Immune mechanisms of toxicity from checkpoint inhibitors

Trends in cancer, Journal Year: 2023, Volume and Issue: 9(7), P. 543 - 553

Published: April 27, 2023

Immunotherapy has changed the treatment landscape for cancer over past decade. Inhibitors of immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset patients with metastatic disease. However, these treatments be limited by inflammatory toxicities that affect any organ system body some cases life threatening. Considerable progress been made understanding drivers as well effective management strategies. Further research into molecular cellular mechanisms drive toxicity will enable better prediction development optimized therapies avoid interfering antitumor immunity. In this review, we discuss our current from inhibitors (ICIs) propose optimal strategies toxicities.

Language: Английский

---

Immunosurveillance in clinical cancer management

CA A Cancer Journal for Clinicians, Journal Year: 2023, Volume and Issue: 74(2), P. 187 - 202

Published: Oct. 25, 2023

The progression of cancer involves a critical step in which malignant cells escape from control by the immune system. Antineoplastic agents are particularly efficient when they succeed restoring such (immunosurveillance) or at least establish an equilibrium state that slows down disease progression. This is true not only for immunotherapies, as checkpoint inhibitors (ICIs), but also conventional chemotherapy, targeted anticancer agents, and radiation therapy. Thus, therapeutics stress kill while provoking tumor-targeting response, referred to immunogenic cell death, useful combination with ICIs. Modern oncology regimens increasingly using combinations, chemoimmunotherapy, well combinations multiple However, latter generally associated severe side effects compared single-agent Of note, success these combinatorial strategies against locally advanced metastatic cancers now spurring successful attempts move them past postoperative (adjuvant) setting preoperative (neoadjuvant) setting, even patients operable cancers. Here, authors critically discuss importance immunosurveillance modern clinical management.

Language: Английский

---

Review of the Immune Checkpoint Inhibitors in the Context of Cancer Treatment

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(13), P. 4301 - 4301

Published: June 27, 2023

Checkpoint proteins are an integral part of the immune system and used by tumor cells to evade response, which helps them grow uncontrollably. By blocking these proteins, checkpoint inhibitors can restore capability attack cancer stop their growth. These findings backed adequate clinical trial data presently, several FDA-approved exist in market for treating various types cancers, including melanoma, hepatocellular, endometrial, lung, kidney others. Their mode action is inhibition targeting CTLA-4, PD-1, PD-L1, etc. They be alone as well amalgamation with other treatments, like surgery, radiation or chemotherapy. Since drugs target only specific side effects reduced comparison traditional chemotherapy drugs, but may still cause a few affects fatigue, skin rashes, fever. In rare cases, known have caused more serious effects, such cardiotoxicity, inflammation intestines lungs. Herein, we provide overview role biomarkers, immune-related adverse outcomes studies treatment present some future perspectives.

Language: Английский

---

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

Cancers, Journal Year: 2024, Volume and Issue: 16(7), P. 1440 - 1440

Published: April 8, 2024

The landscape of cancer treatment has undergone a significant transformation with the introduction Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit potential risk developing immune-related adverse events (irAEs). Here, we reviewed discussed mechanisms action ICIs their pivotal role in regulating immune system to enhance anti-tumor response. We scrutinized intricate pathogenic responsible for irAEs, arising from evasion self-tolerance checkpoints due drug-induced modulation. also summarized main manifestations irAEs categorized by organ types, detailing incidence associated factors. occurrence is more frequent when are combined; neurological, cardiovascular, hematological, rheumatic commonly linked PD1/PD-L1 inhibitors cutaneous gastrointestinal prevalent CTLA4 inhibitors. Due often-nonspecific signs symptoms, diagnosis (especially those rare ones) can be challenging. differential primary autoimmune disorders becomes sometimes intricate, given pathophysiological similarities. In conclusion, considering escalating use ICIs, this area research necessitates additional studies practical insights, especially development biomarkers predicting toxicities. addition, there need heightened education both clinicians patients understanding awareness.

Language: Английский

---

Distinct subtypes of post‐transplant lymphoproliferative disorders: CHIP‐like mutations in early lesions and substantial mutational differences between EBV‐positive and EBV‐negative diffuse large B‐cell lymphomas

British Journal of Haematology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Summary Post‐transplant lymphoproliferative disorders (PTLD) and lymphomas in immunocompromised individuals represent significant clinical challenges, with a limited understanding of their pathogenesis. We investigated PTLD cohort ( n = 50) consisting ‘early lesions’ (infectious mononucleosis‐like PTLD, plasmacytic follicular hyperplasias), polymorphic post‐transplant diffuse large B‐cell (PT‐DLBCL). The study also included 15 DLBCL autoimmune/immunocompromised backgrounds (IS‐DLBCL) 14 DLBCL, not otherwise specified (DLBCL, NOS), as control. To investigate microarchitectural genetic changes, immunohistochemistry, multiplex immunofluorescence (mIF), fluorescence situ hybridisation high‐throughput sequencing were performed. Scarcity viral infections other than Epstein–Barr virus (EBV) was observed. mIF revealed lower Treg infiltration PT‐DLBCL high CD8 + /PD1 T cells IS‐DLBCL. MYC rearrangements most common PT‐DLBCL, followed by IS‐DLBCL NOS, all EBV‐negative. TP53 mutations frequent EBV‐negative NOS but absent lesions’. NOTCH1 predominant (N1 DLBCL‐subgroup). Gene expression profiling showed overlap between PTLD. presence clonal haematopoiesis indeterminate potential (CHIP)‐like the absence immune‐escape gene suggest these may expansions driven exogenic immunosuppression and/or EBV infection ‘substituting’ for latter group genes.

Language: Английский

---

Immune‐Mediated Liver Injury From Checkpoint Inhibitor: An Evolving Frontier With Emerging Challenges

Liver International, Journal Year: 2025, Volume and Issue: 45(2)

Published: Jan. 27, 2025

ABSTRACT Over the past decade, immune checkpoint inhibitors (ICIs) have transformed treatment of cancer, though they come with risk immune‐related adverse (irAEs) events such as hepatotoxicity or Immune‐mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation ICI and initiation immunosuppression. Cytotoxic T Lymphocytes (CTLs) play central role in ILICI; however, are just part picture immunotherapy broadly impacts all aspects microenvironment can directly indirectly activate innate adaptive cells. Clinically, our understanding this entity grows, we encounter new challenges. The presentation heterogeneous respect to latency, pattern injury (hepatitis vs. cholangitis) severity. This review focuses on knowledge regarding factors, including refractory steroids. An emerging topic, possibility rechallenge while accepting some risk, patients who experience but require immunotherapy, also discussed. provides an update current knowns unknowns highlights several gaps where studies needed.

Language: Английский

---

Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes

The Lancet Neurology, Journal Year: 2023, Volume and Issue: 23(1), P. 81 - 94

Published: Dec. 13, 2023

Language: Английский

---

Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors

Current Oncology, Journal Year: 2023, Volume and Issue: 30(7), P. 6805 - 6819

Published: July 18, 2023

Over the past few decades, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for treatment of various cancers. These novel treatments effectively target key mediators pathways. Currently, ICIs primarily consist monoclonal antibodies that specifically block cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), death-ligand (PD-L1), and lymphocyte activation gene 3 protein (LAG-3). Despite notable efficacy in cancer treatment, they can also trigger immune-related adverse events (irAEs), which present autoimmune-like or inflammatory conditions. IrAEs potential to affect multiple organ systems, with cutaneous toxicities being most commonly observed. Although irAEs are typically low-grade severity usually be managed effectively, there cases where severe become life-threatening. Therefore, early recognition a comprehensive understanding mechanisms underlying crucial improving clinical outcomes patients. However, precise pathogenesis remains unclear. This review focuses on skin manifestations induced by ICIs, prognosis related irAEs, exploration involved irAEs.

Language: Английский

---

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti‐PD‐1/PD‐L1 cancer immunotherapy

Cell Proliferation, Journal Year: 2024, Volume and Issue: 57(8)

Published: April 9, 2024

Abstract Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti‐programmed cell death 1 (PD1) ligand (PD‐L1), have shown clinical efficacy in immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses this treatment. An emerging avenue involves triggering non‐apoptotic regulated (RCD), a significant mechanism driving cancer diverse treatments. Recent research demonstrates that combining RCD inducers with significantly enhances their antitumor across various types. The use anti‐PD‐1/PD‐L1 activates CD8 + T cells, prompting initiation novel forms, such as ferroptosis, pyroptosis, necroptosis. functions mechanisms anti‐PD1/PD‐L1 therapy remain insufficiently explored. This review summarises roles necroptosis It emphasises synergy between nanomaterials PD‐1/PD‐L1 induce different Furthermore, targeting signalling pathways combination therapies holds promise prospective strategy for

Language: Английский

---

Preclinical development of novel PD-L1 tracers and first-in-human study of [⁶⁸Ga]Ga-NOTA-RW102 in patients with lung cancers

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(4), P. e008794 - e008794

Published: April 1, 2024

Background The programmed cell death protein-1 (PD-1)/programmed receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors’ immunotherapy landscape. Methods By immunizing an alpaca with recombinant human PD-L1, three clones v ariable domain h eavy chain eavy-chain only antibody (VHH) were screened, and RW102 high binding affinity was selected for further studies. ABDRW102, a VHH derivative, engineered by fusing albumin binder ABD035. Based on two vectors, four PD-L1-specific tracers ([ 68 Ga]Ga-NOTA-RW102, [ Ga]Ga-NOTA-ABDRW102, 64 Cu]Cu-NOTA-ABDRW102, 89 Zr]Zr-DFO-ABDRW102) different circulation times developed. diagnostic efficacies thoroughly evaluated preclinical tumor models, followed first-in-human translational investigation Ga]Ga-NOTA-RW102 patients non-small lung (NSCLC). Results While has to excellent K D value 15.29 pM, ABDRW102 simultaneously binds serum 3.71 pM 3.38 respectively. Radiotracers derived from vivo times. In studies, immunoPET allowed same-day annotation differential specificity, while Cu]Cu-NOTA-ABDRW102 Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization PD-L1. More importantly, pilot clinical trial shows safety NSCLCs its potential predict immune-related adverse effects following PD-L1-targeted immunotherapies. Conclusions We developed validated series tracers. Initial evidence indicates that holds promise visualizing expression, selecting immunotherapies, monitoring receiving treatments. Trial registration number NCT06165874 .

Language: Английский

---