Corrigendum: rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis.
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ABSTRACT:
SUBMITTER: Shen W
PROVIDER: S-EPMC9891283 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
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Corrigendum: rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis.
Shen Weiran W Liu Shengjiang S Ou Li L
Frontiers in immunology 20230118
[This corrects the article DOI: 10.3389/fimmu.2022.1001263.]. ...[more]
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Project description:Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in clinical settings, a meta-analysis of 255 clinical trials was performed. A total of 7,289 patients are planned to be dosed. AAV2 was the most dominantly used serotype (29.8%, n=72), and 8.3% (n=20) of trials used engineered capsids. 38.7% (n=91) of trials employed neutralizing antibody assays for patient enrollment, while 15.3% (n=36) used ELISA-based total antibody assays. However, there was high variability in the eligibility criteria with cut-off tiers ranging from 1:1 to 1:1,600. To address potential immunogenicity, 46.3% (n=118) of trials applied immunosuppressants (prophylactic or reactive), while 32.7% (n=18) of CNS and 37.5% (n=24) of ocular-directed trials employed immunosuppressants, possibly due to the immune-privileged status of CNS and retina. There were a total of 11 patient deaths across 8 trials, and 18 out of 30 clinical holds were due to toxicity findings in clinical studies. 30.6% (n=78) of trials had treatment-emergent serious adverse events (TESAEs), with hepatotoxicity and thrombotic microangiopathy (systemic delivery) and neurotoxicity (CNS delivery) being the most prominent. Additionally, the durability of gene therapy may be impacted by two distinct decline mechanisms: 1) rapid decline presumably due to immune responses; or 2) gradual decline due to vector dilution. The durability varied significantly depending on disease indication, dose, serotypes, and patient individuals. Most CNS (90.0%) and muscle trials (73.3%) achieved durable transgene expression, while only 43.6% of ocular trials had sustained clinical outcomes. The rAAV production system can affect rAAV quality and thus immunogenicity and toxicity. Out of 186 trials that have disclosed production system information, 63.0% (n=126) of trials used the transient transfection of the HEK293/HEK293T system, while 18.0% (n=36) applied the baculovirus/Sf9 (rBac/Sf9) system. There were no significant differences in TESAEs and durability between AAV generated by rBac/Sf9 and HEK293/HEK293T systems. In summary, rAAV immunogenicity and toxicity poses significant challenges for clinical development of rAAV gene therapies, and it warrants collaborative efforts to standardize monitoring/measurement methods, design novel strategies to overcome immune responses, and openly share relevant information.
| S-EPMC9647052 | biostudies-literature
Project description:Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these "à-la-carte" therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed.
| S-EPMC7768510 | biostudies-literature
Project description:Recombinant adeno-associated virus (rAAV) gene therapy has the potential to transform the lives of patients with certain genetic disorders by increasing or restoring function to affected tissues. Following the initial establishment of transgene expression, it is unknown how long the therapeutic effect will last, although animal and emerging human data show that expression can be maintained for more than 10 years. The durability of therapeutic response is key to long-term treatment success, especially since immune responses to rAAV vectors may prevent re-dosing with the same therapy. This review explores the non-immunological and immunological processes that may limit or improve durability and the strategies that can be used to increase the duration of the therapeutic effect.
| S-EPMC9077371 | biostudies-literature
Project description:The objective of this meta-analysis is to assess the safety and immunogenicity of maternal pertussis vaccination based on randomized clinical trials. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Internet, and Wan Fang Database were searched from inception up to the 8th of October 2021, using a protocol registered on PROSPERO with no. 42021287717, and a meta-analysis was conducted. We measured pooled geometric mean concentrations (GMCs) for IgG antibodies against pertussis and the incidence of serious adverse events (SAEs). We identified a total of 522 publications, and after a strict screening, we found that 6 RCTs were eligible for our meta-analysis. GMCs were determined with a standardized mean difference (SMD), and the pooled SMD of anti-PT, anti-FHA, and anti-PRN IgG from cord blood were 0.91 (95% CI: 0.58, 1.24), 1.03 (95% CI: (0.70, 1.35)), and 1.55(95% CI: 1.22, 1.88), respectively. The pooled OR of SAEs of women and infants did not show a statistical difference; the pooled ORs were 1.26 (95% CI: 0.78, 2.05); P = 0.35) and 0.61 (95% CI: 0.37, 1.01); p = 0.053), respectively. Infants of immunized women have significantly higher transplacental antibodies for protection against pertussis disease during the first 2 months of life.
| S-EPMC9797314 | biostudies-literature
Project description:AimCardiotoxicity is a well-recognized complication of chemotherapy with Anthracyclines. However, results from trials evaluating beta-blockers for prevention are controversial. Therefore, we performed a meta-analysis to find whether prophylactic administration of beta-blockers can help prevent Anthracyclines-induced cardiotoxicity.MethodsWe assessed randomized trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal left ventricular ejection fraction (LVEF) receiving Anthracyclines. The primary outcome was EF reduction. The secondary outcome was the development of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD), defined as a decrease in the LVEF of >10% to a value of <53%.ResultsWe included 17 trials comprising 1291 patients (671 patients in the intervention arm and 620 in the control arm). Carvedilol was administered in eight studies, and others used bisoprolol, metoprolol, or nebivolol. Compared with baseline, LVEF reduced in both intervention and control groups after chemotherapy (MD = -1.93%, 95% CI: -2.94, -0.92, p = 0.001, I2 = 72.1% vs. MD = -4.78%, 95% CI: -6.51, -3.04, p = 0.001, I 2 = 91.6%, respectively). LVEF was less reduced among the beta-blocker receivers (MD = 3.44%, 95% CI: 1.41-5.46, p = 0.001, I2 = 94.0%). Among the eight studies reporting the incidence of CTRCD, 45 out of 370 participants in the intervention arm and 54 out of 341 in the control arm were reported to experience this complication (RR = 0.76; 95% CI: 0.53,1.09; I 2 = 24.4%; p = 0.235).ConclusionTreatment with beta-blockers prevents dilatation of the left ventricle, development of diastolic dysfunction, and reduction of LVEF. However, these hemodynamic effects do not translate into a significant reduction in CTRCD incidence and prevention of hospitalization for heart failure or cardiac death.
| S-EPMC9818032 | biostudies-literature
Project description:BackgroundPanitumumab is a fully human antibody against the epidermal growth factor receptor that is indicated for the treatment of metastatic colorectal cancer (mCRC) after disease progression on standard chemotherapy. The purpose of this analysis was to examine the immunogenicity of panitumumab and to evaluate the effect of anti-panitumumab antibodies on pharmacokinetic and safety profiles in patients with mCRC receiving panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapies.MethodsThree validated assays (two screening immunoassays and a neutralizing antibody bioassay) were used to detect the presence of anti-panitumumab antibodies in serum samples collected from patients enrolled in four panitumumab combination chemotherapy clinical trials. The impact of anti-panitumumab antibodies on pharmacokinetic and safety profiles was analyzed using population pharmacokinetic analysis and descriptive statistics, respectively.ResultsOf 1124 patients treated with panitumumab in combination with oxaliplatin- or irinotecan-based chemotherapy with postbaseline samples available for testing, 20 (1.8%) patients developed binding antibodies and 2 (0.2%) developed neutralizing antibodies. The incidence of anti-panitumumab antibodies was similar in patients with tumors expressing wild-type or mutant KRAS and in patients receiving oxaliplatin- or irinotecan-based chemotherapies. No evidence of an altered pharmacokinetic or safety profile was found in patients who tested positive for anti-panitumumab antibodies.ConclusionsThe immunogenicity of panitumumab in the combination chemotherapy setting was infrequent and similar to the immunogenicity observed in the monotherapy setting. Panitumumab immunogenicity did not appear to alter pharmacokinetic or safety profiles. This low rate of immunogenicity may be attributed to the fully human nature of panitumumab.
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Project description:[This corrects the article DOI: 10.1016/j.eclinm.2023.101904.][This corrects the article DOI: 10.1016/j.eclinm.2022.101795.].
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Project description:Background: This meta-analysis evaluated the efficacy and toxicity of gefitinib with other commonly used drugs in different treatment settings and epidermal growth factor receptor (EGFR) mutation status. Methods: Nineteen randomize clinical trials (RCTs) of 6,554 patients with NSCLC were pooled in this meta-analysis by random-effects or fixed-effects model, whichever is proper. Results: In first-line therapy, gefitinib showed higher odds than chemotherapy (OR = 2.19, 95% CI: 1.20-4.01), but less than other targeted therapies (OR = 0.58, 95% CI: 0.38-0.88). As non-first-line therapy, the overall survival (OS) and progression-free survival (PFS) were similar between gefitinib and controls (HR = 1.00, 95% CI: 0.93-1.08; HR = 0.91, 95% CI: 0.72-1.15), respectively. With the regard to toxicity, the incidences of dry skin, rash and pruritus were higher in gefitinib compared with controls, while gefitinib significantly reduced the incidence of hematologic toxicity. Conclusion: Gefitinib might be more efficient than chemotherapy, but less efficient than other targeted therapies in ORR, especially in EGFR mutation-positive patients. Gefitinib can decrease the odds of hematologic toxicity compared to controls. Future studies, especially those with EGFR mutation-positive patients, will be needed to confirm our findings.
| S-EPMC5929091 | biostudies-literature
Project description:BackgroundTyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC.MethodsWe tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies.ResultsWe examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations.ConclusionGefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC.
| S-EPMC4391756 | biostudies-literature
Project description:The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) with nephrotic syndrome are still controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed.The Cochrane Library, PUBMED, EMBASE, Chinese Database, and Clinical Trial Registries (June 2012) were searched to identify RCTs investigating the effect of immunosuppression on adults with IMN and nephrotic syndrome.This review was an update (36 RCTs, 1762 participants) of the 2004 version (18 RCTs, 1025 participants). Immunosuppression significantly reduced all-cause mortality or ESRD (15 RCTs, 791 participants; risk ratio, 0.58 [95% confidence interval, 0.36-0.95]; P=0.03). However, the result was not consistent when prespecified subgroup analyses were undertaken. Immunosuppression increased complete or partial remission (CR + PR) (16 RCTs, 864 participants; 1.31 [1.01-1.70]; P=0.04) but resulted in more withdrawals or hospitalizations (16 RCTs, 880 participants; 5.35 [2.19-13.02]; P=0.002). Corticosteroids combined with alkylating agents significantly reduced all-cause mortality or ESRD (8 RCTs, 448 participants; 0.44 [0.26-0.75]; P=0.002) and increased CR + PR (7 RCTs, 422 participants; 1.46 [1.13-1.89]; P=0.004) but led to more adverse events (4 RCTs, 303 participants; 4.20 [1.15-15.32]; P=0.03). Cyclophosphamide was safer than chlorambucil (3 RCTs, 147 participants; 0.48 [0.26-0.90]; P=0.02). Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria.Alkylating agents plus corticosteroids had long-term and short-term benefits for adult IMN, but resulted in more withdrawals or hospitalizations.
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