Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

The basics of epithelial-mesenchymal transition

Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...

/pdf/safety-and-activity-of-anti-pd-l1-antibody-in-patients-with-2g1sbl9vc4.pdf

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

Introduction: Moving Toward a More Personalized Approach to Kidney Transplantation.

Purpose: Kidney transplant (KT) recipients with BK viremia are at risk for BK virus (BKV) nephropathy and graft loss. There are no approved therapies for BKV infection. Posoleucel (PSL) is an off-the-shelf, allogeneic multivirus-specific T cell therapy that targets BKV as well as adenovirus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and JC virus. In a phase 2 trial of PSL in hematopoietic cell transplant recipients, 100% (27/27) of those with BKV disease had a clinical response. Methods: We are conducting a phase 2 double-blind placebo (PBO)-controlled study of PSL in 60 KT recipients with BK viremia (NCT04605484) in which patients are randomized 1:1:1 to receive PSL (Groups 1 and 2) or placebo for 12 weeks. PSL (4 × 107 PSL cells) is infused once a week for 3 weeks, then every 14 days (Group 1) or every 28 days (Group 2). After these 12-week dosing periods, patients are followed for 12 more weeks (observation period). The primary objective is safety and tolerability with a key secondary objective to assess changes in BK viremia. Results: This interim analysis of the ongoing study includes the first 37 patients enrolled as of 22 Feb 2022; 29 (78%) patients were male and 8 (22%) were female; 20 (54%) Caucasian, 10 (27%) African American, 4 (11%) Asian, and 3 (8%) were other race or not reported; 3 (8%) patients were of Hispanic ethnicity. Patients’ median age was 58.5 years, with a range from 32 to 75 years. Median day of PSL or PBO initiation post KT was 472 days (range 59 to 5158 days). Mean eGFR at start of the dosing period was 48 mL/min/1.73m2 (SD ∓18), and median plasma BK viral load was 5060 copies/mL (range 242 to 5,421,939 copies/mL). At a median follow-up of 40.5 days (range 1 to 173 days), PSL was well tolerated with no treatment-related serious adverse events, and 12 mild (grade 1), transient treatment-related adverse events in 4 patients. There were no discontinuations due to adverse events or adverse events of special interest, specifically no episodes of graft versus host disease, cytokine release syndrome, infusion reactions, or rejection. No patients developed de novo donor-specific antibodies. Kidney allograft function as measured by eGFR and creatinine remained stable during the study, with no change from baseline to latest assessment in either measurement. Mean (95% CI) changes in eGFR and creatinine were 0.9 mL/min/1.73 m2 (-2.9, 4.7) and 0.0 mg/dL (-0.2, 0.1), respectively. Updated safety and viral load data from all enrolled patients will be presented, including analyses of the effect of PSL versus PBO on other immune and viral endpoints. Conclusions: In this ongoing trial—the first randomized, double-blind placebo-controlled therapeutic trial of virus-specific T cell therapy in KT recipients with BK viremia—PSL was generally safe and well tolerated, supporting its continued evaluation as a preemptive therapy in KT recipients at risk for BKV nephropathy. This study was funded by AlloVir. 

310.3: Posoleucel as Preemptive Therapy for BKV Infection in Kidney Transplant Recipients: Safety, Tolerability and Efficacy in a Phase 2 Trial

Agonistic and antagonistic interactions between CTLA4Ig and donor alloantigens in sensitized rat recipients of cardiac allografts.

Purpose of review Despite their effectiveness, calcineurin inhibitors (CNIs) represent a major obstacle in the improvement of long-term graft survival in transplantation. The identification of new agents to implement CNI-free regimens is the focus of current transplant research. The purpose of this review is to summarize the novel immunosuppressive agents, including details about their mechanisms of action, stages of development, potential benefits and challenges. Recent findings Targeting costimulation with belatacept is now an option for controlling the alloimmune response and has proved to be more effective in preserving long-term allograft function than CNIs despite an increased rate of acute rejection in some studies. mTOR inhibitors are also promising with their remarkable antineoplastic properties, though frequent side-effects may limit their broader use. Other agents under development include JAK inhibitors, CD40 blockade and leukocyte adhesion blockers, with unique potential benefits and side-effects in transplantation. Summary

C URRENT OPINION Beyond calcineurin inhibitors: emerging agents in kidney transplantation

Dysfunction of podocytes, cells critical for glomerular filtration, underlies proteinuria and kidney failure. Genetic forms of proteinuric kidney disease can be caused by mutations in several podocyte genes, including nephrin, a critical component of the kidney filter. In contrast, the etiology of acquired acute-onset nephrotic syndrome has remained elusive. Here we identify autoantibodies against nephrin in serum and glomeruli of a subset of adults and children with non-congenital acute nephrotic syndrome. Our findings align with published experimental animal studies and elucidate a novel autoimmune phenomenon in proteinuric kidney disease interfering with glomerular filter integrity.

/pdf/autoantibodies-against-nephrin-elucidate-a-novel-autoimmune-2z5hcrj9nc.pdf

Anil Chandraker

Papers

Introduction: Moving Toward a More Personalized Approach to Kidney Transplantation.

310.3: Posoleucel as Preemptive Therapy for BKV Infection in Kidney Transplant Recipients: Safety, Tolerability and Efficacy in a Phase 2 Trial

Agonistic and antagonistic interactions between CTLA4Ig and donor alloantigens in sensitized rat recipients of cardiac allografts.

C URRENT OPINION Beyond calcineurin inhibitors: emerging agents in kidney transplantation

Autoantibodies against nephrin elucidate a novel autoimmune phenomenon in proteinuric kidney disease