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Oral Oncology Dec 2022Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment... (Meta-Analysis)
Meta-Analysis Review
Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment (TME). In this systematic review and meta-analysis, studies assessing tumor infiltration with CD68+, iNOS+, HLA-DR+, CD11b+, CD163+, CD206+, and CD204+TAMs were included, and correlation to survival hazard was studied. A low number of CD68+TAMs correlated to better overall survival (OS) in multivariate analysis (HR 1.36 95 %CI (1.07-1.72) P = .01). CD68+TAMs did not correlate to disease free survival (DFS), disease specific survival (DSS), progression free survival (PFS), or recurrence free survival (RFS). A low number of CD163+TAMs correlated to better OS in uni- and multivariate analysis (resp. HR 2.65 95 %CI (1.57-4.46) P = .01 and HR 2.42 95 %CI (1.72-3.41) P < .001). A low number of CD163+TAMs also correlated to better DFS and PFS, whereas a low number of CD204+TAMs only correlated to PFS. While IHC analysis of pan macrophage marker CD68 and M2-like marker CD163 both show prognostic utility in OS, CD163 is a stronger prognosticator, as indicated by multivariate meta-analysis. CD163+TAMs also correlate to DFS and PFS; outcomes that are more relevant to patients, thus showing promising results for future clinical implementation.
Topics: Humans; Prognosis; Squamous Cell Carcinoma of Head and Neck; Tumor-Associated Macrophages; Antigens, Differentiation, Myelomonocytic; Tumor Microenvironment; Head and Neck Neoplasms
PubMed: 36335818
DOI: 10.1016/j.oraloncology.2022.106227 -
Frontiers in Immunology 2022There is evidence that the adaptive or acquired immune system is one of the crucial variables in differentiating the course of coronavirus disease 2019 (COVID-19),...
BACKGROUND
There is evidence that the adaptive or acquired immune system is one of the crucial variables in differentiating the course of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This work aimed to analyze the immunopathological aspects of adaptive immunity that are involved in the progression of this disease.
METHODS
This is a systematic review based on articles that included experimental evidence from assays, cohort studies, reviews, cross-sectional and case-control studies from PubMed, SciELO, MEDLINE, and Lilacs databases in English, Portuguese, or Spanish between January 2020 and July 2022.
RESULTS
Fifty-six articles were finalized for this review. CD4+ T cells were the most resolutive in the health-disease process compared with B cells and CD8+ T lymphocytes. The predominant subpopulations of T helper lymphocytes (Th) in critically ill patients are Th1, Th2, Th17 (without their main characteristics) and regulatory T cells (Treg), while in mild cases there is an influx of Th1, Th2, Th17 and follicular T helper cells (Tfh). These cells are responsible for the secretion of cytokines, including interleukin (IL) - 6, IL-4, IL-10, IL-7, IL-22, IL-21, IL-15, IL-1α, IL-23, IL-5, IL-13, IL-2, IL-17, tumor necrosis factor alpha (TNF-α), CXC motivating ligand (CXCL) 8, CXCL9 and tumor growth factor beta (TGF-β), with the abovementioned first 8 inflammatory mediators related to clinical benefits, while the others to a poor prognosis. Some CD8+ T lymphocyte markers are associated with the severity of the disease, such as human leukocyte antigen (HLA-DR) and programmed cell death protein 1 (PD-1). Among the antibodies produced by SARS-CoV-2, Immunoglobulin (Ig) A stood out due to its potent release associated with a more severe clinical form.
CONCLUSIONS
It is concluded that through this study it is possible to have a brief overview of the main immunological biomarkers and their function during SARS-CoV-2 infection in particular cell types. In critically ill individuals, adaptive immunity is varied, aberrantly compromised, and late. In particular, the T-cell response is also an essential and necessary component in immunological memory and therefore should be addressed in vaccine formulation strategies.
Topics: Humans; COVID-19; Programmed Cell Death 1 Receptor; SARS-CoV-2; Interleukin-10; Interleukin-15; Interleukin-17; Interleukin-13; Tumor Necrosis Factor-alpha; Cross-Sectional Studies; Critical Illness; Ligands; Interleukin-2; Interleukin-4; Interleukin-5; Interleukin-7; Adaptive Immunity; HLA-DR Antigens; Interleukin-23; Inflammation Mediators; Transforming Growth Factor beta; Immunoglobulins
PubMed: 36300105
DOI: 10.3389/fimmu.2022.1001198 -
Current Oncology (Toronto, Ont.) Sep 2022Chinese national guidelines recommend various systemic therapies for patients with advanced hepatocellular carcinoma (HCC), but optimal treatment selection remains... (Review)
Review
Chinese national guidelines recommend various systemic therapies for patients with advanced hepatocellular carcinoma (HCC), but optimal treatment selection remains uncertain. To summarize the evidence supporting the systemic treatment of Chinese patients with advanced HCC, we performed a systematic review using a literature search of PubMed, Embase, China National Knowledge Infrastructure, and the Chinese Scientific Journal Database between 1 January 2009 and 15 June 2021, and abstracts from ASCO 2020, ASCO GI 2021, ESMO 2020, and ESMO GI 2020. The inclusion criteria were: Chinese patients aged ≥18 years with advanced HCC; first- or second-line systemic therapy; an evaluation of the efficacy or safety outcomes; and a randomized controlled, non-randomized controlled, prospective, or retrospective design. Thirty reports were identified for the following therapies: the single-agent tyrosine kinase inhibitor (TKI; = 10), single-agent programmed death-1 (PD-1) inhibitor ( = 4), chemotherapy ( = 5), PD-1/programmed death-ligand 1 (PD-L1) inhibitor plus TKI ( = 6), PD-1/PD-L1 inhibitor plus bevacizumab or biosimilar ( = 4), and PD-1/PD-L1 inhibitor plus chemotherapy ( = 1). The heterogeneity between the studies precluded statistical analysis and the data were summarized using tables. In the first-line setting, evidence supported the use of atezolizumab or sintilimab plus bevacizumab or a biosimilar. There remains insufficient evidence to determine the optimal approved TKI-based therapeutic option, and active controlled trials in the second-line setting were lacking.
Topics: Humans; Adolescent; Adult; Carcinoma, Hepatocellular; B7-H1 Antigen; Bevacizumab; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Biosimilar Pharmaceuticals; Retrospective Studies; Prospective Studies; Liver Neoplasms; Protein Kinase Inhibitors
PubMed: 36290852
DOI: 10.3390/curroncol29100575 -
Blood Advances Jan 2023Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and... (Meta-Analysis)
Meta-Analysis
Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Anti-CD19 chimeric antigen receptor (CAR) T cells, effective in systemic large B-cell lymphoma (LBCL), have shown responses in PCNSL and SCNSL in early reports, but with limited sample size. We, therefore, performed a comprehensive systematic review and meta-analysis of all published data describing CAR T-cell use in PCNSL and SCNSL. This identified 128 patients with PCNSL (30) and SCNSL (98). Our primary objectives were to evaluate CAR T-cell specific toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS]) as well as response rates in these 2 populations. Seventy percent of patients with PCNSL had CRS of any grade (13% grade 3-4) and 53% had ICANS of any grade (18% grade 3-4). Comparatively, 72% of the SCNSL cohort experienced CRS of any grade (11% grade 3-4) and 48% had ICANS of any grade (26% grade 3-4). Of the patients with PCNSL, 56% achieved a complete remission (CR) with 37% remaining in remission at 6 months. Similarly, 47% of patients with SCNSL had a CR, with 37% in remission at 6 months. In a large meta-analysis of central nervous system (CNS) lymphomas, toxicity of anti-CD19-CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.
Topics: Humans; Antigens, CD19; Central Nervous System Neoplasms; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasms, Second Primary; Neurotoxicity Syndromes
PubMed: 36260735
DOI: 10.1182/bloodadvances.2022008525 -
Medicine Oct 2022Metastatic melanoma treatment has drastically changed during the past decade with the advent of immunotherapy. We conducted a meta-analysis, to assess PD-1 and CTLA-4... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Metastatic melanoma treatment has drastically changed during the past decade with the advent of immunotherapy. We conducted a meta-analysis, to assess PD-1 and CTLA-4 inhibitors in combination vs. alone for the treatment of advanced melanoma.
METHODS
The EMBASE, Medline via PubMed, Scopus, Cochrane Central, and Web of Science databases were searched. The records retrieved were screened for eligibility. Odds ratio (OR) was applied to compare dichotomous variables. All the results were reported with 95% confidence intervals (CI). Mantel-Haenszel method was used to estimate pooled OR and 95% confidence intervals for dichotomous data.
RESULTS
We retrieved 3092 citations of which we included 3 randomized controlled trials and 2 retrospective, cohort studies. The pooled OR was 2.144 (95% CI: 1.650-2.786, I2 = 80.38% P = .000) for overall response and 2.117 (95% CI: 1.578-2.841, I2 = 70.17% P = .000) for the complete response (CR). Subgroup analysis in nivolumab category showed that the pooled OR was 1.766 (95% CI: 1.324-2.355, I2 = 0.0% P = .000) for the overall response and was 1.284 (95% CI: 0.889-1.855, I2 = 0.0% P = .182) for the CR and in the ipilimumab category the pooled OR was 5.440 (95% CI: 2.896-10.220, I2 = 70.89% P = .001) for the overall response and was 5.169 (95% CI: 3.163-8.446, I2 = 0.0% P = .000) for the CR. The incidence of any treatment-related adverse events was significantly higher in the combination group than that of the nivolumab monotherapy 4.044 (95% CI: 1.740-9.403, I2 = 91.64% P = .001) or the ipilimumab monotherapy 2.465 (95% CI: 0.839-7.236, I2 = 93.02 % P = .101).
CONCLUSION
Combination therapy with ipilimumab plus nivolumab is a promising strategy in the treatment of patients with advanced melanoma with superior overall and complete responses over either monotherapies.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Immune Checkpoint Inhibitors; Ipilimumab; Melanoma; Nivolumab; Programmed Cell Death 1 Receptor; Retrospective Studies
PubMed: 36254050
DOI: 10.1097/MD.0000000000030561 -
Journal For Immunotherapy of Cancer Oct 2022The addition of cetuximab significantly increased the antitumor effect of programmed cell death protein 1 (PD-1) inhibitors in recurrent or metastatic head and neck... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The addition of cetuximab significantly increased the antitumor effect of programmed cell death protein 1 (PD-1) inhibitors in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, preliminary analyses suggested that human papillomavirus (HPV)-positive disease benefited less than HPV-negative disease. Therefore, we conducted a meta-analysis to assess whether the efficacy of the combination therapy varied according to HPV status in HNSCC.
METHODS
We identified clinical trials of patients with recurrent or metastatic HNSCC who received PD-1 inhibitor monotherapy or the combination therapy of cetuximab plus a PD-1 inhibitor. The participants were divided into four groups based on the type of therapy (combination vs monotherapy) and HPV status (positive vs negative). We focused on three comparisons (monotherapy vs combination therapy by HPV status and HPV-positive vs HPV-negative disease in combination therapy). The primary and secondary endpoints were objective response rate (ORR) and 1-year overall survival (OS) rate, respectively. The ORR and 1-year OS rate were pooled using random-effects models for each group and were compared for the different comparisons.
RESULTS
Overall, 802 patients from seven trials were eligible for the ORR assessment; of which, 684 patients received PD-1 inhibitor monotherapy and 118 patients underwent the combination therapy. Compared with PD-1 inhibitor monotherapy, the addition of cetuximab improved the ORR in HPV-negative disease (pooled ORR in monotherapy vs combination therapy: 15% vs 46%, p<0.001) but not in HPV-positive disease (17% vs 18%, p=0.686). The efficacy of adding cetuximab was consistent for the 1-year OS rate in HPV-negative disease (pooled 1-year OS rate in monotherapy vs combination therapy: 36% vs 59%, p<0.001) and in HPV-positive disease (40% vs 55%, p=0.252). After the combination therapy, HPV-positive disease had a significantly lower ORR than HPV-negative disease (odds ratio: 0.29, p=0.004), but no differences were shown in the 1-year OS rate.
CONCLUSIONS
Our meta-analysis suggests that the addition of cetuximab to a PD-1 inhibitor is more effective compared with PD-1 inhibitor monotherapy only in patients with HPV-negative HNSCC. Despite the retrospective nature of this meta-analysis, these findings should help in designing relevant clinical trials rationally.
Topics: Cetuximab; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Papillomaviridae; Papillomavirus Infections; Programmed Cell Death 1 Receptor; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck
PubMed: 36253001
DOI: 10.1136/jitc-2022-005158 -
World Journal of Surgical Oncology Oct 2022Immune checkpoint inhibitors (ICIs) have dramatically prolonged survival in non-small cell lung cancer (NSCLC) patients, but little research had focused on its impact on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immune checkpoint inhibitors (ICIs) have dramatically prolonged survival in non-small cell lung cancer (NSCLC) patients, but little research had focused on its impact on quality of life (QoL). The purpose of our study was to compare the QoL in patients with NSCLC treated with programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors versus chemotherapy.
METHODS
We searched for randomized controlled trials utilizing the Quality of Life Questionnaire Core 30 items (QLQ-C30) and the EuroQol Five Dimensions Questionnaire-3L (EQ-5D-3L) to assess the QoL of NSCLC treated with PD-1/PD-L1 inhibitors versus chemotherapy. We collected hazard ratios (HRs) for the time from baseline to the first clinically significant deterioration (TTD) and effect size as the difference in mean change between and within treatment groups in patients' reported outcomes (PROs). (PROSPERO registration number: CRD42022296680).
RESULTS
In the five trials reported by QLQ-C30, TTD was longer in PD-1/PD-L1 inhibitors compared with control groups (HR = 0.86; 95% CI = 0.76, 0.97; P = 0.013), with similar results in terms of physical function, role function, and pain. The difference in mean change between the PD-1/PD-L1 inhibitors group and the chemotherapy group in QLQ-C30 and EQ-5D VAS was 3.64 (95% CI = 1.62, 5.66; P = 0.001) and 4.74 (95% CI = 2.65, 6.83; P = 0.001), which supported PD-1/PD-L1 inhibitors. However, for the EQ-5D utility index, there was no statistically significant difference between the two groups, with a mean change difference of 0.03 (95% CI = -0.01, 0.07; P = 0.094). The mean change from baseline to follow-up in PD-1/PD-L1 inhibitors group was 2.57 (95% CI = 0.43, 4.71; P = 0.019), and chemotherapy group was -1.31 (95% CI = -3.71, 1.09; P = 0.284), correspondingly. The subgroup analysis showed that no difference was observed between open-label and double-blind trials in patients treated with chemotherapy or PD-1/PD-L1 inhibitors.
CONCLUSION
In conclusion, PD-1/PD-L1 inhibitors could improve the QoL of patients with NSCLC compared to chemotherapy and reduce unfavorable symptoms during treatment.
Topics: Apoptosis Regulatory Proteins; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Ligands; Lung Neoplasms; Programmed Cell Death 1 Receptor; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 36192730
DOI: 10.1186/s12957-022-02800-1 -
Frontiers in Immunology 2022Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of... (Meta-Analysis)
Meta-Analysis
Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of cardiovascular adverse events has not been fully investigated. We aimed to assess the the differences in cardiotoxicity among cancer patients receiving different ICI therapies. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. websites were searched for all randomized controlled trials (RCTs) of ICI. The primary outcomes were any grade cardiotoxicity and Grade 3-5 cardiotoxicity, the secondary outcomes were any grade myocarditis and Grade 3-5 myocarditis, with sub-analyses based on cancer type and does of ICI. A systematic review and frequency network meta-analysis were then performed for cardiotoxicity events. 91 RCTs (n=52247) involving 12 treatment arms were finally included. We observed that PD-L1 + CTLA-4 had the highest risk among all therapies inducing any grade cardiotoxicity, and the differences were significant except PD-1 + CTLA-4, PD-1 + TTD and PD-L1 + TTD. In addition, CTLA-4 had a higher risk of Grade 3-5 cardiotoxicity than PD-1 and anit-PD-L1. For Grade 1-5 myocarditis and Grade 3-5 myocarditis, no significant difference was found among differences therapies. No differences were observed in subgroup analyses according to does and cancer type. There were differences in the incidence of cardiotoxicity among different ICI therapies. For ICI monotherapy, CTLA-4 may be linked to Grade 3-5 cardiotoxicity than PD-1 or PD-L1. For dual therapy, the cardiotoxicity of dual ICI therapy seems to be higher than that of chemotherapy or targeted therapy.
Topics: B7-H1 Antigen; CTLA-4 Antigen; Cardiotoxicity; Humans; Immune Checkpoint Inhibitors; Myocarditis; Neoplasms; Network Meta-Analysis; Programmed Cell Death 1 Receptor
PubMed: 36189211
DOI: 10.3389/fimmu.2022.1006860 -
International Journal of Molecular... Sep 2022Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of... (Review)
Review
Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body's own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016-2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.
Topics: Antineoplastic Agents, Immunological; Apoptosis Regulatory Proteins; B7-H1 Antigen; CTLA-4 Antigen; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Ligands; Liver Neoplasms; Lung Neoplasms; Myocarditis; Programmed Cell Death 1 Receptor
PubMed: 36142866
DOI: 10.3390/ijms231810948 -
International Journal of Molecular... Sep 2022Several studies, although with conflicting results, have sought to determine the concentration of soluble CTLA4 antigens in peripheral blood plasma and peritoneal fluid... (Review)
Review
Several studies, although with conflicting results, have sought to determine the concentration of soluble CTLA4 antigens in peripheral blood plasma and peritoneal fluid in patients with endometriosis-related infertility. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) through a search of the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library, Health Technology Assessment Database and Web of Science, and Clinical Trials research register. We included observational or prospective human and animal studies with any features related to endometriosis and/or infertility studies involving CTLA4-related pathogenesis published in English. The results of studies in which the size and characteristics of the observed groups were not stated were excluded. From the initial pool of 73 publications identified and screened, we finally included 5 articles to summarize the most recent knowledge about CTLA4-linked autoimmunity in the pathogenesis of endometriosis and related infertility. Evidence from clinical studies shows that CTLA4-based autoimmunity is involved in the maintenance of chronic inflammation in the peritoneal environment, with pre-clinical evidence of anti-CTLA antibodies as a potential novel target therapy for endometriosis. However, CTLA4 gene analyses do not support findings of CTLA4-linked autoimmunity as a primary determinant of the pathogenesis of endometriosis. These findings underlie the role of complex interactions within the family of immune checkpoint molecules involved. Further studies are needed to investigate the clinical relevance of anti-CTLA target therapy, taking into account the potential adverse events and repercussions of novel immunologic therapy modalities. However, with the general scarcity of studies investigating this topic, the clinical importance of CTLA4 autoimmunity still remains unclear.
Topics: Animals; Autoimmunity; CTLA-4 Antigen; Endometriosis; Female; Humans; Immune Checkpoint Proteins; Infertility; Prospective Studies
PubMed: 36142815
DOI: 10.3390/ijms231810902