Mechanisms of Immune Checkpoint Inhibitor-Mediated Colitis

Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.

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Bladder-Sparing Chemoradiotherapy Combined with Immune Checkpoint Inhibition for Locally Advanced Urothelial Bladder Cancer—A Review

Cancers ◽

10.3390/cancers14010038 ◽

2021 ◽

Vol 14 (1) ◽

pp. 38

Author(s):

Jons W. van Hattum ◽

Ben-Max de Ruiter ◽

Jorg R. Oddens ◽

Maarten C. C. M. Hulshof ◽

Theo M. de Reijke ◽

...

Keyword(s):

Bladder Cancer ◽

Survival Data ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Locally Advanced ◽

Treatment Strategies ◽

Current Treatment ◽

Term Survival ◽

First Choice ◽

Bladder Sparing

Despite current treatment strategies, the 5-year overall survival of muscle-invasive bladder cancer (MIBC) is approximately 50%. Historically, radical cystectomy (RC) with neoadjuvant chemotherapy has been the first-choice treatment for this patient group. Recently, several studies have reported encouraging results of using immune checkpoint inhibitors (ICI) prior to RC. However, in recent years, bladder-sparing alternatives such as CRT have gained popularity. The effect of radiotherapy on the tumor microenvironment is an important rationale for combining CRT with ICI therapy. Worldwide, twelve immunochemoradiotherapy (iCRT) trials are ongoing. Each study employs a different chemotherapy and radiotherapy regimen and varies the timing of ICI administration concurrent to radiotherapy, adjuvant, or both. Five studies have presented (preliminary) results showing promising safety and short-term survival data. The first peer-reviewed publications are expected in the near future. The preclinical evidence and preliminary patient data demonstrate the potential of iCRT bladder-sparing treatment for bladder cancer.

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Role of immunotherapy in oligometastatic nonsmall cell lung cancer

BMJ Case Reports ◽

10.1136/bcr-2020-241070 ◽

2021 ◽

Vol 14 (5) ◽

pp. e241070

Author(s):

Yehuda Galili ◽

Ahmad El-Far ◽

Jennifer Tseng ◽

Steve Carlan

Keyword(s):

Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Nonsmall Cell Lung Cancer ◽

Current Treatment ◽

Adjunctive Treatment ◽

Comfort Care ◽

Metastatic Lung

The approach to metastatic lung cancer has long been focused on palliation therapy and comfort care. Recently, significant subsets of patients who suffer from a limited form of the disease have shown curative outcomes. The oligometastatic disease theory was first introduced in 1995, and since has been applied to many solid tumours. In oligometastatic nonsmall cell lung cancer, current treatment strategies include surgery, radiation therapy and chemotherapy. There is evidence of astounding survival benefits in selected patients treated with immune checkpoint inhibitors. We present three cases with oligometastatic nonsmall cell lung cancer treated with pembrolizumab, an immune checkpoint inhibitor, and describe the outcomes. Immunotherapy with pembrolizumab appears to be an effective adjunctive treatment with low toxicity in oligometastatic nonsmall cell lung cancer.

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From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽

10.3390/molecules26082278 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2278

Author(s):

Afshin Derakhshani ◽

Zeinab Rostami ◽

Hossein Safarpour ◽

Mahdi Abdoli Shadbad ◽

Niloufar Sadat Nourbakhsh ◽

...

Keyword(s):

Single Cell ◽

Signaling Pathways ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Development ◽

Immune Checkpoints ◽

Single Cell Sequencing ◽

Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytab002 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Shohei Moriyama ◽

Mitsuhiro Fukata ◽

Ryoma Tatsumoto ◽

Mihoko Kono

Keyword(s):

Lung Cancer ◽

Constrictive Pericarditis ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Rescue Therapy ◽

Treatment Strategies ◽

High Dose ◽

Acute Pericarditis ◽

Line Therapy ◽

Steroid Refractory

Abstract Background Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established. Case summary A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed. Discussion IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.

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Thrombotic Complications Associated with Immune Checkpoint Inhibitors

Cancers ◽

10.3390/cancers13184606 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4606

Author(s):

Tzu-Fei Wang ◽

Alok A. Khorana ◽

Marc Carrier

Keyword(s):

Immune Checkpoint ◽

Arterial Thrombosis ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Relevant Information ◽

Anticancer Treatment ◽

Thrombotic Complications ◽

Associated Risk Factors ◽

Cancer Associated Thrombosis

Thromboembolism is a common complication in patients with cancer and is associated with significant morbidity and mortality. Anticancer treatment is a known risk factor of cancer-associated thrombosis. Immune checkpoint inhibitors have become a mainstay of treatment in various cancers. Both venous and arterial thrombosis have been increasingly reported as adverse events associated with immune checkpoint inhibitors in recent studies, with a cumulative incidence of venous thrombosis to be 5–8% at 6 months and over 10% at 12 months. Additionally, rates of approximately 1–5% for arterial thrombosis were reported at 12 months. Data also showed an association of thromboembolism with adverse survival. Many pertinent clinical questions in this population deserve further investigation, including the risks of thrombosis associated with immune checkpoint inhibitors as compared to those with traditional systemic therapy, associated risk factors, and the optimal prevention and treatment strategies. In this review, we synthesize data from available literature, provide relevant information for clinicians and potential future directions for research.

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Cancer Immunotherapy-Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892816666210212145107 ◽

2021 ◽

Vol 16 ◽

Author(s):

Jing Bai ◽

Ping Liang ◽

Qian Li ◽

Rui Feng ◽

Jiang Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Programmed Cell Death ◽

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Locoregional Therapy ◽

Incidence And Mortality

: Hepatocellular Carcinoma (HCC) is one of the most common malignancies, the incidence and mortality of which are increasing worldwide. Cancer immunotherapy has revolutionized cancer treatment in recent years. In particular, Immune Checkpoint Inhibitors (ICIs) as new therapeutic tools have demonstrated encouraging antitumor activity and manageable tolerability in HCC. Immunologic checkpoint blockade with antibodies targeting Programmed cell Death-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), and Cytotoxic T Lymphocyte-Associated protein-4 (CTLA-4) strengthens tumor immunity by restoring exhausted T cells. Although the efficacy of combination treatment strategies using ICIs combined with other ICIs, molecular targeted agents, systemic therapy, or locoregional therapy has been well documented in numerous preclinical and clinical studies on several types of cancers, most HCC patients do not benefit from ICI treatment. This review highlights recent developments and potential opportunities related to ICIs and their combination in the management of HCC. The present article also includes recent patent review coverage on this topic.

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Prognostic Factors and Biomarkers of Responses to Immune Checkpoint Inhibitors in Lung Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20194931 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4931 ◽

Cited By ~ 13

Author(s):

Andrea Bianco ◽

Fabio Perrotta ◽

Giusi Barra ◽

Umberto Malapelle ◽

Danilo Rocco ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Cancer Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

T Cell Subsets ◽

Durable Response ◽

Lung Cancer Treatment ◽

The Impact

Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.

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The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition

International Journal of Molecular Sciences ◽

10.3390/ijms20163934 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3934 ◽

Cited By ~ 16

Author(s):

Gilda Varricchi ◽

Stefania Loffredo ◽

Giancarlo Marone ◽

Luca Modestino ◽

Poupak Fallahi ◽

...

Keyword(s):

Cell Death ◽

Thyroid Cancer ◽

Programmed Cell Death ◽

Immune Cells ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Lymphatic Vessels ◽

The United States ◽

Immune Checkpoints ◽

Antitumor Effects

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.

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Immune Checkpoint Inhibitor Treatment and Ophthalmologist Consultations in Patients with Malignant Melanoma or Lung Cancer—A Nationwide Cohort Study

Cancers ◽

10.3390/cancers14010049 ◽

2021 ◽

Vol 14 (1) ◽

pp. 49

Author(s):

Maria D’Souza ◽

Mette Bagger ◽

Mark Alberti ◽

Morten Malmborg ◽

Morten Schou ◽

...

Keyword(s):

Lung Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Ocular Inflammation ◽

Patients With Cancer ◽

Hazard Ratios ◽

One Year ◽

The One ◽

First Time ◽

Inhibitor Treatment

Purpose: To estimate the frequency of first-time ocular events in patients treated with immune checkpoint inhibitors (ICI). Methods: Patients with cancer in 2011–2018 in Denmark were included and followed. The outcomes were first-time ophthalmologist consultation and ocular inflammation. One-year absolute risks of outcomes and hazard ratios were estimated. Results: 112,289 patients with cancer were included, and 2195 were treated with ICI. One year after the first ICI treatment, 6% of the patients with cancer, 5% and 8% of the lung cancer (LC) and malignant cutaneous melanoma (MM) patients, respectively, had a first-time ophthalmologist consultation. The risk of ocular inflammation was 1% (95% confidence interval (CI) 0.4–1.2). Among patients with MM, ICI was associated with ocular inflammation in women (HR 12.6 (95% CI 5.83–27.31) and men (4.87 (95% CI 1.79–13.29)). Comparing patients with and without ICI treatment, the risk of first-time ophthalmologist consultation was increased in patients with LC (HR 1.74 (95% CI 1.29–2.34) and MM (HR 3.21 (95% CI 2.31–4.44). Conclusions: The one-year risks of first-time ophthalmologist consultation and ocular inflammation were 6% and 1%, respectively, in patients treated with ICI. In patients with LC and MM, the risk was increased in patients with ICI compared with patients without ICI.

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