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Autoimmunity Reviews Jun 2023Giant cell arteritis is the most common form of large vessel vasculitis and preferentially involves large and medium-sized arteries in patients over the age of 50.... (Review)
Review
Giant cell arteritis is the most common form of large vessel vasculitis and preferentially involves large and medium-sized arteries in patients over the age of 50. Aggressive wall inflammation, neoangiogenesis and consecutive remodeling processes are the hallmark of the disease. Though etiology is unknown, cellular and humoral immunopathological processes are well understood. Matrix metalloproteinase-9 mediated tissue infiltration occurs through lysis of basal membranes in adventitial vessels. CD4+ cells attain residency in immunoprotected niches, differentiate into vasculitogenic effector cells and enforce further leukotaxis. Signaling pathways involve the NOTCH1-Jagged1 pathway opening vessel infiltration, CD28 mediated T-cell overstimulation, lost PD-1/PD-L1 co-inhibition and JAK/STAT signaling in interferon dependent responses. From a humoral perspective, IL-6 represents a classical cytokine and potential Th-cell differentiator whereas interferon-γ (IFN- γ) has been shown to induce chemokine ligands. Current therapies involve glucocorticoids, tocilizumab and methotrexate application. However, new agents, most notably JAK/STAT inhibitors, PD-1 agonists and MMP-9 blocking substances, are being evaluated in ongoing clinical trials.
Topics: Humans; Giant Cell Arteritis; Autoimmunity; Programmed Cell Death 1 Receptor; CD4-Positive T-Lymphocytes; Cytokines; Takayasu Arteritis
PubMed: 36990133
DOI: 10.1016/j.autrev.2023.103328 -
Frontiers in Immunology 2023Inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC.
MATERIALS AND METHODS
PubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis.
RESULTS
In total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively.
CONCLUSIONS
PD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.
Topics: Humans; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; B7-H1 Antigen; Triple Negative Breast Neoplasms; Progression-Free Survival
PubMed: 36949944
DOI: 10.3389/fimmu.2023.1060308 -
Hepatology Communications Mar 2023This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment.
METHODS
PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms.
RESULTS
The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3-5 hepatotoxicity than PD-1 inhibitors.
CONCLUSIONS
The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.
Topics: Humans; Chemical and Drug Induced Liver Injury; Immune Checkpoint Inhibitors; Incidence; Programmed Cell Death 1 Receptor
PubMed: 36802366
DOI: 10.1097/HC9.0000000000000063 -
Cancer Gene Therapy Jun 2023Chimeric Antigen Receptor (CAR) T cell therapy is an effective treatment approach for patients with relapsed or refractory acute lymphoblastic leukemia (R/R B-ALL).... (Meta-Analysis)
Meta-Analysis
Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis.
Chimeric Antigen Receptor (CAR) T cell therapy is an effective treatment approach for patients with relapsed or refractory acute lymphoblastic leukemia (R/R B-ALL). However, identifying the factors that influence long-term response to this therapy is necessary to optimize patient selection and treatment allocation. We conducted a literature review and meta-analysis to investigate the use of autologous anti-CD19 CAR T cell therapy in both pediatric and adult patients with R/R B-ALL, using several databases including MEDLINE, Cochrane Central, ScienceDirect, Web of Science, Journals@Ovid, Embase, and clinicaltrial.gov. A total of 38 reports were analyzed, which enrolled 2134 patients. Time-to-event endpoints were estimated using reconstructed patient survival data. The study explored key modulators of response, including costimulatory domains, disease status, age, and lymphodepletion. The median overall survival and event-free survival were 36.2 months [95% CI 28.9, NR] and 13.3 months [95% CI 12.2, 17], respectively. The overall response rate was 76% [95% CI 71, 81]. The use of 4-1BB costimulatory domain in the CAR construct, administration of low-dose cyclophosphamide lymphodepletion, and pretreatment morphologic remission were associated with better overall survival, with hazard ratios of 0.72, 0.56, and 0.66, respectively. Morphologic remission and 4-1BB domain were associated with better event-free survival, with hazard ratios of 0.66 and 0.72, respectively. These findings suggest that CAR T cell therapy may offer long-term benefits to patients with R/R B-ALL. However, further research is needed to optimize patient selection and better understand the impact of various factors on the outcome of CAR T cell therapy.
Topics: Adult; Humans; Child; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antigens, CD19; T-Lymphocytes
PubMed: 36750666
DOI: 10.1038/s41417-023-00593-3 -
Medicine Dec 2022Immunotherapy with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors has been widely used in the treatment of solid tumors and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immunotherapy with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors has been widely used in the treatment of solid tumors and Hodgkin lymphoma, demonstrating powerful efficacy and good safety. However, there is no systematic review and meta-analysis to fully investigate the efficacy and safety of PD-1/PD-L1 inhibitors in treating non-Hodgkin lymphoma (NHL).
METHODS
We searched PubMed, EMBASE, The Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and abstracts of conference proceedings of annual meetings up to January 23, 2022, to identify eligible clinical trials. To evaluate the efficacy of PD-1/PD-L1 inhibitors, objective response rate (ORR), complete response rate (CRR), 1-year overall survival rate, and 1-year progression-free survival rate were analyzed. For safety analysis, we calculated rates of any grade and grade ≥3 treatment-related adverse events.
RESULTS
Overall 22 studies and 1150 participants were enrolled in this meta-analysis. The pooled ORR, CRR, 1-year overall survival, and 1-year progression-free survival rates were 0.43 (95% confidence interval [CI], 0.33-0.54), 0.21 (95% CI, 0.13-0.31), 0.72 (95% CI, 0.58-0.89), and 0.42 (95% CI, 0.29-0.62), respectively. The ORR and CRR in the combination immunochemotherapy subgroup (0.65 and 0.41) were higher than those in the monotherapy (0.27 and 0.09) and combination chemotherapy (0.39 and 0.19) subgroups. This study was registered with PROSPERO (#CRD 42022316805).
CONCLUSION
Given that there were limited clinical trials and relatively few relevant studies, we conducted this meta-analysis to fully elucidate the efficacy and safety of PD-1/PD-L1 inhibitors in NHL. Our results suggested that PD-1/PD-L1 inhibitors improved outcomes of responses as well as survival rates in NHL patients with tolerable adverse events. More well-designed randomized clinical trials are still needed to further confirm our findings.
Topics: Humans; Immune Checkpoint Inhibitors; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Lymphoma, Non-Hodgkin; Hodgkin Disease; Apoptosis; Lung Neoplasms
PubMed: 36550903
DOI: 10.1097/MD.0000000000032333 -
Frontiers in Immunology 2022To provide an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) of the efficacy and safety of programmed cell death 1... (Meta-Analysis)
Meta-Analysis
Combining PD-1 or PD-L1 inhibitors with chemotherapy is a good strategy for the treatment of extensive small cell lung cancer: A retrospective analysis of clinical studies.
OBJECTIVES
To provide an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) of the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of extensive-stage small-cell lung cancer (ES-SCLC).
METHODS
PubMed, Web of Science, Embase, Clinicaltrials and the Cochrane Library were systematically searched to extract RCTs concerning the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of ES-SCLC from the time of database inception to October 31, 2022. The literature was independently selected, information was extracted and the risk of bias of the RCTs was evaluated according to the inclusion and exclusion criteria. Stata14.0 was used for the meta-analysis.
RESULTS
Six studies involving 2,600 patients were included in the analysis. The results of the meta-analysis showed that the combination of PD-1/PD-L1 inhibitors significantly improved the OS (HR: 0.73, 95% CI: 0.66-0.80; <0.0001), prolonged PFS (HR: 0.66,95% CI: 0.55-0.79; <0.0001) and did not increase overall incidence of treatment-related adverse events (TRAEs) (RR: 1.03, 95% CI: 0.97-1.09; =0.330) in ES-SCLC patients compared with chemotherapy alone. The subgroup analysis found that patients with negative PD-L1 expression (< 1%) benefited in OS, whereas patients with positive PD-L1 expression (≥1%) had no statistically significant difference in OS. There was a statistically significant difference in PFS between PD-L1-negative (< 1%) and PD-L1-positive (≥1%) patients. The addition of a PD-1 inhibitor or PD-L1 inhibitor to the chemotherapy regimen can improve OS and prolong PFS in patients with ES-SCLC.
CONCLUSIONS
PD-1/PD-L1 inhibitors combination chemotherapy significantly improves PFS and OS in ES-SCLC patients without increasing the overall incidence of TRAEs.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; B7-H1 Antigen; Programmed Cell Death 1 Receptor
PubMed: 36544769
DOI: 10.3389/fimmu.2022.1059557 -
Frontiers in Immunology 2022Therapies based on the combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) are transforming the treatment landscape of esophageal cancer.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Therapies based on the combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) are transforming the treatment landscape of esophageal cancer. Nevertheless, the available data on adverse events (AEs) mainly stemmed from several prospective clinical trials and retrospective studies, in which, AE data are often handled and reported with less rigor than the primary beneficial outcomes of the study. Thus, we conducted a systematic review to investigate the toxicity spectrum of these novel regimens.
METHOD
We searched for all prospective clinical trials investigating the role of ICIs combined with TRT published between January 2010 and August 2022. Study articles and conference proceedings involving esophageal cancers and reporting the overall incidence or details of treatment-related AEs (trAEs) were synthesized to determine the toxicity profile of combination treatment. We compared trAEs between cancer type, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, and between sequential and concurrent administration of ICIs and TRT to identify potentially high-risk patients.
RESULTS
We obtained toxicity data from 14 clinical trials involving 863 patients. The pooled overall incidence was 88.97% for any-grade trAEs and 18.48% for high-grade trAEs. The three most frequent non-hematologic any-grade trAEs were reactive cutaneous capillary endothelial proliferation (RCCEP, 63.80%), esophagitis (51.54%), and fatigue (33.63%). Meanwhile, RCCEP (15.69%) was the most common non-hematologic high-grade trAE, followed by nausea (4.91%) and anorexia (3.81%). The occurrence rates of any-grade and high-grade pneumonitis were 10.82% and 0.66%, respectively. In subgroup analysis, the toxicity profiles of PD-1 and PD-L1 inhibitors were mostly similar, except for any-grade pneumonitis (15.20% vs 4.88%, p=0.03) and high-grade leukopenia (6.25% vs 59.09%, p=0.00). In addition, concurrent treatment seemed to have a higher incidence of any-grade trAEs (95.20% vs 70.85%, p=0.03) compared with sequential treatment. ESCC seems to have higher incidence of any-grade hypothyroidism (22.55% vs 8.96%, p=0.049) compared to EAC.
CONCLUSION
Our study is the first systematic review to provide a toxicity profile of trAEs in esophageal cancer patients who received ICIs combined with TRT. Most AEs of this combination treatment are tolerable, although the incidence of any-grade trAEs was higher in the concurrent group. The difference in any-grade pneumonitis between PD-1 and PD-L1 inhibitor groups needs further validation in a large clinical trial.
Topics: Humans; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Prospective Studies; Retrospective Studies; Esophageal Neoplasms
PubMed: 36439117
DOI: 10.3389/fimmu.2022.1039020 -
Journal of Cancer Research and... 2022Immune checkpoint inhibitors combined with chemotherapy are being evaluated in neoadjuvant settings in early triple-negative breast cancer (TNBC). (Meta-Analysis)
Meta-Analysis
CONTEXT
Immune checkpoint inhibitors combined with chemotherapy are being evaluated in neoadjuvant settings in early triple-negative breast cancer (TNBC).
AIM
To evaluate efficacy and safety of checkpoint inhibitors in early TNBC.
METHODS
Electronic search was done using PubMed, EMBASE, Google Scholar, Cochrane Central Register of Controlled Trials and clinicaltrials.gov to identify relevant articles till October 31, 2020. Clinical trials evaluating checkpoint inhibitors as neoadjuvant therapy in early-stage TNBC were included. Outcomes assessed included pathologic complete response (pCR), event-free survival (EFS), and safety.
STATISTICAL ANALYSIS USED
Meta-analysis was conducted using Cochrane review manager (RevMan) version 5.4. Randomized controlled trials (RCTs) were assessed for quality using Cochrane Collaboration risk of the bias assessment tool, version 2.0 (ROB-2). GRADE analysis was done to assess the overall quality of evidence for all outcomes.
RESULTS
Out of 116 studies screened, 5 RCTs were included in meta-analysis. Compared to control group, programmed death-1 (PD-1)/programmed death-ligand 1 (PDL-1) inhibitor group was associated with significant increase in rate of pCR (odd ratio [OR] =1.71 [1.38-2.11]; P < 0.00001) and EFS (1.77 [1.21-2.60]; P = 0.003). There was a significant increase in risk of serious adverse events (risk ratio [RR] =1.53 [1.28-1.83]; P < 0.00001), adverse events of special interest (AESI) of any grade (RR: 1.5 [1.34-1.69], P < 0.00001) and grade 3 or higher AESI (RR: 2.8 [1.87-4.19], P < 0.00001) with PD-1/PDL-1 inhibitors compared to control.
CONCLUSIONS
PD-1/PDL-1 inhibitors in combination with neoadjuvant chemotherapy for early TNBC show significant improvement in pCR irrespective of PDL-1 status and cancer stage.
Topics: Humans; Immune Checkpoint Inhibitors; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Programmed Cell Death 1 Receptor; Progression-Free Survival
PubMed: 36412440
DOI: 10.4103/jcrt.jcrt_1867_20 -
Annals of Medicine Dec 2022Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study aimed to systematically review the cytopenias following anti-CD19 CAR-T therapy and further analyse the contributing factors.
METHODS
Databases including PubMed, MEDLINE, Embase and Cochrane were systematically searched on 8 May 2022. A random-effect meta-analysis was used to estimate the incidence of cytopenia, and subgroup analyses were applied to explore heterogeneity.
RESULTS
A total of 68 studies involving 2950 patients were included in this study. The overall incidence of all grade anaemia, thrombocytopenia, neutropenia, leukopoenia, lymphocytopenia and febrile neutropenia was 65%, 55%, 78%, 62%, 70% and 27%, respectively, and the corresponding cytopenias of grade 3 or worse were 33%, 31%, 61%, 45%, 46%, and 21%, respectively. Subgroup analysis showed increased incidence of cytopenias in subgroups with lower median age, proportion of males (<65%) and proportion of bridging therapy (<80%) and in the subgroup with a median line of prior therapy ≥3. In terms of disease and therapeutic target, cytopenias were more frequent in ALL patients and in dual-target CAR-T therapies (targeting CD19 in combination with other targets). Furthermore, CAR-T products manufactured by lentiviral vectors and those with the costimulatory domain of CD28 were more likely to cause haematological toxicity. No significant differences were observed in cytopenia between patients treated with CAR-T products with murine and humanized scFv.
CONCLUSION
In conclusion, neutropenia is the most frequent cytopenia after CAR-T therapy, both in all grades or grade ≥3. The incidence of cytopenias following CAR-T therapy is influenced by the age, sex, disease and number of prior therapy lines of the patients, as well as the target and costimulatory domain of CAR-T cells, and viral vectors used for manufacturing.KEY MESSAGESNeutropenia is the most frequent cytopenia after CAR-T therapy.The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy.
Topics: Male; Humans; Mice; Animals; Receptors, Chimeric Antigen; Quality of Life; Antigens, CD19; Anemia; Thrombocytopenia; Neutropenia; Cell- and Tissue-Based Therapy
PubMed: 36382675
DOI: 10.1080/07853890.2022.2136748 -
Clinical and Experimental Medicine Aug 2023Plasmatic presepsin (PSP) is a novel biomarker reported to be useful for sepsis diagnosis and prognosis. During the pandemic, only few studies highlighted a possible... (Meta-Analysis)
Meta-Analysis Review
Plasmatic presepsin (PSP) is a novel biomarker reported to be useful for sepsis diagnosis and prognosis. During the pandemic, only few studies highlighted a possible correlation between PSP and COVID-19 severity, but results remain inconsistent. The present study aims to establish the correlation between PSP and COVID-19 severity. English-language papers assessing a correlation between COVID-19 and PSP from MEDLINE, PubMed, Google Scholar, Cochrane Library, MeSH, LitCovid NLM, EMBASE, CINAHL Plus and the World Health Organization (WHO) website, published from January 2020 were considered with no publication date limitations. Two independent reviewers performed data abstraction and quality assessment, and one reviewer resolved inconsistencies. The protocol was registered on PROSPERO (CRD42022325971).Fifteen articles met our eligibility criteria. The aggregate study population included 1373 COVID-19 patients who had undergone a PSP assessment. The random-effect meta-analysis was performed in 7 out of 15 selected studies, considering only those reporting the mean PSP levels in low- and high-severity cases (n = 707).The results showed that the pooled mean difference of PSP levels between high- and low-severity COVID-19 patients was 441.70 pg/ml (95%CI: 150.40-732.99 pg/ml).Our data show that presepsin is a promising biomarker that can express COVID-19 severity.
Topics: Humans; COVID-19; Prognosis; Biomarkers; Pandemics; Sepsis; Peptide Fragments; Lipopolysaccharide Receptors
PubMed: 36380007
DOI: 10.1007/s10238-022-00936-8