Journal articles on the topic 'Immune checkpoint inhibitors (ICIs)'
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1
Farshidpour, Maham, and William Hutson. "Immune Checkpoint Inhibitors Induced Hepatotoxicity; Gastroenterologists’ Perspectives." Middle East Journal of Digestive Diseases 14, no. 2 (April 30, 2022): 244–53. http://dx.doi.org/10.34172/mejdd.2022.279.
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BACKGROUND: Immune checkpoint inhibitors (ICIs) have promising clinical activity and are essential medications for patients with several malignancies. However, by deranging the immune system, these novel agents could lead to immune-related adverse events (IRAEs). Hepatotoxicity with checkpoint inhibitors usually results in acute hepatitis or drug-induced liver injury. METHODS: This review article discusses the recent clinical evidence available regarding checkpoint inhibitor-induced hepatitis and reviews an approach to their diagnosis and management. CONCLUSION: ICIs have improved patients’ outcomes with different forms of malignancy; however, ICIs-related liver damage is a clinically significant entity in these patients. All patients should be monitored carefully for IRAEs while undergoing treatment with ICIs.
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Shiravand, Yavar, Faezeh Khodadadi, Seyyed Mohammad Amin Kashani, Seyed Reza Hosseini-Fard, Shadi Hosseini, Habib Sadeghirad, Rahul Ladwa, Ken O’Byrne, and Arutha Kulasinghe. "Immune Checkpoint Inhibitors in Cancer Therapy." Current Oncology 29, no. 5 (April 24, 2022): 3044–60. http://dx.doi.org/10.3390/curroncol29050247.
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The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy.
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Gan, Jiadi, Yihua Huang, Wenfeng Fang, and Li Zhang. "Research progress in immune checkpoint inhibitors for lung cancer in China." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110298. http://dx.doi.org/10.1177/17588359211029826.
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Immune checkpoint inhibitors (ICIs) have come to play an increasingly prominent role in the treatment of lung cancer, and some are recommended as a first-line treatment for late-stage non-small-cell lung cancer, either as a monotherapy or in combination with chemotherapy. Accordingly, the indications of Food and Drug Administration-approved ICIs have increased. In this background, China has implemented various policies to encourage and accelerate the marketing of domestic and imported innovative antitumor drugs. Eight ICIs have been approved in China. Among these, four imported programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have received approval for six indications, and one domestic PD-1 inhibitor has received approval for one indication for lung cancer in 2018. Numerous clinical trials of ICIs for lung cancer are underway in China. This review aims to summarize the recent advances and future directions of ICIs, including PD-1 inhibitors, PD-L1 inhibitors, cytotoxic T lymphocyte-associated antigen-4 inhibitors, bi-specific antibodies, and a novel inhibitor of T-cell immune-receptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains in immunotherapies for lung cancer in China.
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Makaremi, Shima, Zahra Asadzadeh, Nima Hemmat, Amir Baghbanzadeh, Alessandro Sgambato, Farid Ghorbaninezhad, Hossein Safarpour, et al. "Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects." Biomedicines 9, no. 9 (August 24, 2021): 1075. http://dx.doi.org/10.3390/biomedicines9091075.
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Immunotherapy is a new pillar of cancer therapy that provides novel opportunities to treat solid tumors. In this context, the development of new drugs targeting immune checkpoints is considered a promising approach in colorectal cancer (CRC) treatment because it can be induce specific and durable anti-cancer effects. Despite many advances in the immunotherapy of CRC, there are still limitations and obstacles to successful treatment. The immunosuppressive function of the tumor microenvironment (TME) is one of the causes of poor response to treatment in CRC patients. For this reason, checkpoint-blocking antibodies have shown promising outcomes in CRC patients by blocking inhibitory immune checkpoints and enhancing immune responses against tumors. This review summarizes recent advances in immune checkpoint inhibitors (ICIs), such as CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 in CRC, and it discusses various therapeutic strategies with ICIs, including the double blockade of ICIs, combination therapy of ICIs with other immunotherapies, and conventional treatments. This review also delineates a new hopeful path in the combination of anti-PD-1/anti-PD-L1 with other ICIs such as anti-CTLA-4, anti-LAG-3, and anti-TIM-3 for CRC treatment.
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Moshirfar, Majid, Noor F. Basharat, Tanner S. Seitz, Briana K. Ply, Yasmyne C. Ronquillo, and Phillip C. Hoopes. "Corneal Transplant Rejections in Patients Receiving Immune Checkpoint Inhibitors." Journal of Clinical Medicine 11, no. 19 (September 25, 2022): 5647. http://dx.doi.org/10.3390/jcm11195647.
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Immune checkpoint inhibitors (ICIs) are antibodies that target and block immune checkpoints. These biologics were initially approved by the United States Food and Drug Administration (US FDA) in 2011 for the management of melanoma. Since then, the use of ICI therapy has increased, with many new medications on the market that treat approximately 50 types of cancers. Patients receiving this therapy are at an increased risk for transplant rejection, including corneal rejection. Ophthalmologists must be aware of individuals receiving ICI therapy as it may be a relative contraindication for patients with a history of corneal transplantation. Patients on ICIs may also experience ocular side effects, including uveitis, dry eye, and inflammation, while on checkpoint inhibitor therapy. This commentary discusses the current understanding of immune checkpoint inhibitors, their mechanism of action, their ocular side effects, and their role in corneal transplant rejection.
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Kwon, Hyemi, Eun Roh, Chang Ho Ahn, Hee Kyung Kim, Cheol Ryong Ku, Kyong Yeun Jung, Ju Hee Lee, et al. "Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society." Endocrinology and Metabolism 37, no. 6 (December 31, 2022): 839–50. http://dx.doi.org/10.3803/enm.2022.1627.
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Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.
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Nardi Agmon, Inbar, Osnat Itzhaki Ben Zadok, and Ran Kornowski. "The Potential Cardiotoxicity of Immune Checkpoint Inhibitors." Journal of Clinical Medicine 11, no. 3 (February 7, 2022): 865. http://dx.doi.org/10.3390/jcm11030865.
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The use of immune checkpoint inhibitors (ICIs) as a mono- or adjuvant oncologic treatment is rapidly expanding to most fields of cancer. Alongside their efficacy, ICIs carry the risk of immune-related adverse events (irAEs) arising from misguided immune-mediated response to normal tissues. In the cardiovascular system, the cardiac toxicity of ICIs has been primarily related to the development of an acute, immune-mediated myocarditis; beyond this potentially fatal complication, evidence of an increased risk of cardiovascular events and accelerated atherosclerosis is emerging, as well as reports of other cardiovascular adverse events such as arrythmias, Takotsubo-like syndrome and vascular events. The absence of identified risk factors for cardiotoxic complications, specific monitoring strategies or diagnostic tests, pose challenges to the timely recognition and optimal management of such events. The rising numbers of patients being treated with ICIs make this potential cardiotoxic effect one of paramount importance for further investigation and understanding. This review will discuss the most recent data on different cardiotoxic effects of ICIs treatment.
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Hamada, Kazuyuki, Takuya Tsunoda, and Kiyoshi Yoshimura. "Emerging Immune-Monitoring System for Immune Checkpoint Inhibitors." Life 12, no. 8 (August 13, 2022): 1229. http://dx.doi.org/10.3390/life12081229.
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Immune checkpoint inhibitors (ICIs) have a major impact on cancer treatment. However, the therapeutic efficacy of ICIs is only effective in some patients. Programmed death ligand 1 (PD-L1), tumor mutation burden (TMB), and high-frequency microsatellite instability (MSI-high) are markers that predict the efficacy of ICIs but are not universally used in many carcinomas. The gut microbiota has received much attention recently because of its potential to have a significant impact on immune cells in the cancer microenvironment. Metabolites of the gut microbiota modulate immunity and have a strong influence on the therapeutic efficacy of ICI. It has been suggested that the gut microbiota may serve as a novel marker to predict the therapeutic efficacy of ICI. Therefore, there is an urgent need to develop biomarkers that can predict anti-tumor effects and adverse events, and the study of the gut microbiota is essential in this regard.
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Sun, Yining, Nan Wang, and Nuo Zhang. "Immune Checkpoint inhibitor Therapy in Various Cancers." Highlights in Science, Engineering and Technology 14 (September 29, 2022): 318–23. http://dx.doi.org/10.54097/hset.v14i.1840.
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Immune checkpoint inhibitors (ICIs) are a new way of immunotherapy, not simply refers to the improvement of immunity to the body, but by improving the immune microenvironment around the tumor, thereby activating immune cell activity in vivo to achieve anti-tumor purposes. Now, CTLA‐4 and PD‐1 or PD‐L1 monoclonal antibody are mainly developed relatively successfully for immune checkpoints, in addition to other new immune checkpoints that have been discovered and clinically tested. However, while immune checkpoint inhibitors have been developed successively, some vague problems still need to be solved, such as the large gap between the immunotherapy effects of different patients. These issues are critical to the selection of immune checkpoint inhibitors. In this review, based on the study of the immunosuppressive mechanism of CTLA-4 and PD-1/PD-L1, the application of related immune checkpoint inhibitors in cancer treatment is discussed starting from three representative types of cancer. At the same time, according to the existing problems, some common immune-related adverse events and newly discovered immune checkpoints are summarized, and the future research direction of ICIs is further explored.
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Mazloom, Anita, Nima Ghalehsari, Victor Gazivoda, Neil Nimkar, Sonal Paul, Peter Gregos, Janice Rateshwar, and Uqba Khan. "Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies." Journal of Clinical Medicine 9, no. 8 (August 6, 2020): 2533. http://dx.doi.org/10.3390/jcm9082533.
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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.
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Chen, Ru, Min Zhou, and Feng Zhu. "Immune Checkpoint Inhibitors Related to Cardiotoxicity." Journal of Cardiovascular Development and Disease 9, no. 11 (November 3, 2022): 378. http://dx.doi.org/10.3390/jcdd9110378.
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Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancers. Along with development of ICIs, immune-related adverse effects (irAEs) have aroused wide attention. The cardiac irAE, one of the rare but potentially fatal effects, have been reported recently. However, the clinical comprehension of cardiac irAEs remains limited and guidelines are inadequate for cardio-oncologists to tackle the problem. In this review, we have summarized current classifications of, manifestations of, potential mechanisms of, and treatment for ICI-related myocardial injury in order to provide some clues for the understanding of cardiac irAEs in clinical work.
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Garibaldi, Matteo, Fabio Calabrò, Gioia Merlonghi, Silvia Pugliese, Marco Ceccanti, Lara Cristiano, Tommaso Tartaglione, and Antonio Petrucci. "Immune checkpoint inhibitors (ICIs)-related ocular myositis." Neuromuscular Disorders 30, no. 5 (May 2020): 420–23. http://dx.doi.org/10.1016/j.nmd.2020.02.013.
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Chen, Yuxiao, Tingfeng Jian, and Yuandong Shen. "Immune Checkpoint Inhibitors in Lung Cancer." Highlights in Science, Engineering and Technology 8 (August 17, 2022): 111–20. http://dx.doi.org/10.54097/hset.v8i.1117.
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With the fast increase in morbidity and mortality, lung cancer has become one of the greatest threats to physical health in some countries. Immune checkpoint inhibitors (ICIs) have a significant influence on the treatment landscape of lung cancer, including non-small cell lung cancer (NSCLC). This review highlights the most important ICIs used in lung cancer at present, anti-CTLA-4 and PD-1/L1. The application status, efficacy, shortcomings and prospect of each drug, including Ipilimumab (CTLA-4), Nivolumab, Pembrolizumab, and Durvalumab (PD-1/L1), are listed to show the drug indication in the current market. By comparing different drugs, the direction of ICI drug development can be more precise, which can have an important influence on choosing drugs for lung cancer treatment.
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Sae-Tia, Sutthichai, Jarushka Naidoo, and Seema Mehta. "Infections in patients receiving immune checkpoint inhibitors." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 155. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.155.
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155 Background: Immune checkpoint inhibitors (ICIs) - anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, avelumab), anti-CTLA-4 (ipilimumab) - have improved outcomes for several malignancies. ICIs may cause immune-related adverse events (irAEs), often treated with immunosuppression. The incidence of infections arising de novo during ICI therapy or from immunosuppression for irAEs is not well described. Methods: In- and outpatients receiving ICIs were referred for Infectious Diseases consultation between 6/2011-6/2018. Twenty-five were randomly selected for retrospective summarization of the spectrum of infections. Diagnosis of infection was made by the primary oncologist, based upon clinical/radiographic/laboratory data. Results: Solid tumor (24, 96%) and hematologic malignancies (1, 4%) were represented (Table). All 25 had infections. 15 (60%) were male; median age 58 years (29-97). 17 (68%) had irAEs: pneumonitis (10, 40%), thyroiditis (5, 20%), colitis (5, 20%), hepatitis (4, 16%), dermatitis (4, 16%) and myocarditis (1, 4%). 17 (68%) patients developed +1 irAE. 50% with pneumonitis were concurrently treated for pneumonia. Of the 25, 17 (72%) developed de novo infections on ICIs; whereas others were receiving systemic corticosteroids (7, 28%) or infliximab (1, 4%). Initial infections included pneumonia (13, 52%), bacteremia (3, 12%), sinusitis (2, 8%), wound infection (2, 8%), viral infections (HSV, CMV, HCV; 1, 4% each) and 1 (4%) each of empyema, UTI, peritonitis, osteomyelitis, and meningitis. 44% (11) developed a second infection within 60 days of the first. Conclusions: Patients receiving ICIs for cancer developed a myriad of infections, both de novo during ICI therapy, or consequent to immunosuppression for irAEs. Second infections are common, occurring in nearly half the patients. Awareness of this is vital for early diagnosis and appropriate management. Patients with suspected ICI-related infection. (n=25). [Table: see text]
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Kim, Hye Ryeon, Jung Hun Kang, Sung Hyun Kim, Seung Tae Kim, Ilhwan Kim, Young Joo Min, Seong Hoon Shin, et al. "Changes of Immune Cell Fractions in Patients Treated with Immune Checkpoint Inhibitors." Cancers 14, no. 14 (July 15, 2022): 3440. http://dx.doi.org/10.3390/cancers14143440.
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Background: With the development of immunology, immune checkpoint inhibitors (ICIs) have been widely used in various cancer treatments. Although some patients can benefit from ICIs, other patients have no response to ICIs or suffer from hyperprogression. There has been no biomarker for predicting the efficacy of ICIs. Thus, the objective of this study was to find biomarkers for predicting the efficacy of ICIs using peripheral blood. Methods: Adults patients planned to be treated with ICIs were enrolled in this study. Blood sampling was carried out before and after administration of ICIs. Changes of immune cell fraction were analyzed for each patient. Results: Among 182 patients enrolled, immune cell analysis was performed for 90 patients. The objective response rate was 14.4% (n = 13/90). The median progression-free survival (PFS) was 6.0 months (95% CI: 3.1–8.9 months), and the median overall survival (OS) was 13.9 months (95% CI: 5.6–22.2 months). Significant benefits in ORR and OS were shown for patients with increased NKp46-/CD56+ NK cells (p = 0.033 and p = 0.013, respectively). The PFS tended to be longer in these patients, although the difference was not statistically significant (p = 0.050). Conclusion: Changes of immune cell fraction before and after administration of ICIs could be a novel biomarker for predicting the efficacy of immunotherapy.
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Picca, Alberto, Giulia Berzero, Kevin Bihan, Vincent Jachiet, Edouard Januel, Marc Coustans, Cecile Cauquil, et al. "Longitudinally Extensive Myelitis Associated With Immune Checkpoint Inhibitors." Neurology - Neuroimmunology Neuroinflammation 8, no. 3 (February 26, 2021): e967. http://dx.doi.org/10.1212/nxi.0000000000000967.
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ObjectiveTo define the characteristics and the outcome of myelitis associated with immune checkpoint inhibitors (ICIs).MethodsWe performed a retrospective research in the databases of the French Pharmacovigilance Agency and the OncoNeuroTox network for patients who developed myelitis following treatment with ICIs (2011–2020). A systematic review of the literature was performed to identify similar cases.ResultsWe identified 7 patients who developed myelitis after treatment with ICIs (anti-PD1 [n = 6], anti-PD1 + anti-CTLA4 [n = 1]). Neurologic symptoms included paraparesis (100%), sphincter dysfunction (86%), tactile/thermic sensory disturbances (71%), and proprioceptive ataxia (43%). At the peak of symptom severity, all patients were nonambulatory. MRI typically showed longitudinally extensive lesions, with patchy contrast enhancement. CSF invariably showed inflammatory findings. Five patients (71%) had clinical and/or paraclinical evidence of concomitant cerebral, meningeal, caudal roots, and/or peripheral nerve involvement. Despite the prompt discontinuation of ICIs and administration of high-dose glucocorticoids (n = 7), most patients needed second-line immune therapies (n = 5) because of poor recovery or early relapses. At last follow-up, only 3 patients had regained an ambulatory status (43%). Literature review identified 13 previously reported cases, showing similar clinical and paraclinical features. All patients discontinued ICIs and received high-dose glucocorticoids, with the addition of other immune therapies in 8. Clinical improvement was reported for 10 patients.ConclusionMyelitis is a rare but severe complication of ICIs that shows limited response to glucocorticoids. Considering the poor functional outcome associated with longitudinally extensive myelitis, strong and protracted immune therapy combinations are probably needed upfront to improve patient outcome and prevent early relapses.
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Economopoulou, Panagiota, and Amanda Psyrri. "Overview and management of toxicities of immune checkpoint-blocking drugs." Forum of Clinical Oncology 7, no. 1 (March 1, 2016): 28–37. http://dx.doi.org/10.1515/fco-2016-0004.
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Abstract Immunotherapy is considered to be the most important breakthrough in cancer management in the past few years. This success was based on the scientific understanding of immune mechanisms due to improvement in preclinical science and the introduction of new methods of investigation. Immune checkpoint inhibitors (ICIs) are among the most promising drugs in the field of immune-oncology; they represent monoclonal antibodies that modulate the effects of immune checkpoints, such as cytotoxic T lymphocyte Antigen 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), which are co-inhibitory signals responsible for immune suppression. Despite clinical benefits, ICIs are immune activating agents that are associated with a number of important side effects (immune-related adverse events-irAEs), attributed to organ-specific inflammation. Herein, we review the toxicities of ICIs, highlighting the importance of early identification and management.
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Pirš, Boštjan, Erik Škof, Vladimir Smrkolj, and Špela Smrkolj. "Overview of Immune Checkpoint Inhibitors in Gynecological Cancer Treatment." Cancers 14, no. 3 (January 27, 2022): 631. http://dx.doi.org/10.3390/cancers14030631.
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In the last ten years, clinical oncology has been revolutionized by the introduction of oncological immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs) that transformed the standard of care of several advanced solid malignancies. Using ICIs for advanced gynecological cancers has yielded good results, especially for endometrial cancer. In ovarian or cervical cancer, combining ICIs with other established agents has shown some promise. Concurrently with the clinical development of ICIs, biomarkers that predict responses to such therapy have been discovered and used in clinical trials. The translation of these biomarkers to clinical practice was somewhat hampered by lacking assay standardization and non-comprehensive reporting of biomarker status in trials often performed on a small number of gynecological cancer patients. We can expect increased use of ICIs combined with other agents in gynecological cancer in the near future. This will create a need for reliable response prediction tools, which we believe will be based on biomarker, clinical, and tumor characteristics. In this article, we review the basic biology of ICIs and response prediction biomarkers, as well as the latest clinical trials that focus on subgroup effectiveness based on biomarker status in gynecological cancer patients.
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Wu, Zhaozhen, Pengfei Cui, Haitao Tao, Sujie Zhang, Junxun Ma, Zhefeng Liu, Jinliang Wang, et al. "The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors." Clinical Medicine Insights: Oncology 15 (January 2021): 117955492199628. http://dx.doi.org/10.1177/1179554921996288.
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Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.
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Tran, Linda, and Dan Theodorescu. "Determinants of Resistance to Checkpoint Inhibitors." International Journal of Molecular Sciences 21, no. 5 (February 26, 2020): 1594. http://dx.doi.org/10.3390/ijms21051594.
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The development of immune checkpoint inhibitors (ICIs) has drastically altered the landscape of cancer treatment. Since approval of the first ICI for the treatment of advanced melanoma in 2011, several therapeutic agents have been Food and Drug Administration (FDA)-approved for multiple cancers, and hundreds of clinical trials are currently ongoing. These antibodies disrupt T-cell inhibitory pathways established by tumor cells and thus re-activate the host’s antitumor immune response. While successful in many cancers, several types remain relatively refractory to treatment or patients develop early recurrence. Hence, there is a great need to further elucidate mechanisms of resistant disease and determine novel, effective, and tolerable combination therapies to enhance efficacy of ICIs.
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Kaira, Kyoichi, Hisao Imai, and Hiroshi Kagamu. "Perspective of Immune Checkpoint Inhibitors in Thymic Carcinoma." Cancers 13, no. 5 (March 3, 2021): 1065. http://dx.doi.org/10.3390/cancers13051065.
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Thymic carcinoma is a rare neoplasm with a dismal prognosis, and there are no established therapeutic regimens for metastatic or recurrent disease. Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, are widely approved in several human cancers, contributing to prolonging survival in thoracic tumors. Thymic carcinoma exhibits histologic properties of squamous cell carcinoma (SQC), and resembles the SQC of the lung. ICIs are not approved in thymic carcinoma. Thus, several clinical trials have been undertaken to demonstrate if they are therapeutically effective for patients with thymic carcinoma. In our review, three prospective phase II studies and several case series were discussed in thymic carcinoma. We found that the objective response rate, disease control rate, and progression-free survival in PD-1 blockade monotherapy were approximately 20%, 73%, and four months, respectively. Two exploratory investigations indicated that PD-L1 within tumor cells exhibits a possibility of the therapeutic prediction of PD-1 blockade in thymic carcinoma. Several case reports, alongside their treatment content, have also been reviewed. The therapeutic efficacy of PD-1 blockade monotherapy is still limited in patients with thymic carcinoma. Future perspectives focus on the therapeutic implication of tyrokinase inhibitors plus ICIs or new experimental agents plus ICIs alongside several ongoing experimental studies.
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Maiorano, Brigida Anna, Ugo De Giorgi, Davide Ciardiello, Giovanni Schinzari, Antonio Cisternino, Giampaolo Tortora, and Evaristo Maiello. "Immune-Checkpoint Inhibitors in Advanced Bladder Cancer: Seize the Day." Biomedicines 10, no. 2 (February 9, 2022): 411. http://dx.doi.org/10.3390/biomedicines10020411.
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Background: In advanced bladder cancer (BCa), platinum-based chemotherapy represents the first-choice treatment. In the last ten years, immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of many solid tumors. Our review aims to summarize the main findings regarding the clinical use of ICIs in advanced BCa. Methods: We searched PubMed, Embase, and Cochrane databases, and conference abstracts from international congresses (ASCO, ESMO, ASCO GU) for clinical trials, focusing on ICIs as monotherapy and combinations in metastatic BCa. Results: 18 studies were identified. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were used. Survival outcomes have been improved by second-line ICIs, whereas first-line results are dismal. Avelumab maintenance in patients obtaining disease control with chemotherapy has achieved the highest survival rates. Conclusions: ICIs improve survival after platinum-based chemotherapy. Avelumab maintenance represents a new practice-changing treatment. The combinations of ICIs and other compounds, such as FGFR-inhibitors, antibody-drug conjugates, and anti-angiogenic drugs, represent promising therapeutic approaches. Biomarkers with predictive roles and sequencing strategies are warranted for best patient selection.
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Longo, Brunetti, Gnoni, Licchetta, Delcuratolo, Memeo, Solimando, and Argentiero. "Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma." Medicina 55, no. 10 (October 17, 2019): 698. http://dx.doi.org/10.3390/medicina55100698.
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Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70–80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standardcare for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results inan alternative first-line treatment for the Chineseclinical oncology guidelines. Moreover,nivolumab and pembrolizumab,two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approvedfor subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessmentof new ICIs-based combinatory approaches.
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Chen, Xinru, Zhonghan Zhang, Xue Hou, Yaxiong Zhang, Ting Zhou, Jiaqing Liu, Zhihuan Lin, et al. "Immune-related pneumonitis associated with immune checkpoint inhibitors in lung cancer: a network meta-analysis." Journal for ImmunoTherapy of Cancer 8, no. 2 (August 2020): e001170. http://dx.doi.org/10.1136/jitc-2020-001170.
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BackgroundImmune checkpoint inhibitors (ICIs) have dramatically revolutionized lung cancer treatment, providing unprecedented clinical benefits. However, immune-related pneumonitis (IRP) caused by ICIs has aroused widespread concern due to its high rate of discontinuation and mortality. This network meta-analysis (NMA) aims to compare the risks of IRP among different regimens for advanced lung cancer.MethodsPhase II and III randomized clinical trials (RCTs) were searched from electronic databases. The rates of grade 1–5 IRP and grade 3–5 IRP were systematically extracted. An NMA was conducted among chemotherapy, ICIs monotherapy, dual ICIs combination, and ICIs+chemotherapy. Subgroup analysis was also compared based on specific types of ICIs.ResultsTwenty-five RCTs involving 17,310 patients were eligible for inclusion. Compared with chemotherapy, ICI-based regimens were associated with an increased risk of grade 1–5 IRP and grade 3–5 IRP. Compared with ICIs+chemotherapy, ICIs monotherapy (grade 1–5: OR 2.14, 95% credible interval 1.12 to 4.80; grade 3–5: 3.03, 1.491 to 6.69) and dual ICIs combination (grade 1–5: 3.86, 1.69 to 9.89; grade 3–5: 5.12, 2.01 to 13.68) were associated with a higher risk of grade 1–5 IRP and grade 3–5 IRP. No significant difference was found between dual ICIs combination and ICIs monotherapy in grade 1–5 IRP (1.85, 0.91 to 3.37) or in grade 3–5 IRP (1.65, 0.81 to 3.37). Besides, compared with programmed cell death protein 1 (PD-1) inhibitors (2.56, 1.12 to 6.60), a lower risk of grade 1–5 IRP was observed in programmed cell death ligand 1 (PD-L1) inhibitors.ConclusionCompared with chemotherapy, using ICIs is associated with an increased risk of IRP. ICIs+chemotherapy is associated with a lower risk of IRP compared with dual ICIs combination and ICIs monotherapy. PD-1 inhibitors are associated with a higher risk of 1–5 grade IRP compared with PD-L1 inhibitors.
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Houssiau, Hélène, and Emmanuel Seront. "The Evolution of Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma." Cancers 14, no. 7 (March 24, 2022): 1640. http://dx.doi.org/10.3390/cancers14071640.
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Urothelial carcinoma is an aggressive cancer and development of metastases remains a challenge for clinicians. Immune checkpoint inhibitors (ICIs) are significantly improving the outcomes of patients with metastatic urothelial cancer (mUC). These agents were first used in monotherapy after failure of platinum-based chemotherapy, but different strategies explored the optimal use of ICIs in a first-line metastatic setting. The “maintenance” strategy consists of the introduction of ICIs in patients who experienced benefit from first-line chemotherapy in a metastatic setting. This allows an earlier use of ICIs, without waiting for disease progression. We review the optimal management of mUC in the era of ICIs, based on the key clinical messages arising from the pivotal trials.
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Al Nuhait, Mohammed, Eshtyag Bajnaid, Abdulmalik Al Otaibi, Abdullah Al Shammari, and Yousef Al Awlah. "Real-world safety experience with immune checkpoint inhibitors in Saudi Arabia." Science Progress 104, no. 1 (January 2021): 003685042199730. http://dx.doi.org/10.1177/0036850421997302.
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Lay abstract Real-world safety experience with immune checkpoint inhibitors in Saudi Arabia: Immune Checkpoint Inhibitors (ICIs) are rapidly growing and changing cancer care. With introduction of ICIs the landscape for cancer treatment has changed significantly. ICIs are known to induce immune-related adverse effects. This research is intended to shed light on ICIs and describe our safety experience with these agents. This study is a retrospective cohort study aimed to determine the safety of ICIs and its related adverse events at a tertiary hospital in Saudi Arabia. The study was conducted in the oncology center at King Abdulaziz Medical City, Riyadh. We identified study participants by using electronic health care system (BestCare)® to involve patients who received ICIs treatment during the study period from January 2016 up to December 2018, to include a total of 53 patients. Most of our patients were on nivolumab (37 patients) followed by atezolizumab (10 patients), and pembrolizumab (6 patients). The average number of emergency room visits after receiving treatment was three visits per patient. Renal adverse events occurred following ICIs use in nine patients, and none of the reported cases experienced a grade ≥3 event. Moreover, 13 patients experienced a hepatic adverse event, of whom only 1 patient experienced a grade ≥3 event leading to treatment discontinuation. As for diarrhea, among all patients who received ICIs, 14 patients experienced diarrhea, and 5 of them had grade ≥3 events. Also, thyroxine abnormalities occurred in seven patients. While, Pneumonitis occurred in four patients following ICIs use. In addition, we noticed other adverse events with ICIs including (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia, and neurological adverse events). Furthermore, 17 patients required steroids to manage ICIs adverse events. And, no patients in our study required additional management with other immunosuppressive agents. Immunotherapies are rapidly growing and changing cancer care. Immune Checkpoint Inhibitors (ICIs) have the ability to block inhibitory checkpoints and restore the functions of the immune system. ICIs are used for the treatment of several types of cancer, and nowadays, many studies are ongoing in order to get approvals for newer indications. ICIs are known to induce immune-related adverse effects. The safety of ICIs and the most common immune-related adverse events are not yet well recognized for our population since this class of medications is lately introduced in our region, where only limited studies in our population are available in the literature. This research is intended to shed light on ICIs and describe our safety experience with these agents. This study is a retrospective cohort study aimed to determine the safety of ICIs and its related adverse events at a tertiary hospital in Saudi Arabia. The study was conducted in the oncology center at King Abdulaziz Medical City, Riyadh. Study participants were identified by using the electronic health care system (BestCare)® to include patients who were treated with ICIs during the study period from January 2016 up to December 2018. A total of 53 patients were included. Most of our patients were on nivolumab (37 patients) followed by atezolizumab (10 patients), and pembrolizumab (6 patients). The average number of emergency room visits after receiving ICIs was three visits per patient. Renal adverse events occurred following ICIs use in nine patients, and none of the reported cases experienced a grade ≥3 event. Moreover, 13 patients experienced a hepatic adverse event, of whom only 1 patient experienced a grade ≥3 event leading to treatment discontinuation. As for diarrhea, among all patients who received ICIs, 14 patients experienced diarrhea, and 5 of them had grade ≥3 events. Also, thyroxine abnormalities occurred in seven patients. While, pneumonitis occurred in four patients following ICIs use. In addition, we noticed other adverse events with ICIs, including (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia, and neurological adverse events). Furthermore, 17 patients required steroids to manage ICIs adverse events. And, no patients in our study required additional management with other immunosuppressive agents. Patients treated with immune checkpoint inhibitors could have a variety of adverse drug events that might lead to treatment discontinuation and increase overall emergency room visits. This study highlights the most common adverse drug events associated with ICIs use at a tertiary care center in Saudi Arabia.
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Mukherjee, Sarbajit, Kanak Parmar, and Elizabeth Smyth. "Immune checkpoint inhibitors in resectable gastroesophageal cancers - a review." Therapeutic Advances in Medical Oncology 14 (January 2022): 175883592211396. http://dx.doi.org/10.1177/17588359221139625.
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Gastroesophageal cancers (GEC) have a poor survival rate of 20–30% at 5 years, often due to delayed presentations. Neoadjuvant chemoradiotherapy (CRT) followed by surgery or peri-operative chemotherapy and surgery are widely used as the standard of care for patients with resectable GEC. Immune checkpoint inhibitors (ICIs) have improved survival in metastatic and recurrent GEC which led to their application in resectable GEC. Based on the pivotal CheckMate 577 study results, the Food and Drug Administration (FDA) approved nivolumab for patients with completely resected high-risk esophageal or gastroesophageal junction cancer (GEJC). Several ongoing trials with many ICIs could potentially improve resectable GEC outcomes. This review explores the rationale for using ICIs in resectable GEC and discusses the significance of reported clinical trials. Finally, we will examine some ongoing clinical trials and the challenges as well as prospects of ICIs in resectable GEC.
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Fong, Pak Yui, Shing Chuen Chow, Bernard Ming Hong Kwong, Charlene Cheuk Lam Lau, Christy Yik Ching Lau, Athena Hoi Ting Lee, Ha Ying Nip, Cheuk Yin Wong, Benedict Tsz Hin Yan, and Ho Yin Chung. "Management of Immune Checkpoint Inhibitor-Related Rheumatological Toxicities." Journal of Clinical Rheumatology and Immunology 20, no. 01 (May 8, 2020): 25–34. http://dx.doi.org/10.1142/s2661341720300013.
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Immune checkpoint inhibitors (ICIs) have forged a new direction for the treatment of cancer. However, ICIs – programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors – are also known to cause immune-related adverse events (irAEs). Rheumatological adverse events are uncommon and often low grade, but flares of underlying rheumatological diseases may be triggered. Guidelines are available for the effective management of the rheumatological adverse events that more frequently arise from the use of ICIs, such as inflammatory arthritis, inflammatory myopathies, Sjogren syndrome, scleroderma, and polymyalgia rheumatica and eosinophilic fasciitis.
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Siefker-Radtke, Arlene O. "New Settings for Immune Checkpoint Inhibitors in Urothelial Cancer." Journal of the National Comprehensive Cancer Network 19, no. 5.5 (May 2021): 629–32. http://dx.doi.org/10.6004/jnccn.2021.5007.
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The advent of immune checkpoint inhibitors (ICIs) has changed the game in cancer immunotherapy, specifically in the treatment of urothelial bladder cancer. Several clinical trials combining chemotherapy with ICIs have resulted in approvals from the FDA and subsequent revisions within the NCCN Guidelines. The current NCCN Guidelines for Bladder Cancer reflect the most up-to-date, evidence-based data relating to the evaluation and management of urothelial bladder cancer. ICIs have been incorporated into the guidelines as maintenance therapy in response to chemotherapy, sequencing after disease progression from frontline chemotherapy, and for the treatment of non–muscle-invasive bladder cancer.
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Xia, Shuang, Hui Gong, Yichang Zhao, Lin Guo, Yikun Wang, Bikui Zhang, Mayur Sarangdhar, Yoshihiro Noguchi, and Miao Yan. "Association of Pulmonary Sepsis and Immune Checkpoint Inhibitors: A Pharmacovigilance Study." Cancers 15, no. 1 (December 30, 2022): 240. http://dx.doi.org/10.3390/cancers15010240.
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Background: Although some sepsis cases were reported with immune checkpoint inhibitors (ICIs) in clinical trials, the link between pulmonary sepsis and ICIs remains mostly unknown. We aim to investigate the association between pulmonary sepsis and ICIs, and to describe the clinical features. Methods: A disproportionality analysis was performed using FAERS data and compared rates of pulmonary sepsis in cancer patients receiving ICIs vs. other drug regimens (such as chemotherapy and targeted therapy). Associations between ICIs and sepsis were assessed using reporting odds ratios (ROR) and information component (IC). We also detected drug interaction signals based on the Ω shrinkage measure. Age and gender distribution were compared between pulmonary sepsis and all adverse events associated with ICIs. Results: We identified 120 reports of pulmonary sepsis associated with ICIs between Q1, 2011 to Q3, 2021. A total of 82 of 120 (68.3%) patients on ICIs suffered from pulmonary sepsis and progressed to death. In addition, there is no significant difference in age and gender in the occurrence of pulmonary sepsis in cancer patients on ICIs. Overall ICIs, nivolumab, and atezolizumab still have a significant signal of pulmonary sepsis (ROR025 > 1, IC025 > 0, p < 0.001) compared with targeted therapy (such as tyrosine kinase inhibitors) or chemotherapy. Co-administration of ICIs and glucocorticoids or proton pump inhibitors synergistically increased the risk of pulmonary sepsis (Ω025 > 0). Conclusions: Our study suggested ICIs, especially nivolumab and atezolizumab, tended to increase the risk of pulmonary sepsis more than other anticancer regimens. Clinicians should be vigilant in the prevention and management of pulmonary sepsis during ICIs therapy.
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Onoi, Keisuke, Yusuke Chihara, Junji Uchino, Takayuki Shimamoto, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Tadaaki Yamada, and Koichi Takayama. "Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review." Journal of Clinical Medicine 9, no. 5 (May 6, 2020): 1362. http://dx.doi.org/10.3390/jcm9051362.
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The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.
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Xiao, Gang, Zhiyuan Liu, Xuan Gao, Han Wang, Haiqin Peng, Jiahui Li, Lei Yang, Hexin Duan, and Rongrong Zhou. "Immune checkpoint inhibitors for brain metastases in non-small-cell lung cancer: from rationale to clinical application." Immunotherapy 13, no. 12 (August 2021): 1031–51. http://dx.doi.org/10.2217/imt-2020-0262.
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Brain metastases (BM) is common in non-small-cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors (ICIs) have gradually become a routine treatment for NSCLC BM patients. Currently, three PD-1 inhibitors (pembrolizumab, nivolumab and cemiplimab), one PD-L1 inhibitor (atezolizumab) and one CTLA-4 inhibitor (ipilimumab) have been approved for the first-line treatment of metastatic NSCLC. It is still controversial whether PD-L1, tumor infiltrating lymphocytes, and tumor mutation burden can be used as predictive biomarkers for immune checkpoint inhibitors in NSCLC patients with BM. In addition, clinical data on NSCLC BM were inadequate. Here, we review the theoretical basis and clinical data for the application of ICIs in the therapy of NSCLC BM.
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Lopez-Beltran, Antonio, Alessia Cimadamore, Ana Blanca, Francesco Massari, Nuno Vau, Marina Scarpelli, Liang Cheng, and Rodolfo Montironi. "Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer." Cancers 13, no. 1 (January 3, 2021): 131. http://dx.doi.org/10.3390/cancers13010131.
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A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.
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Alkharabsheh, Omar, Zachary Trisel, Sunil Badami, Mohammed A. Aljama, and M. Hasib Sidiqi. "Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises." Cancers 14, no. 1 (December 27, 2021): 113. http://dx.doi.org/10.3390/cancers14010113.
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Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.
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Ando, Hiroyuki, Kunihiro Suzuki, and Toyoshi Yanagihara. "Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis." Biomedicines 9, no. 10 (October 16, 2021): 1484. http://dx.doi.org/10.3390/biomedicines9101484.
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Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment.
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Harris, Kevin B., Pauline Funchain, and Brian B. Baggott. "CMV coinfection in treatment refractory immune checkpoint inhibitor colitis." BMJ Case Reports 13, no. 5 (May 2020): e233519. http://dx.doi.org/10.1136/bcr-2019-233519.
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As immune checkpoint inhibitors (ICIs) are increasingly used, clinicians are more frequently encountering the side effects of these therapies. ICIs have been implicated in numerous adverse effects against healthy tissues. We present a case of a patient who developed treatment refractory checkpoint inhibitor colitis. Following colonoscopy, it was discovered that this patient had cytomegalovirus (CMV) coinfection. This case report highlights the importance of undertaking an appropriate assessment, including endoscopic and histologic investigation, of patients with presumed ICI colitis. Accurately diagnosing a superimposed CMV colitis changes clinical management and can improve patient outcomes.
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Marini, Alessandro, Andrea Bernardini, Gian Luigi Gigli, Mariarosaria Valente, Sergio Muñiz-Castrillo, Jérôme Honnorat, and Alberto Vogrig. "Neurologic Adverse Events of Immune Checkpoint Inhibitors." Neurology 96, no. 16 (March 2, 2021): 754–66. http://dx.doi.org/10.1212/wnl.0000000000011795.
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ObjectiveTo define the clinical characteristics, management, and outcome of neurologic immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs).MethodsSystematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.ResultsA total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on CNS disorders (109/428, 25%). The most common n-irAEs reports were myositis (136/428, 32%), Guillain-Barré syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared with the whole sample, myasthenic syndromes were significantly more Ab positive (33/56, 59%; p < 0.001). Anti–programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; p = 0.005) and less common in meningitis (2/13, 15%; p < 0.001) and cranial neuropathies (13/31, 42%; p = 0.005). Anti–cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; p < 0.001) and less common in encephalitis (2/56, 4%; p = 0.009) and myositis (12/136, 9%; p = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p = 0.003) and less common in encephalitis (19/56, 34%; p = 0.001). The highest mortality rate was reached in myasthenic syndromes (28%).ConclusionConsidering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.
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Schmidt, Laura, Brian McGuire, Wendy Hui, George W. Carro, Thomas A. Hensing, Daniel H. Shevrin, Nicholas Paul Campbell, Britt Erika Hanson, and Bruce Brockstein. "Immune checkpoint inhibitor toxicity in the clinical practice setting." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14128-e14128. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14128.
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e14128 Background: Immune checkpoint inhibitors (ICIs) are changing the landscape of treatment in oncology. The use of ICIs is growing rapidly as the indications for these medications broaden and new ICIs become approved. Given the rapid growth and relative infancy of the use of ICIs, much information stands to be gained on their use in the clinical practice setting, especially regarding toxicity. Methods: The primary objective of this project was to examine the incidence and severity of immune-related adverse events (irAEs), after treatment with single-agent or combination ICIs at a multi-site community cancer center. A retrospective chart review was conducted on all patients who had received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab plus nivolumab from May 1, 2011 to June 30, 2017. Data collected included patient demographics, disease state, treatment information, preexisting autoimmune disease, previous immunotherapy, and adverse event details. The results were analyzed using descriptive statistics. Results: Data was collected on 383 patients. Dermatologic irAEs were common across single agent ICIs (overall incidence 23%). Diarrhea and/or colitis incidence was highest with CTLA-4 inhibitor ipilimumab (26% at 3 mg/kg and 22% at 10 mg/kg) versus the other monotherapy PD-1/PDL-1 inhibitors. Endocrinopathies were most common with ipilimumab 10 mg/kg (55%) and pneumonitis incidence was highest with nivolumab (6%). ICI toxicity occurred in 63% of patients with preexisting autoimmune disease versus 54% of those without a baseline autoimmune disease. Incidence of hospitalization and treatment holds due to irAEs was higher with combination therapy (57% and 66%, respectively) than with monotherapy (10% and 24%, respectively). Conclusions: Overall, there was increased incidence in ICI toxicity in patients at this oncology institution versus what has been reported in clinical trials. Patients with preexisting autoimmune diseases appeared to have mainly low-grade toxicities with slightly increased incidence of irAE compared with those without pre-existing autoimmune disease. Treatment holds and hospitalizations were higher in patients treated with combination therapy ICIs compared to monotherapy ICIs.
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Shek, Dmitrii, Scott A. Read, Liia Akhuba, Liang Qiao, Bo Gao, Adnan Nagrial, Matteo S. Carlino, and Golo Ahlenstiel. "Non-coding RNA and immune-checkpoint inhibitors: friends or foes?" Immunotherapy 12, no. 7 (May 2020): 513–29. http://dx.doi.org/10.2217/imt-2019-0204.
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Non-coding RNAs (ncRNAs) are an abundant component of the human transcriptome. Their biological role, however, remains incompletely understood. Nevertheless, ncRNAs are highly associated with cancer development and progression due to their ability to modulate gene expression, protein translation and growth pathways. Immune-checkpoint inhibitors (ICIs) are considered one of the most promising and highly effective therapeutic approaches for cancer treatment. ICIs are monoclonal antibodies targeting immune checkpoints such as CTLA-4, PD-1 and PD-L1 signalling pathways that stimulate T cell cytotoxicity and can result in tumor growth suppression. This Review will summarize existing knowledge regarding ncRNAs and their role in cancer and ICI therapy. In addition, we will discuss potential mechanisms by which ncRNAs may influence ICI treatment outcomes.
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Özdemir, Berna C. "Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology." Journal for ImmunoTherapy of Cancer 9, no. 2 (February 2021): e002220. http://dx.doi.org/10.1136/jitc-2020-002220.
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Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.
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Karasarides, Maria, Alexandria P. Cogdill, Paul B. Robbins, Michaela Bowden, Elizabeth M. Burton, Lisa H. Butterfield, Alessandra Cesano, et al. "Hallmarks of Resistance to Immune-Checkpoint Inhibitors." Cancer Immunology Research 10, no. 4 (March 14, 2022): 372–83. http://dx.doi.org/10.1158/2326-6066.cir-20-0586.
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Abstract Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.
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De Keukeleire, Stijn J., Tijl Vermassen, Zahra M. Nezhad, Tessa Kerre, Vibeke Kruse, Hans Van Vlierberghe, Karim Vermaelen, and Sylvie Rottey. "Managing viral hepatitis in cancer patients under immune checkpoint inhibitors: should we take the risk?" Immunotherapy 13, no. 5 (April 2021): 409–18. http://dx.doi.org/10.2217/imt-2020-0273.
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More patients with chronic hepatitis B and C infection are being exposed to immune checkpoint inhibitors (ICIs), but the safety and efficacy of ICIs in patients with chronic viral hepatitis are still poorly described. To explore this interaction, we identified eight studies of cancer patients with viral hepatitis treated with one or more ICIs, formally assessed tumor responses and safety by grading liver dysfunction. ICIs appear to be relatively safe in HBV/HCV-infected patients, and hepatitis related to viral reactivation is rare. In some patients, viral load regressed during ICI treatment, so immune checkpoints may play a role in viral clearance. HBV/HCV do not appear to be a contraindication to ICIs, although careful clinical and biochemical follow-up is recommended and, whenever necessary, antiviral therapy commenced.
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An, Ho Jung, Hong Jae Chon, and Chan Kim. "Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors." International Journal of Molecular Sciences 22, no. 17 (August 30, 2021): 9414. http://dx.doi.org/10.3390/ijms22179414.
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As cancer immunotherapy using immune checkpoint inhibitors (ICIs) is rapidly evolving in clinical practice, it is necessary to identify biomarkers that will allow the selection of cancer patients who will benefit most or least from ICIs and to longitudinally monitor patients’ immune responses during treatment. Various peripheral blood-based immune biomarkers are being identified with recent advances in high-throughput multiplexed analytical technologies. The identification of these biomarkers, which can be easily detected in blood samples using non-invasive and repeatable methods, will contribute to overcoming the limitations of previously used tissue-based biomarkers. Here, we discuss the potential of circulating immune cells, soluble immune and inflammatory molecules, circulating tumor cells and DNA, exosomes, and the blood-based tumor mutational burden, as biomarkers for the prediction of immune responses and clinical benefit from ICI treatment in patients with advanced cancer.
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Pandey, Pratibha, Fahad Khan, Huda A. Qari, Tarun Kumar Upadhyay, Abdulhameed F. Alkhateeb, and Mohammad Oves. "Revolutionization in Cancer Therapeutics via Targeting Major Immune Checkpoints PD-1, PD-L1 and CTLA-4." Pharmaceuticals 15, no. 3 (March 9, 2022): 335. http://dx.doi.org/10.3390/ph15030335.
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Numerous research reports have witnessed dramatic advancements in cancer therapeutic approaches through immunotherapy. Blocking immunological checkpoint pathways (mechanisms employed by malignant cells to disguise themselves as normal human body components) has emerged as a viable strategy for developing anticancer immunity. Through the development of effective immune checkpoint inhibitors (ICIs) in multiple carcinomas, advances in cancer immunity have expedited a major breakthrough in cancer therapy. Blocking a variety of ICIs, such as PD-1 (programmed cell death-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved the immune system’s efficacy in combating cancer cells. Recent studies also supported the fact that ICIs combined with other potent antitumor candidates, such as angiogenic agents, could be a solid promising chemopreventive therapeutic approach in improving the effectiveness of immune checkpoint inhibitors. Immune checkpoint blockade has aided antiangiogenesis by lowering vascular endothelial growth factor expression and alleviating hypoxia. Our review summarized recent advances and clinical improvements in immune checkpoint blocking tactics, including combinatorial treatment of immunogenic cell death (ICD) inducers with ICIs, which may aid future researchers in creating more effective cancer-fighting strategies.
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Remon, Jordi, Francesco Facchinetti, and Benjamin Besse. "The efficacy of immune checkpoint inhibitors in thoracic malignancies." European Respiratory Review 30, no. 162 (October 5, 2021): 200387. http://dx.doi.org/10.1183/16000617.0387-2020.
Full textAbstract:
The advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm for multiple cancer types, including thoracic malignancies. In advanced non-small cell lung cancer (NSCLC), ICIs have shifted treatment paradigm and improved overall survival reaching almost one-third of patients alive at 5 years. ICIs therapies have also modified the therapeutic strategy in first-line setting in metastatic small-cell lung cancer (SCLC) patients as well as in malignant pleural mesothelioma (MPM) improving the overall survival compared with standard treatment. This phenomenon is of huge relevance as both SCLC and MPM were considered orphan diseases without any significant improvement in the therapeutic strategy in the first-line setting during the last 15 years. In this review, we aim to review the efficacy of ICI in thoracic malignancies either in monotherapy or in combination, according to predictive biomarkers, and to the US Food and Drug Administration and the European Medicines Agency approvals of treatment strategies. We address the efficacy of these agents, especially in NSCLC according to PD-L1 expression and histologic subtype.
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Melissaropoulos, Konstantinos, Kalliopi Klavdianou, Alexandra Filippopoulou, Fotini Kalofonou, Haralabos Kalofonos, and Dimitrios Daoussis. "Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors." International Journal of Molecular Sciences 21, no. 9 (May 11, 2020): 3389. http://dx.doi.org/10.3390/ijms21093389.
Full textAbstract:
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. Their clinical efficacy is well-documented, but the side effects associated with their use are still under investigation. These drugs cause several immune-related adverse events (ir-AEs), some of which stand within the field of rheumatology. Herein, we present a literature review performed in an effort to evaluate all publicly available clinical data regarding rheumatic manifestations associated with ICIs. The most common musculoskeletal ir-AEs are inflammatory arthritis, polymyalgia rheumatica and myositis. Non-musculoskeletal rheumatic manifestations are less frequent, with the most prominent being sicca, vasculitides and sarcoidosis. Cases of systemic lupus erythematosus or scleroderma are extremely rare. The majority of musculoskeletal ir-AEs are of mild/moderate severity and can be managed with steroids with no need for ICI discontinuation. In severe cases, more intense immunosuppressive therapy and permanent ICI discontinuation may be employed. Oncologists should periodically screen patients receiving ICIs for new-onset inflammatory musculoskeletal complaints and seek a rheumatology consultation in cases of persisting symptoms.
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Vilariño, Noelia, Jordi Bruna, Foteini Kalofonou, Garifallia G. Anastopoulou, and Andreas A. Argyriou. "Immune-Driven Pathogenesis of Neurotoxicity after Exposure of Cancer Patients to Immune Checkpoint Inhibitors." International Journal of Molecular Sciences 21, no. 16 (August 11, 2020): 5774. http://dx.doi.org/10.3390/ijms21165774.
Full textAbstract:
Over the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several cancer types. ICIs work through the blockage of immune inhibitory signals, while increasing the T-cell specific immune antitumoral response. However, due to the fact that ICIs’ mechanism of action is not tissue antigen-specific and not limited to the tumor microenvironment, the use of cancer immunotherapy can produce a broad range of immune-related adverse events (irAEs). Neurological immune-related adverse events (NirAEs) are rare (the overall incidence varies between 1% to 6%), and these adverse events mainly concern the peripheral nervous system, rather than the central nervous system. Due to their potential severity, which could cause interruptions to cancer treatment, NirAEs are of particular clinical importance. Currently, the pathogenesis of these complications is not completely understood, although T-cells seem to play a principal role. Nevertheless, the development of NirAEs is likely to be a multifactorial and complex process. This conclusion can be extracted from the wide range of neurological auto-inflammatory and autoimmune disorders triggered or exacerbated by ICIs, and the extensive variability of the limited histological findings reported. The aim of this review is to summarize the potential immune-driven pathological mechanisms of NirAEs.
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Schmerling, Rafael A., Antonio C. Buzaid, Carolina K. Haddad, Fabio AB Schutz, Fabio R. Kater, Juliana Pimenta, Fernando Maluf, et al. "Immune manifestations with checkpoint inhibitors in a single Brazilian center: experience and literature review." Future Science OA 7, no. 1 (January 2021): FSO655. http://dx.doi.org/10.2144/fsoa-2020-0129.
Full textAbstract:
Objectives: The presence of autoimmune events were recorded in patients receiving immune checkpoint inhibitors. Materials & Methods: Retrospective study in patients receiving immune checkpoint inhibitors (ICIs) during the period of 2012–2019. Results: A total of 554 patients received ICIs of which 123 developed an immune related adverse event. Twenty one (17%) with toxicity were identified as having a pre-existing autoimmune disease and 88 required treatment with corticosteroids or hormone replacement. Thirty two (26%) out of 123 had to temporarily discontinue ICIs due to autoimmune manifestations. Endocrine and skin manifestations were the most prevalent immune disorders in our cohort. In melanoma better efficacy was seen in patients with immune toxicity. Conclusion: Autoimmune diseases appear in patients receiving ICIs in this real world experience. Our results differ from other series on the frequency of autoimmunity. Complete discontinuation of ICIs due to autoimmunity was rare.
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Menshikova, I. V., and V. V. Strogonova. "Immune-mediated adverse rheumatic reactions following administration of immune checkpoint inhibitors." Rheumatology Science and Practice 58, no. 4 (September 4, 2020): 443–46. http://dx.doi.org/10.47360/1995-4484-2020-443-446.
Full textAbstract:
Immunotherapy with immune checkpoint inhibitors (ICIs) opens up new prospects in treatment of malignancies, although this novel therapy quite often results in development of immune-related adverse events (irAEs), which can limit their clinical use. IrAEs can affect almost any organ system, including the endocrine, respiratory, digestive, nervous, other organs and the skin. Most often irAEs are characterized by moderate degree of severity, but complications are fatal in 2% of patients.The nature of irAEs significantly differs from the adverse reactions associated with use of standard chemotherapeutic agents, which usually cause immunosuppression (due to neutropenia). Of particular interest to clinicians are rheumatic irAEs, which can occur at any time after treatment and tend to persist even after ICIs discontinuation. This review analyzes the prevalence, clinical characteristics, and approaches to treatment of rheumatic irAEs.
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Hwang, June Kyu, JinWoo Hong, and Chae-Ok Yun. "Oncolytic Viruses and Immune Checkpoint Inhibitors: Preclinical Developments to Clinical Trials." International Journal of Molecular Sciences 21, no. 22 (November 16, 2020): 8627. http://dx.doi.org/10.3390/ijms21228627.
Full textAbstract:
Immuno-oncology (IO) has been an active area of oncology research. Following US FDA approval of the first immune checkpoint inhibitor (ICI), ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody), in 2011, and of the first oncolytic virus, Imlygic (talimogene laherparepvec), in 2015, there has been renewed interest in IO. In the past decade, ICIs have changed the treatment paradigm for many cancers by enabling better therapeutic control, resuming immune surveillance, suppressing tumor immunosuppression, and restoring antitumor immune function. However, ICI therapies are effective only in a small subset of patients and show limited therapeutic potential due to their inability to demonstrate efficacy in ‘cold’ or unresponsive tumor microenvironments (TMEs). Relatedly, oncolytic viruses (OVs) have been shown to induce antitumor immune responses, augment the efficacy of existing cancer treatments, and reform unresponsive TME to turn ‘cold’ tumors ‘hot,’ increasing their susceptibility to checkpoint blockade immunotherapies. For this reason, OVs serve as ideal complements to ICIs, and multiple preclinical studies and clinical trials are demonstrating their combined therapeutic efficacy. This review will discuss the merits and limitations of OVs and ICIs as monotherapy then progress onto the preclinical rationale and the results of clinical trials of key combination therapies.