scholarly journals Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 305 ◽  
Author(s):  
Michele Porcu ◽  
Pushpamali De Silva ◽  
Cinzia Solinas ◽  
Angelo Battaglia ◽  
Marina Schena ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Clinical Symptoms ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Multidisciplinary Teams ◽  
Programmed Cell Death 1 ◽  
Radiological Patterns

The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial. Immune-related pulmonary toxicity was most frequently observed in trials of lung cancer and of melanoma patients treated with the combination of the anti-cytotoxic T lymphocyte antigen (CTLA)-4 and the anti-programmed cell death-1 (PD-1) antibodies. The most frequent immune-related adverse event in the lung is represented by pneumonitis due to the development of infiltrates in the interstitium and in the alveoli. Clinical symptoms and radiological patterns are the key elements to be considered for an early diagnosis, rendering the differential diagnosis crucial. Diagnosis of immune-related pneumonitis may imply the temporary or definitive suspension of immunotherapy, along with the start of immuno-suppressive treatments. The aim of this work is to summarize the biological bases, clinical and radiological findings of lung toxicity under immune checkpoint blockade, underlining the importance of multidisciplinary teams for an optimal early diagnosis of this side effect, with the aim to reach an improved patient care.

scholarly journals Management of pulmonary toxicity associated with immune checkpoint inhibitors

2019 ◽  
Vol 28 (154) ◽  
pp. 190012 ◽  
Author(s):  
Myriam Delaunay ◽  
Grégoire Prévot ◽  
Samia Collot ◽  
Laurent Guilleminault ◽  
Alain Didier ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Programmed Cell Death 1 ◽  
Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

scholarly journals Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution

2014 ◽  
Vol 21 (2) ◽  
pp. 371-381 ◽  
Author(s):  
Mabel Ryder ◽  
Margaret Callahan ◽  
Michael A Postow ◽  
Jedd Wolchok ◽  
James A Fagin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Hormone Replacement ◽  
Symptomatic Relief ◽  
Hormone Secretion ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Increased Risk

Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.

scholarly journals Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events

2017 ◽  
Vol 9 (415) ◽  
pp. eaan0401 ◽  
Author(s):  
Jun Ishihara ◽  
Kazuto Fukunaga ◽  
Ako Ishihara ◽  
Hans M. Larsson ◽  
Lambert Potin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Autoimmune Diabetes ◽  
Systemic Exposure ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Affinity Peptide

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.

scholarly journals A review on the role of gut microbiota in immune checkpoint blockade therapy for cancer

2021 ◽  
Author(s):  
Esther Kim ◽  
Hyeok Ahn ◽  
Hansoo Park
Keyword(s):  
Gut Microbiota ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Cytotoxic T Lymphocyte ◽  
Response Prediction ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Bacterial Strains ◽  
Programmed Cell Death 1 ◽  
Health And Disease

AbstractGut microbiota has been studied in relation to human health and disease prediction for decades. Also, immune checkpoints (ICPs) are enthusiastically investigated for anti-tumor immunotherapy. Recent studies show potential of gut microbiome and gut cytokines as biomarkers for carcinogenesis and response prediction of immune checkpoint inhibitor (ICI) response. Evidence has revealed that intestinal microorganisms play a major role in the effectiveness of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade. In this review, we have focused on how microbiome and microbiome-generated cytokines affect immune checkpoints. We have also described the molecular mechanisms behind this interplay and the bacterial strains that have a potential role in immunotherapy.

scholarly journals Immune checkpoint blockade in hematologic malignancies

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3393-3400 ◽  
Author(s):  
Philippe Armand
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Hematologic Malignancies ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Natural Target ◽  
Tumor Types

Abstract Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T-lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, we may begin to envision its morning.

scholarly journals In Situ Crosslinked Hydrogel Depot for Sustained Antibody Release Improves Immune Checkpoint Blockade Cancer Immunotherapy

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 471
Author(s):  
Jihoon Kim ◽  
David M. Francis ◽  
Susan N. Thomas
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Rate ◽  
Immune Checkpoints ◽  
Safe Delivery ◽  
Therapeutic Class

The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8+ T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an in situ crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy.

scholarly journals Treatment Progress of Immune Checkpoint Blockade Therapy for Glioblastoma

2020 ◽  
Vol 11 ◽  
Author(s):  
Na Zhang ◽  
Li Wei ◽  
Meng Ye ◽  
Chunsheng Kang ◽  
Hua You
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanism ◽  
Primary Brain Tumor ◽  
Immune Checkpoint Blockade ◽  
Brain Parenchyma ◽  
Checkpoint Blockade ◽  
Research Progress ◽  
Recent Success

Glioblastoma (GBM) is a highly malignant and aggressive primary brain tumor mostly prevalent in adults and is associated with a very poor prognosis. Moreover, only a few effective treatment regimens are available due to their rapid invasion of the brain parenchyma and resistance to conventional therapy. However, the fast development of cancer immunotherapy and the remarkable survival benefit from immunotherapy in several extracranial tumor types have recently paved the way for numerous interventional studies involving GBM patients. The recent success of checkpoint blockade therapy, targeting immunoinhibitory proteins such as programmed cell death protein-1 and/or cytotoxic T lymphocyte-associated antigen-4, has initiated a paradigm shift in clinical and preclinical investigations, and the use of immunotherapy for solid tumors, which would be a potential breakthrough in the field of drug therapy for the GBM treatment. However clinical trial showed limited benefits for GBM patients. The main reason is drug resistance. This review summarizes the clinical research progress of immune checkpoint molecules and inhibitors, introduces the current research status of immune checkpoint inhibitors in the field of GBM, analyzes the molecular resistance mechanism of checkpoint blockade therapy, proposes corresponding re-sensitive strategies, and describes a reference for the design and development of subsequent clinical studies on immunotherapy for GBM.

scholarly journals Prospects for combining immune checkpoint blockade with PARP inhibition

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Anping Li ◽  
Ming Yi ◽  
Shuang Qin ◽  
Qian Chu ◽  
Suxia Luo ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Parp Inhibition ◽  
Cancer Immunity ◽  
Anti Cancer

Abstract The immunogenicity of a cancer cell is derived from accumulated somatic mutations. However, on the contrary to increased immunogenicity, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including loss of immunodominant epitopes, downregulation of major histocompatibility complex, and immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals. Immune checkpoint inhibitors block negative co-stimulatory signals such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, ultimately reactivating anti-cancer immunity. Immune checkpoint inhibitors elicit potent anti-cancer effect and have been approved for multiple cancers. Nevertheless, there still are significant potential improvements for the applications of checkpoint inhibitor, especially considering frequent resistance. Recent studies demonstrated that additional PARP inhibition could alleviate resistance and enhance efficacy of immune checkpoint blockade therapy via promoting cross-presentation and modifying immune microenvironment. We proposed that PARP inhibitors could enhance the priming and tumor-killing activities of T cell, boost the whole cancer-immunity cycle, and thereby improve the response to immune checkpoint blockade. In this review, we focused the latest understanding of the effect of PARP inhibitors on anti-cancer immunity and PARP inhibitors combining immune checkpoint blockade therapy. Moreover, we summarized the preclinical and clinical evidence and discussed the feasibility of this combination therapy in future clinical practice.

scholarly journals Neutrophils in the era of immune checkpoint blockade

2021 ◽  
Vol 9 (7) ◽  
pp. e002242
Author(s):  
Julien Faget ◽  
Solange Peters ◽  
Xavier Quantin ◽  
Etienne Meylan ◽  
Nathalie Bonnefoy
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Neutrophil Infiltration ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cancer Management ◽  
Origin Function ◽  
And Function

The immune checkpoint blockade-based immunotherapies are revolutionizing cancer management. Tumor-associated neutrophils (TANs) were recently highlighted to have a pivotal role in modulating the tumor microenvironment and the antitumor immune response. However, these cells were largely ignored during the development of therapies based on programmed cell death receptor or ligand-1 and cytotoxic T lymphocyte antigen-4 immune checkpoint inhibitors (ICIs). Latest evidences of neutrophil functional diversity in tumor raised many questions and suggest that targeting these cells can offer new treatment opportunities in the context of ICI development. Here, we summarized key information on TAN origin, function, and plasticity that should be considered when developing ICIs and provide a detailed review of the ongoing clinical trials that combine ICIs and a second compound that might affect or be affected by TANs. This review article synthetizes important notions from the literature demonstrating that: (1) Cancer development associates with a profound alteration of neutrophil biogenesis and function that can predict and interfere with the response to ICIs, (2) Neutrophil infiltration in tumor is associated with key features of resistance to ICIs, and (3) TANs play an important role in resistance to antiangiogenic drugs reducing their clinical benefit when used in combination with ICIs. Finally, exploring the clinical/translational aspects of neutrophil impact on the response to ICIs offers the opportunity to propose new translational research avenues to better understand TAN biology and treat patients.

scholarly journals PLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Julia Koerner ◽  
Dennis Horvath ◽  
Valerie L. Herrmann ◽  
Anna MacKerracher ◽  
Bruno Gander ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Therapeutic Modality ◽  
Adjuvant Effect ◽  
Biodegradable Poly ◽  
Human Dendritic Cells

AbstractWith emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.

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