Immune-related adverse events of immune checkpoint inhibitors: a review

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Май 25, 2023

Since the first Immune Checkpoint Inhibitor was developed, tumor immunotherapy has entered a new era, and response rate survival of many cancers have also been improved. Despite success immune checkpoint inhibitors, resistance limits number patients who can achieve lasting response, immune-related adverse events complicate treatment. The mechanism (irAEs) is unclear. We summarize discuss mechanisms action different types their possible mechanisms, describe strategies targets for prevention therapeutic interventions to mitigate them.

Язык: Английский

---

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

mAbs, Год журнала: 2023, Номер 15(1)

Опубликована: Фев. 1, 2023

The clinical development of 4–1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. first generation agonistic antibodies entering clinic, urelumab (BMS-663513) and utomilumab (PF-05082566), failed due to (liver) toxicity or lack efficacy, respectively. two display differences in affinity receptor epitope recognition, as well isotype, which determines Fc-gamma-receptor (FcγR) crosslinking activity. Based on this experience a very diverse landscape second-generation addressing liabilities first-generation recently been developed, with many Phase 1 2 studies. This review provides an overview focusing their scientific rationale, challenges foreseen these molecules.

Язык: Английский

---

Nanoparticles and bone microenvironment: a comprehensive review for malignant bone tumor diagnosis and treatment

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Ноя. 1, 2024

Malignant bone tumors, which are difficult to treat with current clinical strategies, originate from tissues and can be classified into primary secondary types. Due the specificity of microenvironment, results traditional means treating tumors often unsatisfactory, so there is an urgent need develop new treatments for malignant tumors. Recently, nanoparticle-based approaches have shown great potential in diagnosis treatment. Nanoparticles (NPs) gained significant attention due their versatility, making them highly suitable applications tissue engineering, advanced imaging techniques, targeted drug delivery. For diagnosis, NPs enhance contrast sensitivity by integrating targeting ligands, significantly improve specific recognition localization tumor cells early detection. treatment, enable delivery, increasing accumulation at sites while reducing systemic toxicity. In conclusion, understanding microenvironment using unique properties holds promise improving disease management, enhancing treatment outcomes, ultimately quality life patients Further research development will undoubtedly contribute advancement personalized medicine field oncology.

Язык: Английский

---

Bacterially mediated drug delivery and therapeutics: Strategies and advancements

Advanced Drug Delivery Reviews, Год журнала: 2022, Номер 187, С. 114363 - 114363

Опубликована: Май 29, 2022

Язык: Английский

---

Immune-Mediated Hepatitis During Immune Checkpoint Inhibitor cancer Immunotherapy: Lessons From Autoimmune Hepatitis and Liver Immunology

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Июнь 30, 2022

Immune checkpoint inhibitors (ICI) are being increasingly used to successfully treat several types of cancer. However, due their mode action, these treatments associated with immune-related adverse events (irAEs), including immune-mediated autoimmune-like hepatitis in 5 10% cases. The specific immune mechanism responsible for the development liver injury caused by (ILICI) is currently unknown. This review summarizes current knowledge on hepatic irAEs during cancer immunotherapy. It also addresses clinical management ILICI and how it becoming an important issue. Clinical, histological, laboratory features autoimmune (AIH) compared, shared distinctive traits discussed effort better understand irAEs. Finally, based immunology AIH pathogenesis, we propose a series that could trigger observed ICI-treated patients. model be useful design future studies aiming identify mechanism(s) at play improve inhibitor

Язык: Английский

---

Checkpoint inhibitor hepatotoxicity: pathogenesis and management

Hepatology, Год журнала: 2023, Номер 79(1), С. 198 - 212

Опубликована: Янв. 12, 2023

Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable responses across range of primary malignancies. ICI drugs increase activity against tumor cells, but may also reduce tolerance to self-antigens, resulting immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and occur 2%–25% ICI-treated patients. Although is clinically pathologically distinct from idiopathic autoimmune hepatitis, our understanding its pathogenesis continues evolve. Pending greater the pathophysiology, mainstay management remains through treatment with high-dose corticosteroids. This approach works for many patients, up 30% patients high-grade not respond corticosteroids alone. Furthermore, atypical cholestatic presentations are increasingly recognized, rare cases fulminant hepatitis due have reported. Optimal these challenging uncertain. Herein, we review current toxicities, focus on hepatotoxicity. Based existing literature, propose evolving approaches incorporate strategies limit excess corticosteroid exposure, address important liver failure. Finally, frequently occurs context advanced malignancy, impact outcomes, overall safety re-challenge ICI, who limited options.

Язык: Английский

---

2023 Update of Indian National Association for Study of the Liver Consensus on Management of Intermediate and Advanced Hepatocellular Carcinoma: The Puri III Recommendations

Journal of Clinical and Experimental Hepatology, Год журнала: 2023, Номер 14(1), С. 101269 - 101269

Опубликована: Авг. 19, 2023

Язык: Английский

---

Liver endothelial cells in NAFLD and transition to NASH and HCC

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(11)

Опубликована: Окт. 5, 2023

Язык: Английский

---

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

Liver International, Год журнала: 2025, Номер 45(2)

Опубликована: Янв. 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.

Язык: Английский

---

Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors

Cell Death and Disease, Год журнала: 2024, Номер 15(2)

Опубликована: Фев. 14, 2024

Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these to avoid destruction. checkpoint inhibitors (ICIs) activate cells restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on tolerogenic mechanisms, disruption with ICI use can trigger unintended side effect of hepatotoxicity termed immune-mediated injury from ICIs (ILICI). Learning how uncouple ILICI anti-tumor is paramount clinical importance. We developed a murine model recapitulate human using CTLA4+/- mice treated either combined anti-CTLA4 + anti-PDL1 or IgG1 IgG2. tested two forms antisense oligonucleotides knockdown caspase-3 in total (parenchymal non-parenchymal cells) hepatocyte-specific manner. also employed imaging mass cytometry (IMC), powerful multiplex modality for immunophenotyping cell interaction analysis our model. ICI-treated had significant evidence injury. detected cleaved (cC3), indicating apoptosis was occurring, well Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total worsened injury, induced further Gasdermin-D-mediated pyroptosis. Hepatocyte-specific reduced NLRP3 activation. IMC-generated single-cell data 77,692 used identify 22 unique phenotypic clusters. Spatial revealed cC3+ hepatocytes significantly closer interactions macrophages, Kupffer cells, NLRP3hi myeloid than other types. observed zones three-way between hepatocytes, CD8 T-cells, macrophages. Our work first hepatocyte activation drivers ILICI. Furthermore, we report interplay adaptive innate critical

Язык: Английский

---