Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

https://www.nejm.org/doi/pdf/10.1056/NEJMra033540

Immunosuppressive Drugs for Kidney Transplantation

Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study

Background. Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. Methods. In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. Results. At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P<0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. Conclusions. Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.

This article provides a comprehensive, up-to-date review of methods to prevent early and late renal-allograft loss and to improve long-term outcomes in patients. The authors focus particular attention on the problem of late graft loss and discuss current antirejection therapy, including calcineurin blockers such as cyclosporine and tacrolimus, the interleukin-2 signal-transduction inhibitor sirolimus, and the purine-synthesis inhibitor mycophenolate mofetil, which inhibits the proliferation of T cells and B cells.

Strategies to improve long-term outcomes after renal transplantation.

A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).

Background The search for more effective and less toxic immunosuppressive agents to control transplant rejection has led to the extensive testing of mycophenolate mofetil (MMF) in clinical renal transplantation. Methods A pooled analysis of three phase III, randomized, double-blind, multicenter clinical trials conducted in the United States, Canada, Europe, and Australia was performed to further characterize the efficacy of MMF in renal allograft recipients. The three studies enrolled a total of 1493 patients. Triple- and quadruple-therapy regimens of cyclosporine, corticosteroids, and standardized MMF dosages with and without antilymphocyte induction were used: MMF in twice-daily doses of 1.0 g or 1.5 g (MMF 2 g or 3 g) was compared with placebo (PLA) or azathioprine (AZA). The primary efficacy endpoint in the individual trials was biopsy-proven rejection or treatment failure at 6 months. This pooled analysis focused on graft loss, patient death, incidence and treatment of rejection episodes, and graft function (serum creatinine) at 1 year. Results At 1 year, the graft survival rate was 90.4% and 89.2% in the MMF 2 g and 3 g groups, respectively, compared with 87.6% in the PLA/AZA group. This difference was not statistically significant. MMF significantly reduced the incidence of rejection episodes: 40.8% for PLA/AZA patients versus 19.8% and 16.5% for the MMF 2 g and MMF 3 g groups, respectively. Renal function was consistently better for both MMF treatment groups at 3, 6, and 12 months. Conclusions MMF proved superior to AZA as a posttransplant immunosuppressant in conjunction with cyclosporine and corticosteroids. MMF-treated groups showed reduced incidence and severity of rejection episodes, similar graft survival, and better graft function over 12 months.

Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups

6028 Background: ISA101b (peltopepimut-S), a therapeutic vaccine against the HPV-specific E6/E7 oncoproteins, induces specific expansion of HPV16 targeted T-cells when given together with cemiplimab, an anti-PD-1 agent. Previously we showed that ISA101 with nivolumab achieved a higher response rate compared to immune checkpoint inhibitor (ICI) alone in trials for patients with recurrent/metastatic (R/M) HPV16+ oropharyngeal cancer (OPC)1,2. Methods: In this single arm phase 2 study, patients with R/M HPV16+ OPC with progressive disease (PD) within 6 months after prior 1st or 2nd line anti-PD-1 ICI were treated with ISA101b (subcutaneously 100µg/peptide on days 1, 29, and 50) with cemiplimab (intravenously 350mg as a 3-weekly regimen) until PD. Patients without PD at 6 months were offered a booster ISA101b injection. HPV16 positive tumor status was confirmed by a central reference laboratory with an established PCR assay. The primary efficacy endpoint was defined as overall response rate (ORR) as per RECIST1.1. An analysis was planned at the end of Stage 1, when 26 patients who had received at least one dose of ISA101b had been followed for 6 months. The cut-off date for this analysis, approved by the DSMB, was 31 January 2023. Results: Twenty-six patients (mean age 60.7 ±12.9 years; 22 (84.6%) male and 4 (15.4%) female) enrolled in Stage 1. Median follow-up was 16.2 weeks (range 1.6-78.8). Three patients were confirmed with partial response (PR) (11.5%); two of the 3 patients with PR never responded to previous ICI treatment. In 13 patients (50.0%) best overall response (BOR) was stable disease (SD); in 8 patients (30.8%) BOR was PD. Two (7.7%) patients did not have a tumor assessment after baseline: one patient died on day 8 due to OPC and one patient withdrew consent shortly after enrolment. The clinical benefit ratio (CBR) was 61.5%. Nine (34.6%) patients received a booster injection. At the time of the booster, 2 patients had PR and 5 patients had meaningful (≥6 months) SD. Time to response ranged between 127 and 307 days. Median duration of study treatment was 13.1 weeks (range 1.1-75.9), with 4 patients still on treatment. There were two grade 3 adverse events (AEs) related to ISA101b: erythema at the injection site and diarrhea. Two patients (7.7%) had grade 3 ICI-related auto-immune events. Grade 4-5 AEs related to study treatment did not occur. Median overall survival was 8.1 months (range 0.3-17.5). Conclusions: This treatment appears promising for HPV16+ OPC patients who failed prior anti-PD-1 ICI therapy, with an ORR of 11.5% and a CBR of 61.5%. In this small, ongoing study the combination of cemiplimab and ISA101b was well tolerated with a safety profile resembling anti-PD-1 monotherapy. This is the first study of the combination of ISA101b and cemiplimab in 2nd/3rd line R/M anti-PD-1 refractory OPC patients. 1Massarelli E. JAMA Oncol 2019 2de Sousa LG. J Immunother Cancer 2022. Clinical trial information: NCT04398524 .

L Hooftman

Papers

Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups

Phase 2 study of ISA101b (peltopepimut-S) and cemiplimab in patients with advanced HPV16+ oropharyngeal cancer who failed anti-PD1 therapy.