or lymphocyte-depleting agents, and anti-thymocyte globulin (ATG). This study aimed to investigate their effects on T cell dynamics during the early post-transplantation period. This prospective observational study included 157 KTRs. Peripheral blood samples were collected from each patient within 5 days before and 4 and 12 weeks after transplantation. Flow cytometric analysis was performed to assess various T cell subsets whose changes were then analyzed. In the ATG group, CD4+ T cell expression decreased significantly compared with that in the BXM group. However, CD4+CD161+ and CD4+CD25+CD127low T cell expression levels increased significantly. In the CD8+ T cell subset, a decrease in CD8+CD28nullCD57+ and CD8+CCR7+ T cell expression was observed in the ATG group. However, among patients diagnosed with biopsy-proven acute rejection, T cell subset expression did not significantly differ relative to non-rejection cases. In conclusion, ATG induction therapy resulted in more pronounced changes in T lymphocyte subsets than BXM induction, with increased CD4+CD161+ and CD4+CD25+CD127low T cells and an early decrease in CD8+CD28nullCD57+ and CD8+CCR7+ T cells, some of which are associated with acute rejection.

Unique Reduced-Intensity Conditioning Haploidentical Peripheral Blood Stem Cell Transplantation Protocol for Patients with Hematologic Malignancy

Reduced-intensity conditioning (RIC) haploidentical (haplo-) hematopoietic stem cell transplantation (HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs a stronger graft-versus-leukemia effect. Peripheral blood stem cells (PBSCs) offer advantages over bone marrow; however, the use of higher-dose non-T cell-depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft-versus-host disease (GVHD). This prospective, single-arm clinical study was performed to investigate using high-dose non-TCD in vitro PBSCs as the graft source, using fludarabine/Ara-C/busulfan (FAB) as the conditioning regimen, using rabbit antithymocyte globulin to remove T cells in vivo, and enhancing GVHD prophylaxis with an IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematologic malignancies age 50 to 70 years or <50 years with comorbidities (Hematopoietic Cell Transplantation Comorbidity Index score ≥2) classified as intermediate to high risk. The primary endpoint was day 100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range, 30 to 68 years), the median duration of follow-up was 34 months (range, 2 to 99 months), and the medium-infused doses of mononuclear cells, CD34+ cells, and CD3+ cells were 15.93×108/kg, 8.68×106/kg, and 5.57×108/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day 100 was 30.3% (95% confidence interval [CI], 15.9% to 44.8%), and that of grade III-IV aGVHD was 10.2% (95% CI, .6% to 19.8%). The 2-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI, 19.0% to 50.8%). The 2-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI, 11.80% to 40.40%) and 8.7% (95% CI, 3.26% to 20.65%), respectively. The 2-year cumulative incidence of relapse was 17.3% (95% CI, 5.1% to 29.5%), the 2-year overall survival rate was 71.2% (95% CI, 57.9% to 84.5%), and the 2-year disease-free survival rate was 66.2% (95% CI, 52.1% to 80.3%). The incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrates that this unique RIC-haplo-PBSC transplantation protocol was effective in treating hematologic malignancies. Nonetheless, larger prospective multicenter clinical trials and experimental studies should be performed to further confirm our findings.

Outcomes of Primary Simultaneous Pancreas-kidney Transplants by Induction Agent in the United States.

Utilizing the Scientific Registry of Transplant Recipients, we examined all primary SPK transplants between 2000 and 2020, excluding crossmatch-positive recipients. We grouped recipients according to induction regimen into 3 groups: rabbit anti-thymocyte globulin (r-ATG) (n = 5678), alemtuzumab (n = 1199), and interleukin-2 receptor antagonist (IL-2RA; n = 1593). We analyzed the 10-y recipient and composite (kidney and pancreas) graft survival using the Kaplan-Meier survival function. Cox-proportion hazard models were generated to examine the association between induction type, the 10-y recipient, and graft survival. Models were adjusted for recipient age, sex, ethnicity, HLA-mismatch, diabetes type, dialysis dependency, cold-ischemia time, local versus imported organs, panel reactive antibody, steroid maintenance, and Pancreas Donor Risk Index. r-ATG was associated with the lowest 1-y kidney and pancreas rejection rates compared with other agents (P < 0.001). In the univariable analysis, induction type was not associated with recipient (log-rank P = 0.11) or graft survival (log-rank P = 0.36). In the multivariable model for the composite graft survival, alemtuzumab use was associated with 22% increased kidney or pancreas graft loss compared with r-ATG (adjusted hazard ratio, 1.22; 95% confidence interval, 1.05-1.42), whereas IL-2RA use was not a predictor of graft survival. Induction type did not influence recipient survival in the adjusted model. r-ATG use was associated with the lowest SPK rejection rates. Compared with r-ATG, alemtuzumab but not IL-2RA was associated with worse long-term death-censored SPK graft outcome. Our analysis supports the common use of r-ATG for induction in US primary SPK recipients.

Basiliximab as maintenance immunosuppression in heart transplant recipients: A single pediatric center experience.

Pediatric heart transplant recipients are at risk for complications from prolonged exposure to immunosuppressive drugs, pharmacokinetic challenges in maintaining consistent immunosuppression, and medication non-adherence. Basiliximab (BAS), an interleukin-2 receptor antagonist, is used for induction therapy across many pediatric heart transplant centers, but use as maintenance immunosuppression has not been well described. This was a retrospective, single pediatric center cohort study of heart transplant recipients who received BAS for maintenance immunosuppression (defined as >2 monthly doses) from January 1, 2011, to December 31, 2021. Ten patients met study criteria with a median age of 17.5 (5-22)years and median 9.6 (1.2-18.9)years since transplant at time of BAS initiation. The primary indications for BAS use were recurrent rejection (n=4), fluctuating immunosuppression levels (n=3), and renal dysfunction (n=3). A median of 5.5 (3-32) monthly BAS doses were received. Three patients had a rejection event while on BAS. Calcineurin inhibitor exposure was reduced in 70% of patients. Three of the 10 patients were alive at last follow-up. There was one documented infection during BAS use, and no hypersensitivity reactions. Monthly BAS infusions were well tolerated and allowed for reduced calcineurin inhibitor exposure in most patients. Mortality commonly occurred despite BAS use, potentially reflecting the acuity of this patient cohort. BAS can be considered for maintenance immunosuppression in pediatric patients with fluctuating immunosuppressive levels and/or renal dysfunction. More studies are needed to determine long-term outcomes and explore expanded use of BAS in the pediatric heart transplant population.

Preemptive Second Kidney Transplant Outcomes by Induction Type in the United States

The role of induction in preemptive second kidney recipients is unclear. We examined the association between induction therapy and the long-term graft and recipient survival in the settings of tacrolimus and mycophenolate maintenance. We identified all preemptive second kidney transplant recipients between 2000 and 2020 in the Scientific Registry of Transplant Recipients. We excluded those with missing or mixed induction regimens and positive crossmatch. We grouped recipients by induction type into 3 groups: anti-thymocyte globulin (n=1442), alemtuzumab (n=362), and interleukin-2 receptor antagonist (IL-2RA; n=481). We generated Kaplan-Meier curves of the recipient and death-censored graft survival (DCGS) with follow-up censored at 10 years. We used multivariable Cox proportional hazards models to examine the association between induction and the above outcomes. We adjusted the models for recipient and donor variables. Rates of delayed graft function, rejection, hospitalization, and post-transplant lymphoproliferative disorder at one year were not statistically different. Recipient survival did not vary by induction type in the Kaplan-Meier analysis (log-rank P=.189) or in the multivariable model. However, DCGS was the lowest in the Alemtuzumab group (log-rank P=.01). In the multivariable models, alemtuzumab was associated with a 57% increased risk of graft loss (1.57, 95% confidence interval (1.08, 2.30), P=.019) compared to anti-thymocyte. Live-donor kidneys were associated with significantly better recipient survival and DCGS. Compared to anti-thymocyte induction, alemtuzumab, but not IL-2RA, was associated with inferior graft survival in preemptive second transplant recipients discharged on tacrolimus and mycophenolate.

311.7: Outcomes of Preemptive Second Kidney Transplant by Induction Type in the United States

Background: The role of induction in preemptive second kidney recipients is unclear. We examined the association between induction therapy and the long-term graft and recipient survival in the settings of tacrolimus and mycophenolate maintenance. Methods: We identified all preemptive second kidney transplant recipients between 2000 and 2020 in the Scientific Registry of Transplant Recipients. We excluded those with missing or mixed induction regimens and positive crossmatch. We grouped recipients by induction type into three groups: Anti-thymocyte globulin (n=1442), Alemtuzumab (n=362), IL-2 Receptor Antagonist (n=481). We generated Kaplan-Meier curves of the recipient and death-censored graft survival (DCGS) with follow-up censored at ten years. We used multivariable Cox Proportional Hazards models to examine the association between induction and the above outcomes. We adjusted the models for recipient and donor variables. Results: Rates of delayed graft function (DGF), rejection, hospitalization, and post-transplant lymphoproliferative disorder (PTLD) at one year were not statistically different. Recipient survival did not vary by induction type in the Kaplan-Meier analysis (log-rank P=0.189) or in the multivariable model.However, DCGS was the lowest in the Alemtuzumab group (log-rank P=0.01).In the multivariable models, alemtuzumab was associated with a 57% increased risk of graft loss [1.57, 95% C.I. (1.08, 2.30), P=0.019] compared to anti-thymocyte. Live-donor kidneys were associated with significantly better recipient survival [aHR 0.67, 95% C.I. (0.51, 0.89), P = 0.005] and DCGS [aHR 0.55, 95% C.I. (0.40, 0.76), P < 0.001]. Conclusion: Compared to anti-thymocyte induction, alemtuzumab, but not IL-2RA, was associated with inferior graft survival in preemptive second transplant recipients discharged on tacrolimus and mycophenolate.

245.3: Outcomes of Dialysis Dependent Second Kidney Transplant Recipients by Induction Type in the United States

Background: We examined the association between induction type for second kidney transplant in dialysis dependent recipients and the long-term outcomes. Material and Methods: Using the Scientific Registry od transplant Recipients SRTR standard analysis file, we identified all second kidney transplant recipients who returned to dialysis prior to re-transplantation. Exclusion criteria included: missing, unusual, or no-induction regimens, maintenance regimens other than tacrolimus and mycophenolate, and positive crossmatch status. We grouped recipients by induction type into three groups: Anti-thymocyte group (n=9899), Alemtuzumab group (n=1982) and IL-2 Receptor Antagonist group (n=1904). We analyzed recipient and death-censored graft survival (DCGS) using the Kaplan-Meier survival function with follow up censored at ten-year post-transplant. We used Cox proportional hazard models to examine the association between induction and the outcomes of interest. To account for center specific effect, we included center as a random effect. We adjusted the models for pertinent recipient and organ variables. Results: In the Kaplan-Meier analyses, induction type did not alter recipient survival (log-rank p=0.419) or DCGS (log-rank p=0.146). Similarly, in the fully adjusted models, induction type was not a predictor of recipient or graft survival. Live-donor kidney was a favorable predictor of recipient survival [HR 0.73, 95% C.I. (0.65, 0.83), p<0.001] and graft survival [HR 0.75, 95% C.I. (0.66, 0.85), p<0.001]. Publicly insured recipients had worse recipient and allograft survival outcomes. Conclusion: In this large cohort of second kidney transplant recipients, who were on dialysis prior to transplantation and discharged on tacrolimus and mycophenolate maintenance, induction type did not influence the outcomes of recipient or graft survival. Live-donor kidneys improved recipient and graft survival.

Interleukin - 2 Receptor Antagonists Induction Therapy in Simultaneous Heart - Kidney Transplantation

<h3>Purpose</h3> SRTR data currently suggests that induction therapy in simultaneous heart-kidney transplantation (SHKT) with rabbit antithymoglobulin (ATG) provides survival advantage compared to interleukin-2 receptor antagonist (IL2-RA). We are reporting the outcomes of recipients with SHKT treated with IL2-RA as induction therapy. <h3>Methods</h3> This is a single center, retrospective study of 26 patients who received SHKT at our institution from Dec 2018 to Oct 2021. A multidisciplinary team composed of heart and kidney transplant medical and surgical members determined appropriate recipient-donor SHKT candidate pairs. The majority of patients received IL2-RA induction therapy, and all patients received triple immunosuppression therapy with prednisone, mycophenolate mofetil and tacrolimus. Adjustments in long term therapy were made in collaboration between the heart and kidney transplant teams. <h3>Results</h3> From Dec 2018 to Oct 2021, 26 patients underwent SHKT. 23 patients (88%) were male, the median age was 57 years, and 5.4% were ≥ 65 years. 18 patients (69%) had non ischemic cardiomyopathy and 24 patients (92%) had CKD (mean GFR ≤ 35%). 18 patients were listed Status 2 and 2 patient Status 5. One patient received a DCD donor and 12 patients (46%) received hep C donors. 25 patients (96%) received induction therapy with IL2-RA. During the first 3 months post-transplant, the only patient who received ATG had 7 severe infections; 11 patients (44%) and 13 patients (52%) who received IL2 -RA had no infections and ≤ 4 mild infections, respectively. One patient died due to COVID 19 pneumonia complicated by multisystem organ failure. For a median follow up period of 410 (187-707) days, 8% patients in the IL2-RA induction cohort experienced a 2R/3A heart rejection, 8% patients remained on HD due to primary kidney graft non-function, and the survival rate was 96%. <h3>Conclusion</h3> Compared with present literature, our data support the use of IL2- RA as an induction strategy in SHKT with excellent patient survival.

The Impact of Induction Immunosuppression Agent on Retransplant-Free and Bronchiolitis Obliterans-Free Survival in Sensitized Lung Transplant Recipients

<h3>Purpose</h3> There is significant variability in induction immunosuppression for sensitized (PRA≥1%) and highly sensitized (PRA>60%) lung transplant recipients. We compared retransplant-free and bronchiolitis obliterans (BOS)-free survival among sensitized recipients based on cytolytic versus interleukin-2 receptor antagonist (IL2-RA) versus corticosteroid only induction. <h3>Methods</h3> This was a retrospective study sensitized adult lung transplant recipients in SRTR from 5/5/2005-5/31/2019. Subjects were categorized according to cytolytic (ATG, OKT3, alemtuzumab), IL2-RA (daclizumab, basiliximab), or corticosteroid-only induction. Cox proportional-hazard models were used to compare retransplant-free survival and BOS-free survival according to induction, adjusting for clinical covariates. <h3>Results</h3> Of the 5696 included recipients, 1281 (22.5%) received cytolytic, 3057 (53.7%) IL2-RA, and 908 (15.9%) corticosteroid-only induction. Compared to IL2-RA, cytolytic induction was associated with improved adjusted retransplant-free survival (HR=0.80, 95% CI=0.05-1.00, p=0.052) and improved adjusted BOS-free survival (HR=0.79, 95% CI=0.88-0.97, p=0.009) (Figure 1). Cytolytic induction was also associated with decreased need for plasmapheresis after index hospitalization (OR=0.47, p=0.04). Among highly sensitized recipients (n=712) cytolytic induction (n=161) was not associated with retransplant-free (p=0.51) or BOS-free survival (p=0.73) compared to IL2-RA (n=551). Among all sensitized recipients, the use of corticosteroid-only induction was associated with worse BOS-free survival (HR=1.19, 95% CI=1.08-1.31, p<0.001). <h3>Conclusion</h3> The use of cytolytic induction compared to IL2-RA is associated with a small improvement in retransplant-free and BOS-free survival among sensitized lung transplant recipients. Corticosteroid-only induction is associated with worse BOS-free survival.

Basiliximab versus Methylprednisolone for Induction in Adult Heart Transplantation

<h3>Purpose</h3> Induction immunosuppression in heart transplant (OHTX) recipients varies greatly by center. Roughly 50% receive induction immunosuppression and no regimen has been shown to improve survival. Basiliximab (BAS) is an IL-2 receptor antagonist used as induction in OHTX. The objective of this retrospective study was to compare rejection, infection, and mortality within the first-year following heart transplant in patients who received BAS or steroid induction. <h3>Methods</h3> This was a retrospective cohort study of adult OHTX recipients given BAS or steroid induction from 1/1/2017 to 5/31/2021. Previous organ transplant or multi-organ transplant patients were excluded. Induction strategy was determined by chart review. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 1 year post-transplant. Secondary endpoints included ACR at 90 days post-transplant, incidence of antibody-mediated rejection (AMR) at 90 days and one year, incidence of infections (CMV, bacterial, fungal), and mortality after discharge at 1 year. <h3>Results</h3> 108 patients received BAS and 26 patients received steroid induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the steroid induction group (27.7 vs 68.2%, p < 0.002). Additionally, BAS was associated with a lower probability of having a rejection event during the first-year post-transplant (figure 1; p < 0.001). There was a statistically significant difference in CMV infections between BAS and steroid induction at 30- and 90-days post-transplant (0 vs 4%, p = 0.04; 0 vs. 8%, p = 0.004) but no difference in bacterial or fungal infections within the first 30 or 90 days. There was no difference in mortality after hospital discharge at one-year post-transplant (6 vs 0%, p = 0.20). <h3>Conclusion</h3> BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred induction strategy for patients undergoing heart transplantation.

Restrictive Rather Than Routine Use Of Basiliximab For Heart Transplant Induction

Introduction The use of immunosuppression induction strategies greatly varies between heart transplant (HT) centers. Clinicians must weigh the risk of allograft rejection with infection and malignancies. Our center stopped routine induction with the Interleukin-2 receptor antagonist basiliximab in 2016 after findings of increased infection, malignancy, and a trend towards higher mortality. Hypothesis We aimed to assess the effect of our protocol change abandoning routine use of basiliximab on survival, allograft rejection, infection, and malignancy. Methods Retrospective single-center analysis of consecutive HT recipients from 2003 to 2015 and 2017-2019. In 2016 the induction protocol was changed, and the adjustment period was excluded. Furthermore, patients bridged to transplant with LVAD, re-transplantation and multi-organ transplants were not included. Results : A total of 398 patients were identified (mean age 55±11, 72% male) and grouped by induction with basiliximab or no induction. There were no clinically significant differences in baseline characteristics between the groups including age, panel reactive antibody % (PRA) and kidney function (Table). One-year mortality was significantly lower in the no-basiliximab group 1.9 vs 6.75% p 0.03 (Figure 1). Multivariate regression for basiliximab, PRA, age, gender, diabetes mellitus, creatinine did not identify independent risk factors for mortality. Significantly more patients in the no-basiliximab group had ≥ 1 rejection (≥ 2R ISHLT 2004) 68 vs 44% with significantly lower rejection free survival (p 0.0001) per log-rank test (Figure 2). There was no longer a significant difference in rates of bacterial and fungal infections as well as CMV-viremia and malignancies during the first-year post-transplant year. Conclusion Restrictive rather than routine use of basiliximab induction is no longer associated with increased infectious and early malignancy but remains associated with inferior survival despite lower incidence of early rejection and comparable immunological risk based on PRA. In the future improved individual immunologic risk profiling might be helpful to better risk stratify transplant candidates, who might benefit from induction. The use of immunosuppression induction strategies greatly varies between heart transplant (HT) centers. Clinicians must weigh the risk of allograft rejection with infection and malignancies. Our center stopped routine induction with the Interleukin-2 receptor antagonist basiliximab in 2016 after findings of increased infection, malignancy, and a trend towards higher mortality. We aimed to assess the effect of our protocol change abandoning routine use of basiliximab on survival, allograft rejection, infection, and malignancy. Retrospective single-center analysis of consecutive HT recipients from 2003 to 2015 and 2017-2019. In 2016 the induction protocol was changed, and the adjustment period was excluded. Furthermore, patients bridged to transplant with LVAD, re-transplantation and multi-organ transplants were not included. : A total of 398 patients were identified (mean age 55±11, 72% male) and grouped by induction with basiliximab or no induction. There were no clinically significant differences in baseline characteristics between the groups including age, panel reactive antibody % (PRA) and kidney function (Table). One-year mortality was significantly lower in the no-basiliximab group 1.9 vs 6.75% p 0.03 (Figure 1). Multivariate regression for basiliximab, PRA, age, gender, diabetes mellitus, creatinine did not identify independent risk factors for mortality. Significantly more patients in the no-basiliximab group had ≥ 1 rejection (≥ 2R ISHLT 2004) 68 vs 44% with significantly lower rejection free survival (p 0.0001) per log-rank test (Figure 2). There was no longer a significant difference in rates of bacterial and fungal infections as well as CMV-viremia and malignancies during the first-year post-transplant year. Restrictive rather than routine use of basiliximab induction is no longer associated with increased infectious and early malignancy but remains associated with inferior survival despite lower incidence of early rejection and comparable immunological risk based on PRA. In the future improved individual immunologic risk profiling might be helpful to better risk stratify transplant candidates, who might benefit from induction.

A Transplant Center Experience with Basiliximab Induction Strategies - A Double Edged Sword?

<h3>Purpose</h3> The benefit of immunosuppression induction for heart transplant (HT) is debated given potential risks of infection and malignancy. Here, we report 18 years of patient outcomes from a large HT center to define the risks and benefits of Interleukin-2 receptor antagonist basiliximab (BX) induction when used as standardized induction or in selected patients only. <h3>Methods</h3> Retrospective single-center analysis of 475 consecutive HT recipients from 2003-2020. Patients were grouped by use of induction strategy in basiliximab group (BG) and no-basiliximab group (NBG). A subgroup analysis by era compared 2003-2015 standard BX induction and 2016-present with selective BX use. <h3>Results</h3> There were no clinically significant differences in gender and age between BG and NBG, though BG patients had lower baseline GFR than the NBG (62.8 vs 73.2, p=0.001) as well as higher PRA (p=0.01) (Fig A). When adjusted for confounders (sex, age, PRA, GFR) the BG was less likely to have acute cellular rejection (ACR) (OR 0.42, p <0.001), but had more antibody mediated rejection (AMR) (OR 11.7, p < 0.001) and more cardiac allograft vasculopathy at 5-years post HT (OR 3.8, p=0.04). There was no difference between BG and NBG in ejection fraction, DSA, malignancies and infections. When stratified by era (2003-2015 vs. 2016-present), ACR remains less common in the BG than NBG (35% vs 50%, p=0.045) while AMR remained more common (9.7 vs 0% p=0.005).In the pre-2016 the BG had more DSA (0 vs 11%, p <0.001). Notably there was no significant difference in survival comparing pre-and post-2016 NBG group, however both pre-2016 BG and post-2016 BG have significantly higher mortality (p=0.045 and 0.03) during post HT year 1-5 (Fig B). <h3>Conclusion</h3> Basiliximab reduces the incidence of ACR but increases AMR and CAV possibly associated with increased mortality both with use of standard and selective induction protocols. Further mechanistic studies are needed to describe a T-cell escape mechanism with enhanced humoral immunity and late complications.

Use and Outcomes of Induction Therapy in Well-Matched Kidney Transplant Recipients.

The optimal induction treatment in low-immune risk kidney transplant recipients is uncertain. We therefore investigated the use and outcomes of induction immunosuppression in a low-risk cohort of patients who were well matched with their donor at HLA-A, -B, -DR, -DQB1 on the basis of serologic typing. Our study was an observational study of first adult kidney-only transplant recipients in the United States recorded by the Organ Procurement and Transplant Network. Among 2976 recipients, 57% were treated with T cell-depleting antibodies, 28% were treated with an IL-2 receptor antagonist, and 15% were treated without induction. There was no difference in allograft survival, death-censored graft survival, or death with function between patients treated with an IL-2 receptor antagonist and no induction therapy. In multivariable models, patients treated with T cell-depleting therapy had a similar risk of graft loss from any cause, including death (hazard ratio, 1.19; 95% confidence interval, 0.98 to 1.45), compared with patients treated with an IL-2 receptor antagonist or no induction. The findings were consistent in subgroup analyses of Black recipients, patients grouped by calculated panel reactive antibody, and donor source. The incidence of acute rejection at 1 year was low (≤5%) and did not vary between treatment groups. Use of induction therapy with T cell-depleting therapy or IL-2 receptor antagonists in first kidney transplant recipients who are well matched with their donor at the HLA-A, -B, -DR, -DQB1 gene loci is not associated with improved post-transplant outcomes.

The impact of induction therapy on mortality and treated rejection in cardiac transplantation: A retrospective study

Evidence regarding the utility of routine induction therapy on outcomes is not clear. This study aims to evaluate whether induction therapy is associated with a reduced risk of treated rejection and improved overall survival. We retrospectively analyzed all adult patients (age ≥ 18 years) that are included in the UNOS database who underwent heart transplantation between 2000 and 2017. Patients with prior transplants and dual organ transplants were excluded. 34,361 patients were included in the final analysis. We assessed the impact of induction therapy with T cell depleting agents (TC-DA), IL2 receptor antagonists (IL2R antagonist) and compared that to no induction therapy using Cox regression models adjusted for propensity scores. The primary outcome measure was all-cause mortality, whereas treated rejection at one year was analyzed as a secondary outcome measure (available in 77% of patients). A total of 52% of the cohort did not receive any induction therapy. A total of 27% received IL2R antagonist and the rest received TC-DA. Median age of the recipients was 55 (IQR: 46-62) years. A total of 25% of the population were women and 39% were supported on left ventricular assist device therapy at the time of transplantation. Median follow-up was 4.2 (IQR: 1.1-8.5) years with 32% reported mortality. Multivariate analysis with propensity score adjustment showed that TC-DA induction did not have any effect on mortality (HR=0.98, 95% CI 0.93-1.03, p=0.48). However, IL2R antagonist was associated with a modestly increased risk of all-cause mortality compared to no induction (HR=1.06, 95% CI 1.01-1.11, p=0.02, respectively). A total of 25% of patients were found to have treated rejection at one year, TC-DA induction was associated with reduced odds of rejection at one year (OR=0.82, 95% CI 0.76-0.88, p < 0.001). However, induction with IL2R antagonist was not found to have a significant impact (OR=1.03, 95% CI 0.96-1.11, p = 0.36). Compared to no induction therapy, induction with TC-DA was associated with reduction in risk of treated rejection at 1 year with no effect on mortality and IL2R antagonist was associated with a small but statistically significant increase in mortality without any impact on risk of rejection.

Abstract 11003: Racial Disparities in Induction Immunosuppression Use Among Heart Transplant Recipients in the United States

Introduction: Black heart transplant recipients have higher rates of acute rejection, graft failure, and mortality compared to other races. Induction immunosuppression in the immediate peri-transplant period may lower the risk of acute rejection among high-risk patients, including Black transplant recipients. However, it is not known whether the odds of receiving this treatment are different across races. Therefore, we evaluated whether there are disparities in the use of induction immunosuppression following heart transplants among Black patients compared to other races. Methods: We conducted a cross-sectional study of U.S. adults in the Scientific Registry of Transplant Recipients who received their first heart transplant between 2008 - 2018. We used mixed-effects logistic regression to compare the odds of receiving induction immunosuppression agents (IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, and CD52 monoclonal antibodies) across different races. Results: Among 23,935 adult heart transplant recipients, 5,160 (21.6%) were Black, including 2,797 (54.2%) who received induction immunosuppression, and 18,775 (78.4%) were non-Black, including 9,499 (50.6%) who received induction immunosuppression. After accounting for demographic and clinical characteristics and treatment center, Black race was associated with 28% higher odds (Odds Ratio=1.28, 95% CI 1.17-1.40) of induction immunosuppression use compared to other races. Similar results were observed when race was further stratified (Table 1). Conclusions: In our study, Black heart transplant recipients were more likely to receive induction immunosuppression than transplant recipients of other races. However, further research on post-transplant clinical outcomes including survival following induction immunosuppression among Black patients is needed to formulate treatment guidelines.

Impact of induction therapy on outcomes after heart transplantation

Abstract Introduction Approximately 50% of heart transplant (HT) programs currently employ a strategy of induction therapy (IT) with either interleukin-2 receptor antagonists (IL2RA) or polyclonal anti-thymocyte antibodies (ATG) during the early postoperative period. However, the overall utility of such therapy is uncertain and data comparing induction protocols are limited. Methods Adult HT recipients were identified in the United Network for Organ Sharing (UNOS) registry between 1990 and 2020. Patients were grouped according to administration of induction in the post-operative period after HT. Accounting for re-transplantation, Fine and Gray's test compared cumulative incidences of all-cause mortality between groups. Univariate and multivariate analysis were performed using the competing risk model. The risk of treated rejection and hospitalization for infection or rejection was analyzed with multivariable logistic regression. Results A total of 63,849 HT recipients were included in the study and among those 59% did not receive induction, 16.6% received ATG, 19.1% IL2RA, 0.7% alemtuzumab, and 4.6% OKT3. Since 2000 IL2RA is the most frequently used form of induction therapy whereas OK3 is not used in the past decade. In multivariable logistic regression models, use of ATG is associated with lower risk of treated rejection at one year after HT (relative risk ratio 0.55, 95% CI 0.47–0.63, p&amp;lt;0.001) compared with no induction whereas IL2RA had similar risk of treated rejection. Similarly, the risk of rejection requiring hospitalization was significantly lower with ATG than no induction. No significant differences in rates of infection requiring hospitalization were noted between groups. Moreover, no differences in rates of post-transplant lymphoproliferative disease and any malignancy were noted between those receiving induction versus no induction. Adjusted all-cause mortality was significantly lower among those treated with ATG than patients that did not receive induction therapy (sub-hazard ratio 0.72, 95% CI 0.63–0.82, p&amp;lt;0.001) (Figure). Conclusion Induction therapy with IL2RA is the most used approach. ATG is associated with lower risk of treated rejection and all-cause mortality than no induction and IL2RA. Funding Acknowledgement Type of funding sources: None.

Meta-Analysis of Interleukin-2 Receptor Antagonists as the Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Corticosteroid is the first-line treatment for aGVHD, but its response rate is only approximately 50%. At present, no uniformly accepted treatment for steroid-refractory aGVHD (SR-aGVHD) is available. Blocking interleukin-2 receptors (IL-2Rs) on donor T cells using pharmaceutical antagonists alleviates SR-aGVHD. This meta-analysis aimed to compare the efficacy and safety of four commercially available IL-2R antagonists (IL-2RAs) in SR-aGVHD treatment. A total of 31 studies met the following inclusion criteria (1): patients of any race, any sex, and all ages (2); those diagnosed with SR-aGVHD after HSCT; and (3) those using IL-2RA-based therapy as the treatment for SR-aGVHD. The overall response rate (ORR) at any time after treatment with basiliximab and daclizumab was 0.81 [95% confidence interval (CI): 0.74–0.87)] and 0.71 (95% CI: 0.56–0.82), respectively, which was better than that of inolimomab 0.54 (95% CI: 0.39–0.68) and denileukin diftitox 0.56 (95% CI: 0.35–0.76). The complete response rate (CRR) at any time after treatment with basiliximab and daclizumab was 0.55 (95% CI: 0.42–0.68) and 0.42 (95%CI: 0.29–0.56), respectively, which was better than that of inolimomab 0.30 (95% CI: 0.16–0.51) and denileukin diftitox 0.37 (95% CI: 0.24–0.52). The ORR and CRR were better after 1-month treatment with basiliximab and daclizumab than after treatment with inolimomab and denileukin diftitox. The incidence of the infection was higher after inolimomab treatment than after treatment with the other IL-2RAs. In conclusion, the efficacy and safety of different IL-2RAs varied. The response rate of basiliximab was the highest, followed by that of daclizumab. Prospective, randomized controlled trials are needed to compare the efficacy and safety of different IL-2RAs.