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Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis.

ABSTRACT: BACKGROUND:Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated with inhibitors to programmed death-1 (PD-1), PD-ligand1 (PD-L1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), or B- and T-lymphocyte attenuator (BTLA) versus control. RESULTS:Nineteen experiments from 11 studies (n = 709) were included. All experiments were in mice, and 10 of the 19 were published from a single research group. Sample size calculations and randomization were not reported in any studies, and blinding procedures were reported in just 1. Across all 19 experiments, CPIs increased the odds ratio for survival (OR, 95% CI) [3.37(1. 55, 7.31)] but with heterogeneity (I2 = 59%, p < 0.01). After stratification by checkpoint molecule targeted, challenge site or type, or concurrent antibacterial treatment, CPIs had consistent effects over most experiments in the 9 that included antibacterial treatment [OR = 2.82 (1.60, 4.98), I2 = 6%, p = 0.39 with versus 4.01 (0.89, 18.05), I2 = 74%, p < 0.01 without]. All 9 antibiotic experiments employed cecal-ligation and puncture (CLP) bacterial challenge while 6 also included a Candida albicans challenge 3-4?days after CLP. In these six experiments (n = 322), CPIs were directed at the fungal challenge when CLP lethality had resolved, and were consistently beneficial [2.91 (2.41, 3.50), I2 = 0%, p = 0.99]. In the three experiments (n = 66) providing antibiotics without fungal challenge, CPIs were administered within 1 day of CLP and had variable and non-significant effects [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); and 8.50 (0.90, 80.03)]. No experiment examined pneumonia. CONCLUSIONS:Preclinical studies showing that CPIs add benefit to antibiotic therapy for the common bacterial infections causing sepsis clinically are needed to support this therapeutic approach. Studies should be reproducible across multiple laboratories and include procedures to reduce the risk of bias.

SUBMITTER: Busch LM

PROVIDER: S-EPMC7000606 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis.

Busch Lindsay M LM Sun Junfeng J Cui Xizhong X Eichacker Peter Q PQ Torabi-Parizi Parizad P

Intensive care medicine experimental 20200204 1

<h4>Background</h4>Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated ...[more]

PMID: 32020483

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Project description:BackgroundClinical studies suggest obesity paradoxically increases survival during bacterial infection and sepsis but decreases it with influenza, but these studies are observational. By contrast, animal studies of obesity in infection can prospectively compare obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity's survival effect in infection and sepsis.MethodsDatabases were searched for studies comparing survival in obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity's survival effect in infection and sepsis. Methods. Databases were searched for studies comparing survival in obese versus nonobese animals following bacteria, lipopolysaccharide, or influenza virus challenges.ResultsTwenty-one studies (761 obese and 603 control animals) met the inclusion criteria. Obesity reduced survival in 19 studies (11 significantly) and the odds ratio (95% CI) of survival (0.21(0.13, 0.35); I 2?=?64%, p < 0.01p < 0.01p?<?0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n?=?6 studies, 0.21(0.13, 0.34); I 2?=?64%, p < 0.01p?<?0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n?=?6 studies, 0.21(0.13, 0.34); I 2?=?64%, p < 0.01p?<?0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n?=?6 studies, 0.21(0.13, 0.34); I 2?=?64%, p < 0.01p?<?0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n?=?6 studies, 0.21(0.13, 0.34); I 2?=?64%, p < 0.01p < 0.01p?<?0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n?=?6 studies, 0.21(0.13, 0.34); I 2?=?31%, p=0.20 and n?=?5, 0.22(0.13, 0.36); I 2?=?0%, p=0.59, respectively), (2) not significantly with cecal ligation and puncture (n?=?4, 0.72(0.08, 6.23); I 2?=?75%, p < 0.01), and (3) significantly with influenza but with high heterogeneity (n?=?6, 0.12(0.04, 0.34); I 2?=?73%, p < 0.01). Obesity's survival effects did not differ significantly comparing the four challenge types (p=0.49). Animal models did not include antimicrobials or glycemic control and study quality was low.ConclusionsPreclinical and clinical studies together emphasize the need for prospective studies in patients accurately assessing obesity's impact on survival during severe infection.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) have been increasingly used in cancer treatment, and a subset of patients undergo pseudoprogression. Recognizing the incidence of pseudoprogression is critical for clinical practice.PurposeTo evaluate by systematic review and meta-analysis the incidence of pseudoprogression in cancer treatment with ICIs, and compare the incidence according to response criteria, tumor types, and immunotherapeutic agents.Materials and MethodsMedline and Embase were searched to identify relevant studies published before December 31, 2018. Clinical trials, post hoc analysis of clinical trials, and prospective studies on ICI treatment in patients with malignant solid tumors were included. Pooled incidence of pseudoprogression for all included studies, per definition of pseudoprogression, cancer type, and drug type, was obtained by random-effects models with inverse variance weighting model.ResultsSeventeen studies with 3402 patients were analyzed. The pooled incidence of pseudoprogression was 6.0% (95% confidence interval: 5.0%, 7.0%). The definition of pseudoprogression were divided into four categories: progressive disease followed by partial response (PR) or complete response (CR) but not stable disease (SD) with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (six studies); progressive disease followed by SD or PR or CR with RECIST 1.1 (five studies); progressive disease followed by SD or PR or CR with RECIST 1.0 (three studies); and progressive disease followed by SD or PR or CR with immune-related response criteria (irRC) (three studies). Incidence of pseudoprogression varied from 4.5% to 8.0% per definition, ranged from 5.0% to 7.0% per cancer type, and was 5.6% with the monotherapy of programmed cell death-1 inhibitor.ConclusionThe overall incidence of pseudoprogression was 6.0% and was less than 10% in subgroup analyses according to the definitions of pseudoprogression, cancer type, and immune checkpoint inhibitor type. Varying definitions across trials and studies indicates the need for uniform criteria of pseudoprogression for solid tumors.© RSNA, 2020Online supplemental material is available for this article.See also the article by Dodd and MacDermott in this issue.

Project description:BackgroundAlzheimer's disease (AD) is a common progressive neurodegenerative disease characterized by memory impairments, and there is no effective therapy. Neural stem/progenitor cell (NSPC) has emerged as potential novel therapy for AD, and we aim to explore whether neural stem/progenitor cell therapy was effective for rodent models of AD.MethodsWe searched PubMed, Embase, Cochrane Library and Web of Science up to December 6, 2022. The outcomes included cognitive function, pathological features and BDNF. The GetData Graph Digitizer software (version 2.26) was applied to extract numerical values, and RevMan 5.3 and Stata 16 were used to analyze data. The SYRCLE risk of bias tool was used to assess study quality.ResultsWe evaluated 22 mice studies and 8 rat studies. Compared to control groups, cognitive function of NSPC groups of both mice studies (SMD = - 1.96, 95% CI - 2.47 to - 1.45, I2 = 75%, P < 0.00001) and rat studies (SMD = - 1.35, 95% CI - 2.11 to - 0.59, I2 = 77%, P = 0.0005) was apparently improved. In mice studies, NSPC group has lower Aβ deposition (SMD = - 0.96, 95% CI - 1.40 to - 0.52, P < 0.0001) and p-tau level (SMD = - 4.94, 95% CI - 7.29 to - 2.95, P < 0.0001), higher synaptic density (SMD = 2.02, 95% CI 0.50-3.55, P = 0.009) and BDNF (SMD = 1.69, 95% CI 0.61-2.77, P = 0.002). Combined with nanoformulation (SMD = - 1.29, 95% CI - 2.26 to - 0.32, I2 = 65%, P = 0.009) and genetically modified (SMD = - 1.29, 95% CI - 1.92 to - 0.66, I2 = 60%, P < 0.0001) could improve the effect of NSPC. In addition, both xenogeneic and allogeneic transplant of NSPC could reverse the cognitive impairment of AD animal models.ConclusionsOur results suggested that NSPC therapy could improve the cognitive function and slow down the progression of AD. Due to the limitations of models, more animal trials and clinical trials are needed.

Project description:BackgroundThe importance of investigating sex- and gender-dependent differences has been recently emphasized by major funding agencies. Notably, the influence of biological sex on clinical outcomes in sepsis is unclear, and observational studies suffer from the effect of confounding factors. The controlled experimental environment afforded by preclinical studies allows for clarification and mechanistic evaluation of sex-dependent differences. We propose a systematic review to assess the impact of biological sex on baseline responses to disease induction as well as treatment responses in animal models of sepsis. Given the lack of guidance surrounding sex-based analyses in preclinical systematic reviews, careful consideration of various factors is needed to understand how best to conduct analyses and communicate findings.MethodsMEDLINE and Embase will be searched (2011-present) to identify preclinical studies of sepsis in which any intervention was administered and sex-stratified data reported. The primary outcome will be mortality. Secondary outcomes will include organ dysfunction, bacterial load, and IL-6 levels. Study selection will be conducted independently and in duplicate by two reviewers. Data extraction will be conducted by one reviewer and audited by a second independent reviewer. Data extracted from included studies will be pooled, and meta-analysis will be conducted using random effects modeling. Primary analyses will be stratified by animal age and will assess the impact of sex at the following time points: pre-intervention, in response to treatment, and post-intervention. Risk of bias will be assessed using the SYRCLE's risk-of-bias tool. Illustrative examples of potential methods to analyze sex-based differences are provided in this protocol.DiscussionOur systematic review will summarize the current state of knowledge on sex-dependent differences in sepsis. This will identify current knowledge gaps that future studies can address. Finally, this review will provide a framework for sex-based analysis in future preclinical systematic reviews.Systematic review registrationPROSPERO CRD42022367726.

Project description:BackgroundSubphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.MethodsWe will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.DiscussionThis study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.Systematic review registrationPROSPERO (ID: CRD42019157236).

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Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis.

Publications

Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis.

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