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The Lancet. Microbe May 2024Surrogates of antiviral efficacy are needed for COVID-19. We aimed to investigate the relationship between the virological effect of treatment and clinical efficacy as... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Surrogates of antiviral efficacy are needed for COVID-19. We aimed to investigate the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in outpatients treated for mild-to-moderate COVID-19.
METHODS
In this systematic review and meta-analysis, we searched PubMed, Scopus, and medRxiv from database inception to Aug 16, 2023, for randomised placebo-controlled trials that tested virus-directed treatments (ie, any monoclonal antibodies, convalescent plasma, or antivirals) in non-hospitalised individuals with COVID-19. We only included studies that reported both clinical outcomes (ie, rate of disease progression to hospitalisation or death) and virological outcomes (ie, viral load within the first 7 days of treatment). We extracted summary data from eligible reports, with discrepancies resolved through discussion. We used an established meta-regression model with random effects to assess the association between clinical efficacy and virological treatment effect, and calculated I to quantify residual study heterogeneity.
FINDINGS
We identified 1718 unique studies, of which 22 (with a total of 16 684 participants) met the inclusion criteria, and were in primarily unvaccinated individuals. Risk of bias was assessed as low in 19 of 22 studies for clinical outcomes, whereas for virological outcomes, a high risk of bias was assessed in 11 studies, some risk in ten studies, and a low risk in one study. The unadjusted relative risk of disease progression for each extra log copies per mL reduction in viral load in treated compared with placebo groups was 0·12 (95% CI 0·04-0·34; p<0·0001) on day 3, 0·20 (0·08-0·50; p=0·0006) on day 5, and 0·53 (0·30-0·94; p=0·030) on day 7. The residual heterogeneity in our meta-regression was estimated as low (I=0% [0-53] on day 3, 0% [0-71] on day 5, and 0% [0-43] on day 7).
INTERPRETATION
Despite the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes, this review provides evidence that treatment-induced acceleration of viral clearance within the first 5 days after treatment is a potential surrogate of clinical efficacy to prevent hospitalisation with COVID-19. This work supports the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy.
FUNDING
Australian Government Department of Health, Medical Research Future Fund, and Australian National Health and Medical Research Council.
Topics: Humans; COVID-19; Antiviral Agents; Viral Load; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment; Outpatients; Immunization, Passive; Randomized Controlled Trials as Topic; COVID-19 Serotherapy; Disease Progression; Hospitalization
PubMed: 38583464
DOI: 10.1016/S2666-5247(23)00398-1 -
Clinical Lymphoma, Myeloma & Leukemia Jun 2024The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate.
METHODS
In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL.
RESULTS
After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel.
CONCLUSIONS
Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages.
Topics: Humans; Immunotherapy, Adoptive; Lymphoma, Non-Hodgkin; Receptors, Chimeric Antigen
PubMed: 38582666
DOI: 10.1016/j.clml.2024.02.007 -
Journal of Thrombosis and Haemostasis :... Jul 2024Chimeric antigen receptor T-cell (CAR T-cell) therapy is increasingly utilized for treatment of hematologic malignancies. Hematologic toxicities including thrombosis and... (Meta-Analysis)
Meta-Analysis
A meta-analysis to assess the risk of bleeding and thrombosis following chimeric antigen receptor T-cell therapy: Communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy.
BACKGROUND
Chimeric antigen receptor T-cell (CAR T-cell) therapy is increasingly utilized for treatment of hematologic malignancies. Hematologic toxicities including thrombosis and bleeding complications have been reported. Accurate estimates for thrombotic and bleeding outcomes are lacking.
OBJECTIVES
We performed a systematic review and meta-analysis in patients who received CAR T-cell therapy for an underlying hematologic malignancy with the objective to: a) assess the thrombosis and bleeding risk associated with CAR T-cell therapy, b) assess the impact of CRS and ICANS on the risks of thrombosis and bleeding, and c) assess the safety of anticoagulant or antiplatelet use in the period following treatment with CAR T-cell therapy.
METHODS
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to February 2022 for studies reporting thrombotic or bleeding outcomes in patients receiving CAR T-cell therapy. Pooled event rates were calculated using a random-effects model. We performed subgroup analyses stratified by follow-up duration, CAR T-cell target antigen, and underlying hematologic malignancy.
RESULTS
We included 47 studies with a total of 7040 patients. High heterogeneity between studies precluded reporting of overall pooled rates of thrombotic and bleeding events. In studies with follow-up duration of ≤6 months, the pooled incidence of venous thrombotic events was 2.4% (95% CI, 1.4%-3.4%; I = 0%) per patient-month, whereas the rate was 0.1% (95% CI, 0%-0.1%; I = 0%) per patient-month for studies with longer follow-up periods (>6 months). The pooled incidences of any bleeding events per patient-month in studies with follow-up duration of ≤6 months and >6 months were 1.9% (95% CI, 0.6%-3.1%; I = 78%) and 0.3% (95% CI: 0%-0.8%, I = 40%), respectively. Secondary analyses by CAR T-cell target antigen, underlying malignancy, and primary outcome of the studies did not reveal significant differences in the rates of thromboembolism, any bleeding events, or major bleeding events.
CONCLUSION
The risk of both thrombosis and bleeding following CAR T-cell therapy appears to be highest in the initial months following infusion.
Topics: Humans; Hemorrhage; Immunotherapy, Adoptive; Thrombosis; Hematologic Neoplasms; Risk Assessment; Risk Factors; Treatment Outcome; Hemostasis; Receptors, Chimeric Antigen; Anticoagulants; Male; Female; Middle Aged; Platelet Aggregation Inhibitors; Adult; Aged
PubMed: 38574863
DOI: 10.1016/j.jtha.2024.03.021 -
Biomedicine & Pharmacotherapy =... May 2024Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues... (Review)
Review
Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues like poor trafficking, limited penetration, and insufficient persistence within the tumor microenvironment (TME). CAR-T cells are engineered to express receptors that target specific cancer antigens, enhancing their ability to recognize and eliminate cancer cells. This review paper explores the intricate interplay between CAR-T therapy and radiotherapy (RT), investigating their synergistic potential. Radiotherapy, a standard cancer treatment, involves using high doses of radiation to target and damage cancer cells, disrupting their ability to grow and divide. We highlight that RT modulates the TME, augments antigen presentation, and promotes immune cell infiltration, bolstering CAR-T cell-mediated tumor eradication. Molecular insights shed light on RT-induced alterations in tumor stroma, T cell recruitment promotion, and induction of immunogenic cell death. Noteworthy, strategies, such as combining hypofractionated radiotherapy with myeloid-derived suppressor cell blockade, underscore innovative approaches to enhance CAR-T cell therapy in solid tumors. Bridging indications for RT and CAR-T cells in hematological malignancies are discussed, emphasizing scenarios where RT strategically enhances CAR-T cell efficacy. The paper critically evaluates the RT as a bridge compared to traditional chemotherapy, highlighting timing and dosage considerations crucial for optimizing CAR-T therapy outcomes. In summary, the paper provides valuable insights into the intricate molecular mechanisms activated by RT and innovative strategies to improve CAR-T cell therapy, fostering a deeper understanding of their combined potential in cancer treatment.
Topics: Humans; Neoplasms; Tumor Microenvironment; Immunotherapy, Adoptive; Animals; Receptors, Chimeric Antigen; Combined Modality Therapy; Radiotherapy
PubMed: 38574625
DOI: 10.1016/j.biopha.2024.116532 -
Ocular adverse events following CAR-T cell therapy: A pharmacovigilance study and systematic review.European Journal of Haematology Jul 2024The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in...
The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in hematologic malignancies. However, data on their adverse events, particularly of the eye, is under-reported. To assess the ocular adverse events associated with the six FDA-approved CAR-T cell therapies, a disproportionality analysis utilizing the FAERS database was conducted from the first quarter of 2017 to the third quarter of 2023, as well as a systematic review of case reports of ocular events following CAR-T cell therapy up to December 20, 2023. A total of 53 ocular adverse events were identified from the FDAs FAERS database. The adverse events most frequently observed were mydriasis and xerophthalmia with tisagenlecleucel (Kymriah). The systematic review resulted in 8 case reports encompassing 19 patients which included a total of 27 events. This study demonstrates the importance of anticipation of potential ocular adverse events by ophthalmologists and oncologists as they can greatly contribute to morbidity in patients with cancer.
Topics: Humans; Eye Diseases; Hematologic Neoplasms; Immunotherapy, Adoptive; Pharmacovigilance
PubMed: 38549191
DOI: 10.1111/ejh.14208 -
Frontiers in Immunology 2024Immunotherapy treatments aim to modulate the host's immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer....
Immunotherapy treatments aim to modulate the host's immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer. Among different immunotherapies reaching clinical application during the last years, chimeric antigen receptor (CAR) immunotherapy has emerged as an effective treatment for cancer where different CAR T cells have already been approved. Yet their use against infectious diseases is an area still relatively poorly explored, albeit with tremendous potential for research and clinical application. Infectious diseases represent a global health challenge, with the escalating threat of antimicrobial resistance underscoring the need for alternative therapeutic approaches. This review aims to systematically evaluate the current applications of CAR immunotherapy in infectious diseases and discuss its potential for future applications. Notably, CAR cell therapies, initially developed for cancer treatment, are gaining recognition as potential remedies for infectious diseases. The review sheds light on significant progress in CAR T cell therapy directed at viral and opportunistic fungal infections.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy; Immunotherapy, Adoptive; Neoplasms; Communicable Diseases
PubMed: 38352878
DOI: 10.3389/fimmu.2024.1289303 -
Transplantation and Cellular Therapy Jun 2024Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory... (Meta-Analysis)
Meta-Analysis Comparative Study
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory aggressive large B cell lymphoma (LBCL). Significant costs and complex manufacturing underscore the importance of evidence-based counseling regarding the outcomes of these treatments. With the aim of examining the efficacy and safety of axi-cel versus tisa-cel in patients with relapsed/refractory aggressive LBCL, we performed a systematic literature search of comparative studies evaluating outcomes in relapsed/refractory aggressive LBCL after treatment with axi-cel or tisa-cel. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for response, progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity. Meta-analysis and meta-regression were used to generate summary statistics. A total of 2372 participants were included in the 8 studies in our analysis. The dropout rate between apheresis and infusion was 13% for axi-cel versus 18% for tisa-cel, and the median time from apheresis to infusion was 32 days versus 45 days. Axi-cel showed higher odds for a complete response (OR, 1.65; P < .001) and was associated with higher odds for PFS at 1 year after infusion (OR, .60; P < .001). OS appeared to be improved with axi-cel (OR, .84; 95% CI, .68 to 1.02; P = .08), whereas the cumulative incidence of nonrelapse mortality (NRM) was 11.5% for axi-cel versus 3.7% for tisa-cel (P = .002). The main predictors for survival were lactate dehydrogenase level, Eastern Cooperative Oncology Group Performance Status, and response to bridging, and axi-cel maintained superior efficacy even in elderly patients. In terms of safety, axi-cel was associated with significantly higher odds of any-grade CRS (OR, 3.23; P < .001), but not of grade ≥3 CRS (P = .92). Axi-cel was associated with significantly higher odds of severe ICANS grade ≥3 (OR, 4.03; P < .001). In terms of hematotoxicity, axi-cel was significantly associated with higher odds of severe neutropenia at 1 month after infusion (OR, 2.06; P = .003). As a result, axi-cel was associated with significantly greater resource utilization, including prolonged hospital stay, more frequent intensive care admission, and use of agents such as tocilizumab for toxicity management. We provide strong evidence of the greater efficacy of axi-cel versus tisa-cel in relapsed/refractory aggressive LBCL. The higher toxicity and NRM seen with axi-cel might not counterbalance the overall results, highlighting the need for timely intervention and careful selection of patients, balancing resource utilization and clinical benefit.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Biological Products; Immunotherapy, Adoptive; Antigens, CD19; Receptors, Antigen, T-Cell; Cytokine Release Syndrome; Treatment Outcome
PubMed: 38281590
DOI: 10.1016/j.jtct.2024.01.074 -
Clinical Lymphoma, Myeloma & Leukemia Apr 2024Chimeric Antigen Receptor T-cell (CAR T-cell) therapy is an effective treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, patients with... (Meta-Analysis)
Meta-Analysis Review
Chimeric Antigen Receptor T-cell (CAR T-cell) therapy is an effective treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, patients with central nervous system (CNS) lymphoma were excluded in most of the CAR T-cell therapy trials. This meta-analysis assesses the efficacy with CAR T-cell therapy in LBCL patients with CNS involvement. Two reviewers independently searched PubMed and Cochrane Library to identify all published literature associated with United States Food and Drug Administration approved CAR T-cell therapies for LBCL. Patients with CNS LBCL were included. Meta-analysis of proportion was performed to evaluate the overall response (ORR), complete response (CR) for efficacy, and cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome for safety assessment. Nineteen studies were qualified for inclusion with 141 CNS LBCL patients. The ORR and CR rates were 61% and 55% respectively. The median overall survival (OS) was 8.8 months, and the median progression free survival (PFS) was 4.4 months. Severe immune effector cell-associated neurotoxicity syndrome (grade≥3) were reported in 25% (32/130) patients and severe cytokine release syndrome (grade≥3) were found in 10% (13/124) of the patients. The safety and efficacy of CAR T-cell therapy in CNS LBCL patients appears comparable to patients without CNS involvement.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Cytokine Release Syndrome; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neurotoxicity Syndromes; Central Nervous System; Cell- and Tissue-Based Therapy; Antigens, CD19
PubMed: 38267353
DOI: 10.1016/j.clml.2023.12.012 -
Zeitschrift Fur Evidenz, Fortbildung... Mar 2024Up-to-date systematic reviews (SRs) are essential for making evidence-based decisions. During the 2019 coronavirus (COVID-19) pandemic, there was a particular need for...
INTRODUCTION
Up-to-date systematic reviews (SRs) are essential for making evidence-based decisions. During the 2019 coronavirus (COVID-19) pandemic, there was a particular need for up-to-date evidence, making the living systematic review (LSR) approach an appropriate review type. However, this approach poses certain challenges.
OBJECTIVE AND OUTLINE
We aim to provide practice insights and report challenges that we faced while conducting two Cochrane LSRs on COVID-19 treatments with (i) convalescent plasma and (ii) systemic corticosteroids. We address our objective with an experience report and share challenges of the following components based on Iannizzi et al. (2022): study design, publication types, intervention/comparator, outcomes, search strategy, review updates and transparent reporting of differences between review updates.
RESULTS
Regarding the study design, the plasma LSR included different study designs because RCT data were not available at the beginning of the pandemic, whereas for the corticosteroids LSR, which started several months later, RCT data were already available. The challenges in both LSRs included the publication types (preprints were included with caution) and the intervention/comparator, for instance the unavailability of standard of care for either LSR, or SARS-CoV-2 variants occurrence. Further challenges in both LSRs occurred in the components "outcome sets" (which had to be adjusted) and "literature search". The decision criteria for updating were based on important studies and available resources in both LSRs and policy relevance in the plasma LSR. Transparent reporting of the differences between the various update versions were discussed for both LSRs.
DISCUSSION AND CONCLUSION
In summary, there are similarities and differences regarding challenges of review components for both LSRs. It is important to keep in mind that the two LSR examples presented here were conducted in the wake of the COVID-19 pandemic. Therefore, many of the challenges are attributable to the pandemic and are not specific to LSRs, such as constant adjustments of the outcome sets or changes in the database search. Nevertheless, we believe that some of these aspects are helpful for LSR authors and are applicable to other LSRs outside the pandemic context, particularly in areas where new evidence is rapidly emerging.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; COVID-19 Serotherapy; Germany; Adrenal Cortex Hormones
PubMed: 38220533
DOI: 10.1016/j.zefq.2023.11.004 -
The American Journal of Geriatric... May 2024Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically described. Thus, the systematic review and meta-analysis were conducted to explore the effect and potential mechanism of immunotherapy on AD animal experiments based on behavioral indicators.
METHODS
According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Collaboration guidelines and the inclusion/exclusion criteria of immunotherapy in animal studies, 15 studies were systematically reviewed after extraction from a collected database of 3,742 publications. Finally, the effect and mechanism of immunotherapy on AD models were described by performing multiple subgroup analyses.
RESULTS
After immunotherapy, the escape latency was reduced by 18.15 seconds and the number of crossings over the platform location was increased by 1.60 times in the Morris Water Maze. Furthermore, compared to the control group, active and passive immunization could markedly ameliorate learning and memory impairment in 3 × Tg AD animal models, and active immunization could ameliorate the learning and memory ability of the APPswe/PS1ΔE9 AD animal model. Meanwhile, it could be speculated that cognitive dysfunction was improved by immunotherapy, perhaps mainly via reducing Aβ40, Aβ42, and Tau levels, as well as increasing IL-4 levels.
CONCLUSION
Immunotherapy significantly ameliorated the cognitive dysfunction of AD animal models by assessing behavioral indicators.
Topics: Mice; Animals; Alzheimer Disease; Amyloid beta-Peptides; Mice, Transgenic; Cognitive Dysfunction; Immunotherapy; Disease Models, Animal; Cognition; Maze Learning
PubMed: 38158285
DOI: 10.1016/j.jagp.2023.11.011