The role of immunosuppressive agents in the management of severe and refractory immune‐related adverse events

The advent of immune checkpoint inhibitors has improved survival in some types of cancer and brought promising prospects to cancer immunotherapy. Despite their clinical benefits, significant off‐target toxicities resulting from the immune system activation have been observed, namely immune‐related adverse events (irAEs), which pose to clinicians a new challenge of optimal management. With steroids being the mainstay of current management of irAEs, immunosuppressive agents are especially indicated for severe or steroid‐refractory cases, based on current immunopathophysiological knowledge and on extrapolations of treatment options for primary autoimmune disorders. This review focuses on the status and recent clinical progress of immunosuppressive agents in the management of severe and steroid‐refractory irAEs.     

Higher rates of rejection in HIV‐infected kidney transplant recipients on ritonavir‐boosted protease inhibitors: 3‐year follow‐up study

Rejection rates in HIV‐infected kidney transplant (KTx) recipients are higher than HIV‐negative recipients. Immunosuppression and highly active antiretroviral therapy (HAART) protocols vary with potentially significant drug‐drug interactions, likely influencing outcomes. This is an IRB‐approved, single‐center, retrospective study of adult HIV‐infected KTx patients between 5/2009 and 12/2014 with 3‐year follow‐up, excluding antibody‐depleting induction. A total of 42 patients were included; median age was 52 years, 81% male, 50% African American, 29% Hispanic, 17% Caucasian. The most common renal failure etiology was hypertensive nephrosclerosis (50%) with 5.8 median years of pre‐transplant dialysis. All patients received IL‐2 receptor antagonist, were maintained on tacrolimus (76%) or cyclosporine (17%), and 40% received ritonavir‐boosted PI‐based HAART (rtv+) regimen. Patient and graft survival at 3 years were 93% and 90%. At 1‐, 2‐, and 3‐year time points, median serum creatinine was 1.49, 1.35, and 1.67; treated biopsy‐proven rejection was 38%, 38%, and 40.5%; and 92% of episodes were acute rejection. At these time points, rejection rates were significantly higher with boosted PI HAART regimens compared to other HAART regimens, 59% vs 24% (P = 0.029), 59% vs 24% (P = 0.029), and 68% vs 24% (P = 0.01). Despite higher rejection rates, HIV‐infected KTx recipients have reasonable outcomes. Given significantly higher rejection rates using rtv+ regimens, alternative HAART regimens should be considered prior to transplantation.     

The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

Immune checkpoint inhibitors are among the newest, cutting‐edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD‐1/PD‐L1 and CTLA‐4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the “Don't Eat Me” molecule, CD47, antibody‐based drugs that target the macrophage‐related innate immunosuppressive signalling pathway, CD47‐SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti‐CD47 antibodies, a second “Don't Eat Me” molecule on tumour cells, beta 2 microglobulin (β2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition. However, other tumour cells highly express β2m complexed with the MHC class I heavy chain to send a “Don't Eat Me” signal by binding to leucocyte immunoglobulin‐like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I‐LILRB1 signalling axis in tumour‐associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical‐based tumour immunotherapy.     

镰形棘豆黄酮苷元对免疫抑制小鼠细胞因子的影响

目的:研究藏药镰形棘豆黄酮苷元对免疫抑制小鼠细胞因子的影响。方法:将60只昆明种小鼠随机分为6组:空白组,模型组,镰形棘豆黄酮苷元高、中、低剂量组(336、168、84 mg/kg)和盐酸左旋咪唑组(25 mg/kg),每组10只。镰形棘豆黄酮苷元高、中、低剂量组分别灌胃不同剂量的黄酮苷元;盐酸左旋咪唑组灌胃左旋咪唑25 mg/kg;空白组和模型组灌服等体积5%吐温-80溶液,共10天。第8天开始注射环磷酰胺制备免疫低下小鼠模型,除空白组腹腔注射生理盐水外,其他各组分别腹腔注射环磷酰胺,共3天。采用酶免仪分别测定血清中白细胞介素1、2、4、8、10(IL-1、IL-2、IL-4、IL-8、IL-10),肿瘤坏死因子α(TNF-α),干扰素γ(IFN-γ)的含量及脾淋巴细胞培养上清液中IL-2、IL-4、IL-10、TNF-α、IFN-γ的含量,观察镰形棘豆黄酮苷元对免疫抑制小鼠细胞因子的影响。结果:与模型组比较,镰形棘豆黄酮苷元各剂量组能有效升高免疫抑制小鼠血清和脾淋巴细胞培养液中各细胞因子的含量,差异有统计学意义(P0.05)。结论:镰形棘豆黄酮苷元能够拮抗环磷酰胺所致小鼠的免疫抑制作用,增强小鼠的免疫功能。     

Association of Anti-PLA2R Antibodies with Outcomes after Immunosuppressive Therapy in Idiopathic Membranous Nephropathy

Background

The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A₂ receptor (PLA₂R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate.

Design, setting, participants, & measurements

This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months. Patients were prospectively followed, and outcome was ascertained up to 5 years after completion of immunosuppressive therapy. Serum samples were collected before and after completion of therapy. PLA₂R antibodies were determined retrospectively in stored samples using ELISA.

Results

In total, 48 patients (37 men) were included. The median age was 55 years (range, 34–75), and the median serum creatinine level was 1.60 mg/dl (range, 0.98–3.37 mg/dl). Twenty-two patients received MMF and 26 received CP. At baseline, PLA₂R-abs were present in 34 patients (71%). Baseline characteristics and outcome did not significantly differ between patients negative or positive for PLA₂R-ab. In PLA₂R-ab–positive patients, treatment resulted in a rapid decrease of antibodies: median anti–PLA₂R-ab, 428 U/ml (range, 41–16,260 U/ml) at baseline and 24 U/ml (range, 0–505 U/ml) after 2 months. The PLA₂R-ab levels at baseline did not predict initial response, but antibody status at end of therapy predicted long-term outcome: After 5 years, 14 of 24 (58%) antibody-negative patients were in persistent remission compared with 0 of 9 (0%) antibody-positive patients (P=0.003).

Conclusions

These data suggest that in PLA₂R-ab–positive patients, measuring PLA₂R-abs at the end of therapy predicts the subsequent course.     

First‐line choice for severe aplastic anemia in children: Transplantation from a haploidentical donor vs immunosuppressive therapy

We retrospectively compared the outcomes of children with severe aplastic anemia (SAA) who received immunosuppressive therapy (IST) or who underwent hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (HID), between 2007 and 2016. A total of 52 children with SAA under the age of 17 years were initially treated with IST (n = 24) or haploidentical HSCT (n = 28) as first‐line treatment. The estimated 10‐year overall survival was 73.4 ± 12.6% and 89.3 ± 5.8% in patients treated with IST or HID‐HSCT (P = .806). The failure‐free survival was significantly inferior in patients receiving IST than in those undergoing transplantation from an HID (52.6 ± 10.5% vs 89.3 ± 5.8, P = .008). In univariate and multivariate analysis, the choice of first‐line immunosuppressive therapy was the only adverse predictor for failure‐free survival. At the last follow‐up, completely normal blood count was observed in 11 of 20 (55.0%) and 24 of 25 (96.0%) live cases in IST and HID‐HSCT cohort (P = .003). These suggest that HSCT from a haploidentical donor could be considered as first‐line treatment in children who lack a matched related donor, especially in experienced transplantation centers.