Lights and Shadows on Managing Immune Checkpoint Inhibitors in Oncology during the COVID-19 Era.
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ABSTRACT:
SUBMITTER: Burgaletto C
PROVIDER: S-EPMC8071446 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDuring COVID-19 outbreak, oncological care has been reorganized. Patients with cancer have been reported to experience a more severe COVID-19 syndrome; moreover, there are concerns of a potential interference between immune checkpoint inhibitors (ICIs) and SARS-CoV-2 pathogenesis.Materials and methodsBetween 6 and 16 May 2020, a 22-item survey was sent to Italian physicians involved in administering ICIs. It aimed at exploring the perception about SARS-CoV-2-related risks in cancer patients receiving ICIs, and the attitudes towards their management.ResultsThe 104 respondents had a median age of 35.5 years, 58.7% were females and 71.2% worked in Northern Italy. 47.1% of respondents argued a synergism between ICIs and SARS-CoV-2 pathogenesis leading to worse outcomes, but 97.1% would not deny an ICI only for the risk of infection. During COVID-19 outbreak, to reduce hospital visits, 55.8% and 30.8% opted for the highest labelled dose of each ICI and/or, among different ICIs for the same indication, for the one with the longer interval between cycles, respectively. 53.8% of respondents suggested testing for SARS-CoV-2 every cancer patient candidate to ICIs. 71.2% declared to manage patients with onset of dyspnoea and cough as infected by SARS-CoV-2 until otherwise proven; however, 96.2% did not reduce the use of steroids to manage immune-related toxicities. The administration of ICIs in specific situations for different cancer types has not been drastically conditioned.ConclusionsThese results highlight the uncertainties around the perception of a potential interference between ICIs and COVID-19, supporting the need of focused studies on this topic.
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Project description:At the end of December 2019, a novel coronavirus, the severe acute respiratory syndrome coronavirus 2, caused an outbreak of pneumonia spreading from Wuhan, Hubei province, to the whole country of China and then the entire world, forcing the World Health Organization to make the assessment that the coronavirus disease (COVID-19) can be characterized as a pandemic, the first ever caused by a coronavirus. To date, clinical evidence and guidelines based on reliable data and randomized clinical trials for the treatment of COVID-19 are lacking. In the absence of definitive management protocols, many treatments for COVID-19 are currently being evaluated and tested worldwide. Some of these options were soon abandoned due to ineffectiveness, while others showed promising results. The basic treatments are mainly represented by antiviral drugs, even if the evidence is not satisfactory. Among the antivirals, the most promising appears to be remdesivir. Corticosteroids and tocilizumab seem to guarantee positive results in selected patients so far, although the timing of starting therapy and the most appropriate therapeutic schemes remain to be clarified. Efficacy of the other drugs is still uncertain, and they are currently used as a cocktail of treatments in the absence of definitive guidelines. What will represent the real solution to the enormous problem taking place worldwide is the identification of a safe and effective vaccine, for which enormous efforts and investments are underway.
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Project description:Genetic alterations in CRC have shown a negative predictive and prognostic role in specific target therapies. The onset of immunotherapy has also undergone remarkable therapeutic innovation, although limited to a small subgroup of patients, the MSI-H/dMMR, which represents only 5% of CRC. Research is moving forward to identify whether other biomarkers can predict response to ICIs, despite various limitations regarding expression and identification methods. For this purpose, TMB, LAG3, and PD-L1 expression have been retrospectively evaluated in several solid tumors establishing the rationale to design clinical trials with concurrent inhibition of LAG3 and PD-1 results in a significant advantage in PFS and OS in advanced melanoma patients. Based on these data, there are clinical trials ongoing in the CRC as well. This review aims to highlight what is already known about genetic mutations and genomic alterations in CRC, their inhibition with targeted therapies and immune checkpoints inhibitors, and new findings useful to future treatment strategies.
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Project description:Cancer manifestation is a multistep process involving accumulation of various genetic and epigenetic changes that results in oncogenic "hallmarks of cancer" processes including genomic instability. Exploitation of aberrant DNA-damage response (DDR) mechanisms in cancer is in part a goal of many therapeutic strategies, and recent evidence supports the role of targeting DDR in modulating the tumor immune microenvironment to enhance immunotherapeutic response. Improved cancer profiling, including next-generation and whole-genome mutational sequencing of tumor tissue, as well as circulating nucleic acids, has enhanced our understanding of the genetic and epigenetic molecular mechanisms in tumorigenesis and will become fundamental to precisely target tumors and achieve cancer control. With the successes of poly(ADP-ribose) polymerase inhibitors (PARPi) and immunotherapies, the intersection of DDR molecular machinery and corresponding antitumor immune response has gained much interest with a focus on achieving therapeutic synergy using DNA damage-targeting agents and immunotherapy. In this review, we provide a bench-to-bedside overview of the fundamentals of DDR signaling and repair as they relate to cancer therapeutic strategies including novel DDR-targeting agents. We also discuss the underlying mechanisms that link DDR signaling to antitumor immunity and immunotherapy efficacy, and how this knowledge can be used to improve precision medicine approaches in the treatment of cancer.
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Project description:Congenital abnormalities cause serious fetal consequences. The term TORCH is used to designate the most common perinatal infections, where: (T) refers to toxoplasmosis, (O) means "others" and includes syphilis, varicella-zoster, parvovirus B19, zika virus (ZIKV), and malaria among others, (R) refers to rubella, (C) relates to cytomegalovirus infection, and (H) to herpes simplex virus infections. Among the main abnormalities identified in neonates exposed to congenital infections are central nervous system (CNS) damage, microcephaly, hearing loss, and ophthalmological impairment, all requiring regular follow-up to monitor its progression. Protein changes such as mutations, post-translational modifications, abundance, structure, and function may indicate a pathological condition before the onset of the first symptoms, allowing early diagnosis and understanding of a particular disease or infection. The term "proteomics" is defined as the science that studies the proteome, which consists of the total protein content of a cell, tissue or organism in a given space and time, including post-translational modifications (PTMs) and interactions between proteins. Currently, quantitative bottom-up proteomic strategies allow rapid and high throughput characterization of complex biological mixtures. Investigating proteome modulation during host-pathogen interaction helps in elucidating the mechanisms of infection and in predicting disease progression. This "molecular battle" between host and pathogen is a key to identify drug targets and diagnostic markers. Here, we conducted a survey on proteomic techniques applied to congenital diseases classified in the terminology "TORCH", including toxoplasmosis, ZIKV, malaria, syphilis, human immunodeficiency virus (HIV), herpes simplex virus (HSV) and human cytomegalovirus (HCVM). We have highlighted proteins and/or protein complexes actively involved in the infection. Most of the proteomic studies reported have been performed in cell line models, and the evaluation of tissues (brain, muscle, and placenta) and biofluids (plasma, serum and urine) in animal models is still underexplored. Moreover, there are a plethora of studies focusing on the pathogen or the host without considering the triad mother-fetus-pathogen as a dynamic and interconnected system.
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Project description:In cases of cellular injury, there is an observed increase in the production of reactive oxygen species (ROS). When this production becomes excessive, it can result in various conditions, including cancerogenesis. Glutathione (GSH), the most abundant thiol-containing antioxidant, is fundamental to re-establishing redox homeostasis. In order to evaluate the role of GSH and its antioxi-dant effects in patients affected by cancer, we performed a thorough search on Medline and EMBASE databases for relevant clinical and/or preclinical studies, with particular regard to diet, toxicities, and pharmacological processes. The conjugation of GSH with xenobiotics, including anti-cancer drugs, can result in either of two effects: xenobiotics may lose their harmful effects, or GSH conjugation may enhance their toxicity by inducing bioactivation. While being an interesting weapon against chemotherapy-induced toxicities, GSH may also have a potential protective role for cancer cells. New studies are necessary to better explain the relationship between GSH and cancer. Although self-prescribed glutathione (GSH) implementation is prevalent among cancer patients with the intention of reducing the toxic effects of anticancer treatments and potentially preventing damage to normal tissues, this belief lacks substantial scientific evidence for its efficacy in reducing toxicity, except in the case of cisplatin-related neurotoxicity. Therefore, the use of GSH should only be considered under medical supervision, taking into account the appropriate timing and setting.
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Project description:Vaccines to prevent acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicit an immune neutralizing response. Some concerns have been raised regarding the safety of SARS-CoV-2 vaccines, largely based on case-reports of serious thromboembolic events after vaccination. Some mechanisms have been suggested which might explain the adverse cardiovascular reactions to SARS-CoV-2 vaccines. Different vaccine platforms are currently available which include live attenuated vaccines, inactivated vaccines, recombinant protein vaccines, vector vaccines, DNA vaccines and RNA vaccines. Vaccines increase the endogenous synthesis of SARS-CoV-2 Spike proteins from a variety of cells. Once synthetized, the Spike proteins assembled in the cytoplasma migrate to the cell surface and protrude with a native-like conformation. These proteins are recognized by the immune system which rapidly develops an immune response. Such response appears to be quite vigorous in the presence of DNA vaccines which encode viral vectors, as well as in subjects who are immunized because of previous exposure to SARS-CoV-2. The resulting pathological features may resemble those of active coronavirus disease. The free-floating Spike proteins synthetized by cells targeted by vaccine and destroyed by the immune response circulate in the blood and systematically interact with angiotensin converting enzyme 2 (ACE2) receptors expressed by a variety of cells including platelets, thereby promoting ACE2 internalization and degradation. These reactions may ultimately lead to platelet aggregation, thrombosis and inflammation mediated by several mechanisms including platelet ACE2 receptors. Whereas Phase III vaccine trials generally excluded participants with previous immunization, vaccination of huge populations in the real life will inevitably include individuals with preexisting immunity. This might lead to excessively enhanced inflammatory and thrombotic reactions in occasional subjects. Further research is urgently needed in this area.
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Project description:Cancer is classically considered a disease of aging, with over half of all new cancer diagnoses occurring in patients over the age of 65 years. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet the participation of older adults with cancer in ICI trials has been suboptimal, particularly at the extremes of age. Despite significant improvement in treatment response and an improved toxicity profile when compared with conventional cytotoxic chemotherapies, many cancers develop resistance to ICIs, and these drugs are not free of toxicities. This becomes particularly important in the setting of older adults with cancer, who are generally frailer and harbor more comorbidities than do their younger counterparts. Immunosenescence, a concept involving age-related changes in immune function, may also play a role in differential responses to ICI treatment in older patients. Data on ICI treatment response in older adult with cancers remains inconclusive, with multiple studies revealing conflicting results. The molecular mechanisms underlying response to ICIs in older cancer patients are poorly understood, and predictors of response that can delineate responders from non-responders remain to be elucidated. In this review, we explore the unique geriatric oncology population by analyzing existing retrospective datasets, and we also sought to highlight potential cellular, inflammatory, and molecular changes associated with aging as potential biomarkers for response to ICIs.
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Project description:This review aims to provide an understanding of the diagnostic and therapeutic challenges of uveitis associated with immune checkpoint inhibitors (ICI). In the wake of these molecules being increasingly employed as a treatment against different cancers, cases of uveitis post-ICI therapy have also been increasingly reported in the literature, warranting an extensive exploration of the clinical presentations, risk factors, and pathophysiological mechanisms of ICI-induced uveitis. This review further provides an understanding of the association between ICIs and uveitis, and assesses the efficacy of current diagnostic tools, underscoring the need for advanced techniques to enable early detection and accurate assessment. Further, it investigates the therapeutic strategies for ICI-related uveitis, weighing the benefits and limitations of existing treatment regimens, and discussing current challenges and emerging therapies in the context of their potential efficacy and side effects. Through an overview of the short-term and long-term outcomes, this article suggests recommendations and emphasizes the importance of multidisciplinary collaboration between ophthalmologists and oncologists. Finally, the review highlights promising avenues for future research and development in the field, potentially informing transformative approaches in the ocular assessment of patients under immunotherapy and the management of uveitis following ICI therapy.
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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy.
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