-
Journal For Immunotherapy of Cancer Dec 2022The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently... (Review)
Review
The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50-100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.
Topics: Child; Humans; Adolescent; T-Lymphocytes; Immunotherapy, Adoptive; Neoplasms; Hematologic Neoplasms; Treatment Outcome
PubMed: 36549782
DOI: 10.1136/jitc-2022-005678 -
Diseases (Basel, Switzerland) Dec 2022Background: Tixagevimab/cilgavimab (TGM/CGM) are neutralizing monoclonal antibodies (mAbs) directed against different epitopes of the receptor-binding domain of the... (Review)
Review
Background: Tixagevimab/cilgavimab (TGM/CGM) are neutralizing monoclonal antibodies (mAbs) directed against different epitopes of the receptor-binding domain of the SARS-CoV-2 spike protein that have been considered as pre-exposure prophylaxis (PrEP). Objectives: This study seeks to assess the efficacy and safety of TGM/CGM to prevent COVID-19 in patients at high risk for breakthrough and severe SARS-CoV-2 infection who never benefited maximally from SARS-CoV-2 vaccination and for those who have a contraindication to SARS-CoV-2 vaccines. Design: This study is a systematic review and meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was followed. Methods: Electronic databases (PubMed, CINAHL, Embase, medRxiv, ProQuest, Wiley online library, Medline, and Nature) were searched from 1 December 2021 to 30 November 2022 in the English language using the following keywords alone or in combination: 2019-nCoV, 2019 novel coronavirus, COVID-19, coronavirus disease 2019, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, tixagevimab, cilgavimab, combination, monoclonal, passive, immunization, antibody, efficacy, clinical trial, cohort, pre-exposure, prophylaxis, and prevention. We included studies in moderate to severe immunocompromised adults (aged ≥18 years) and children (aged ≥12 years) who cannot be vaccinated against COVID-19 or may have an inadequate response to SARS-CoV-2 vaccination. The effect sizes of the outcome of measures were pooled with 95% confidence intervals (CIs) and risk ratios (RRs). Results: Of the 76 papers that were identified, 30 articles were included in the qualitative analysis and 13 articles were included in the quantitative analysis (23 cohorts, 5 case series, 1 care report, and 1 randomized clinical trial). Studies involving 27,932 patients with high risk for breakthrough and severe COVID-19 that reported use of TGM/CGM combination were analyzed (all were adults (100%), 62.8% were men, and patients were mainly immunocompromised (66.6%)). The patients’ ages ranged from 19.7 years to 79.8 years across studies. TGM/CGM use was associated with lower COVID-19-related hospitalization rate (0.54% vs. 1.2%, p = 0.27), lower ICU admission rate (0.6% vs. 5.2%, p = 0.68), lower mortality rate (0.2% vs. 1.2%, p = 0.67), higher neutralization of COVID-19 Omicron variant rate (12.9% vs. 6%, p = 0.60), lower proportion of patients who needed oxygen therapy (8% vs. 41.2%, p = 0.27), lower RT-PCR SARS-CoV-2 positivity rate (2.1% vs. 5.8%, p < 0.01), lower proportion of patients who had severe COVID-19 (0% vs. 0.5%, p = 0.79), lower proportion of patients who had symptomatic COVID-19 (1.8% vs. 6%, p = 0.22), and higher adverse effects rate (11.1% vs. 10.7%, p = 0.0066) than no treatment or other alternative treatment in the prevention of COVID-19. Conclusion: For PrEP, TGM/CGM-based treatment can be associated with a better clinical outcome than no treatment or other alternative treatment. However, more randomized control trials are warranted to confirm our findings and investigate the efficacy and safety of TGM/CGM to prevent COVID-19 in patients at risk for breakthrough or severe SARS-CoV-2 infection.
PubMed: 36547204
DOI: 10.3390/diseases10040118 -
JCO Oncology Practice Mar 2023Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse...
Development of a Core Set of Patient- and Caregiver-Reported Signs and Symptoms to Facilitate Early Recognition of Acute Chimeric Antigen Receptor T-Cell Therapy Toxicities.
PURPOSE
Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post-CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy.
METHODS
We performed a systematic review of phase II/III trials of US Food and Drug Administration-approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell-dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers.
RESULTS
From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments.
CONCLUSION
This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Caregivers; Receptors, Antigen, T-Cell; Outpatients; Cell- and Tissue-Based Therapy
PubMed: 36508702
DOI: 10.1200/OP.22.00501 -
Transfusion Medicine (Oxford, England) Feb 2023Evaluate the safety and effectiveness of convalescent plasma (CP) or hyperimmune immunoglobulin (hIVIG) in severe respiratory disease caused by coronaviruses or...
A systematic review of the safety and efficacy of convalescent plasma or immunoglobulin treatment for people with severe respiratory viral infections due to coronaviruses or influenza.
OBJECTIVE
Evaluate the safety and effectiveness of convalescent plasma (CP) or hyperimmune immunoglobulin (hIVIG) in severe respiratory disease caused by coronaviruses or influenza, in patients of all ages requiring hospital admission.
METHODS
We searched multiple electronic databases for all publications to 12th October 2020, and RCTs only to 28th June 2021. Two reviewers screened, extracted, and analysed data. We used Cochrane ROB (Risk of Bias)1 for RCTs, ROBINS-I for non-RCTs, and GRADE to assess the certainty of the evidence.
RESULTS
Data from 30 RCTs and 2 non-RCTs showed no overall difference between groups for all-cause mortality and adverse events in four comparisons. Certainty of the evidence was downgraded for high ROB and imprecision. (1) CP versus standard care (SoC) (20 RCTS, 2 non-RCTs, very-low to moderate-high certainty); (2) CP versus biologically active control (6 RCTs, very-low certainty); (3) hIVIG versus SoC (3 RCTs, very-low certainty); (4) early CP versus deferred CP (1 RCT, very-low certainty). Subgrouping by titre improved precision in one outcome (30-day mortality) for the 'COVID high-titre' category in Comparison 1 (no difference, high certainty) and Comparison 2 (favours CP, very-low certainty). Post hoc analysis suggests a possible benefit of CP in patients testing negative for antibodies at baseline, compared with those testing positive.
CONCLUSION
A minimum titre should be established and ensured for a positive biological response to the therapy. Further research on the impact of CP/hIVIG in patients who have not yet produced antibodies to the virus would be useful to target therapies at groups who will potentially benefit the most.
Topics: Humans; Influenza, Human; COVID-19; COVID-19 Serotherapy; Immunoglobulins
PubMed: 36412541
DOI: 10.1111/tme.12942 -
Journal of Global Health Nov 2022Severe acute respiratory infections (SARIs) remain a leading cause of death globally, particularly in low- and middle-income countries (LMICs). Early intervention is...
A systematic review of acute and emergency care interventions for adolescents and adults with severe acute respiratory infections including COVID-19 in low- and middle-income countries.
BACKGROUND
Severe acute respiratory infections (SARIs) remain a leading cause of death globally, particularly in low- and middle-income countries (LMICs). Early intervention is critical, considering the potential for rapid decompensation in patients with SARIs. We aimed to evaluate the impact of acute and emergency care interventions on improving clinical outcomes in patients >10 years old with SARIs in LMICs.
METHODS
A systematic literature search was performed in PubMed, Global Health, and Global Index Medicus databases to identify peer-reviewed studies containing SARI, LMICs, and emergency care interventions. Studies published prior to November 2020 focusing on patients >10 years old were included. A narrative synthesis was performed due to the heterogeneity of identified articles. Risk of bias was assessed using the Risk of Bias 2 and Risk of Bias In Non-Randomized Studies of Interventions tools.
RESULTS
20 223 studies were screened and 58 met the inclusion criteria. Thirty-four studies focused on coronavirus-2019 (COVID-19), 15 on pneumonia, seven on influenza, one study on severe acute respiratory syndrome, and one on undifferentiated SARI. Few COVID-19 studies found a benefit of the tested intervention on clinical status, mortality, or hospital length-of-stay. Little to no benefit was found for azithromycin, convalescent plasma, or zinc, and potential harm was found for hydroxychloroquine/chloroquine. There was mixed evidence for immunomodulators, traditional Chinese medicine, and corticosteroids among COVID-19 studies, with notable confounding due to a lack of consistency of control group treatments. Neuraminidase inhibitor antivirals for influenza had the highest quality of evidence for shortening symptom duration and decreasing disease severity.
CONCLUSIONS
We found few interventions for SARIs in LMICs with have high-quality evidence for improving clinical outcomes. None of the included studies evaluated non-pharmacologic interventions or were conducted in low-income countries. Further studies evaluating the impact of antivirals, immunomodulators, corticosteroids, and non-pharmacologic interventions for SARIs in LMICs are urgently needed.
REGISTRATION
PROSPERO registration number: CRD42020216117.
Topics: Humans; Adolescent; Child; COVID-19; Developing Countries; Influenza, Human; Antiviral Agents; Emergency Medical Services; COVID-19 Serotherapy
PubMed: 36342777
DOI: 10.7189/jogh.12.05039 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2023Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities,... (Review)
Review
Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Prospective Studies; Transplantation, Autologous; Receptors, Antigen, T-Cell; Antigens, CD19; Lymphoma; Central Nervous System Neoplasms; Lymphoma, Non-Hodgkin; Neoplasms, Second Primary; Central Nervous System; Lymphoma, Large B-Cell, Diffuse
PubMed: 36328891
DOI: 10.1016/j.clml.2022.09.008 -
Nature Communications Oct 2022The latest SARS-CoV-2 variant of concern Omicron, with its immune escape from therapeutic anti-Spike monoclonal antibodies and WA-1 vaccine-elicited sera, demonstrates...
The latest SARS-CoV-2 variant of concern Omicron, with its immune escape from therapeutic anti-Spike monoclonal antibodies and WA-1 vaccine-elicited sera, demonstrates the continued relevance of COVID-19 convalescent plasma (CCP) therapies. Lessons learnt from previous usage of CCP suggests focusing on early outpatients and immunocompromised recipients, with high neutralizing antibody titer units. Here, we systematically review Omicron-neutralizing plasma activity data, and report that approximately 47% (424/902) of CCP samples from unvaccinated pre-Omicron donors neutralizes Omicron BA.1 with a very low geometric mean of geometric mean titers for 50% neutralization GM(GMT) of ~13, representing a > 20-fold reduction from WA-1 neutralization. Non-convalescent subjects who had received two doses of mRNA vaccines had a GM(GMT50) for Omicron BA.1 neutralization of ~27. However, plasma from vaccinees recovering from either previous pre-Omicron variants of concern infection, Omicron BA.1 infection, or third-dose uninfected vaccinees was nearly 100% neutralizing against Omicron BA.1, BA.2 and BA.4/5 with GM(GMT()) all over 189, 10 times higher than pre-Omicron CCP. Fully vaccinated and post-BA.1 plasma (Vax-CCP) had a GM(GMT) > 450 for BA.4/5 and >1,500 for BA.1 and BA.2. These findings have implications for both CCP stocks collected in prior pandemic periods and for future plans to restart CCP collections. Thus, Vax-CCP provides an effective tool to combat ongoing variants that escape therapeutic monoclonal antibodies.
Topics: Humans; Neutralization Tests; SARS-CoV-2; Antibodies, Viral; COVID-19; Antibodies, Monoclonal; Antibodies, Neutralizing; Spike Glycoprotein, Coronavirus; COVID-19 Serotherapy
PubMed: 36309490
DOI: 10.1038/s41467-022-33864-y -
British Journal of Haematology Jan 2023
Meta-Analysis
Topics: Humans; Receptors, Chimeric Antigen; Standard of Care; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Cell- and Tissue-Based Therapy; Antigens, CD19; Receptors, Antigen, T-Cell
PubMed: 36281746
DOI: 10.1111/bjh.18506 -
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 -
Journal of the Indian Society of... 2022Passive immunization using egg yolk-based antibodies has been tested against oral microorganisms. Our study assessed the effect of immunoglobulin Y (IgY) formulations on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Passive immunization using egg yolk-based antibodies has been tested against oral microorganisms. Our study assessed the effect of immunoglobulin Y (IgY) formulations on Streptococcus mutans, Porphyromonas gingivalis, and Candida albicans in human subjects.
HIGHLIGHTS
VS and UT independently searched articles using keyword combinations in four search engines; studies in English were selected. Either parallel-arm or split-mouth randomized controlled trials on healthy human subjects were considered. Ten studies remained in the selection; six studies compared the effect of IgY formulations on S. mutans, three on P. gingivalis, and one on C. albicans. Five studies (422 subjects) compared the effect of IgY formulations on S. mutans. When fixed-effect model (FEM) was applied, the risk ratio (RR) (confidence interval [CI]) was found to be 7.81 (6.00, 10.18). Three studies (167 subjects) compared the effect of IgY formulations on P. gingivalis. When FEM was applied, the RR (CI) was found to be 0.06 (-0.03, 0.15) in relation to reduction in probing depth. When FEM was applied, for percentage reduction in bleeding on probing (BOP), the RR (CI) was 1.99 (1.64, 2.41). Only one study (26 subjects) was available of IgY formulation and C. albicans; hence meta-analysis was not performed.The search was extended using Google Scholar, Semantic Scholar, cross-references and by contacting authors and researchers in the field which further yielded five articles. .
CONCLUSIONS
IgY formulations were effective in the reduction of S. mutans. They were not effective on P. gingivalis in relation to probing depth but were effective in relation to reduction in BOP. No harms were reported. Evidence is of low quality due to high heterogeneity. The ROB was moderate and publication bias was low.
Topics: Humans; Immunoglobulins; Porphyromonas gingivalis; Streptococcus mutans; Research Subjects; Randomized Controlled Trials as Topic
PubMed: 36260461
DOI: 10.4103/jisppd.jisppd_226_22