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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 -
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 -
BMC Public Health Dec 2023A significant proportion of the global respiratory syncytial virus (RSV) associated morbidity is accounted for by infants aged 0 to 6 months, who are particularly...
BACKGROUND
A significant proportion of the global respiratory syncytial virus (RSV) associated morbidity is accounted for by infants aged 0 to 6 months, who are particularly vulnerable to severe disease. In 2015, 44% of global hospitalisations in infants in this age group were secondary to RSV. The objective of this systematic review is to appraise and synthesise the local evidence of RSV infection morbidity among Australian infants aged 0 to 6 months and to assess the implications for future immunisation strategies.
METHODS
Electronic databases (Medline, Embase, Pubmed and Global Health) were searched for full-text articles published between 2000 and 2023 in English language. Studies that examined markers of RSV disease morbidity in infants aged 0 to 6 months in Australia who had laboratory confirmed RSV infection were eligible for inclusion. The outcomes of interest were incidence, prevalence, testing rate, positivity rate, mortality, emergency department visits, community health visits, hospitalisation, intensive care unit admission, supplementary oxygen use, mechanical ventilation, risk factors for disease severity and monoclonal antibody use.
RESULTS
The database search identified 469 studies. After removal of duplicates and full-text review, 17 articles were eligible for inclusion. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Synthesis without meta-analysis guidelines.
CONCLUSIONS
Qualitative analysis of the included studies showed that Australian infants aged 0 to 6 months have higher rates of RSV testing, positivity and incidence; and more likely to develop severe disease that requires hospitalisation, intensive care unit admission or respiratory support, compared to children and adults of all ages. Aboriginal and Torres Strait Islander infants aged 0 to 6 months demonstrated higher rates of RSV infection and hospitalisation, compared to non-Indigenous infants. Age-related trends persisted in geographic areas with varying seasonal transmission of RSV, and during the SARS-CoV-2 pandemic. Passive immunisation strategies targeting infants in their first 6 months of life, either via vaccination of pregnant women or administration of long-acting monoclonal antibody during infancy, could effectively reduce RSV disease burden in Australia.
Topics: Pregnancy; Infant; Child; Adult; Humans; Female; Respiratory Syncytial Virus Infections; Australia; Communicable Diseases; Antibodies, Monoclonal; Respiratory Syncytial Virus, Human; Hospitalization; Prevalence
PubMed: 38129854
DOI: 10.1186/s12889-023-17474-x -
Clinical Immunology Communications Dec 2022Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against...
Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.
PubMed: 38013970
DOI: 10.1016/j.clicom.2022.08.003 -
The Lancet. Microbe Nov 2023Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have not been identified. We aimed to assess how the dose and timing of administration affect treatment outcome.
METHODS
In this systematic review and meta-analysis, we extracted data from published studies of passive antibody treatment from Jan 1, 2019, to Jan 31, 2023, that were identified by searching multiple databases, including MEDLINE, PubMed, and ClinicalTrials.gov. We included only randomised controlled trials of passive antibody administration for the prevention or treatment of COVID-19. To compare administered antibody dose between different treatments, we used data on in-vitro neutralisation titres to normalise dose by antibody potency. We used mixed-effects regression and model fitting to analyse the relationship between timing, dose and efficacy.
FINDINGS
We found 58 randomised controlled trials that investigated passive antibody therapies for the treatment or prevention of COVID-19. Earlier clinical stage at treatment initiation was highly predictive of the efficacy of both monoclonal antibodies (p<0·0001) and convalescent plasma therapy (p=0·030) in preventing progression to subsequent stages, with either prophylaxis or treatment in outpatients showing the greatest effects. For the treatment of outpatients with COVID-19, we found a significant association between the dose administered and efficacy in preventing hospitalisation (relative risk 0·77; p<0·0001). Using this relationship, we predicted that no approved monoclonal antibody was expected to provide more than 30% efficacy against some omicron (B.1.1.529) subvariants, such as BQ.1.1.
INTERPRETATION
Early administration before hospitalisation and sufficient doses of passive antibody therapy are crucial to achieving high efficacy in preventing clinical progression. The relationship between dose and efficacy provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19.
FUNDING
The Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council, the University of New South Wales, Monash University, Haematology Society of Australia and New Zealand, Leukaemia Foundation, and the Victorian Government.
Topics: Humans; COVID-19; SARS-CoV-2; COVID-19 Serotherapy; Australia; Treatment Outcome; Antibodies, Monoclonal
PubMed: 37924835
DOI: 10.1016/S2666-5247(23)00194-5 -
International Journal of Molecular... Oct 2023Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients... (Review)
Review
Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.
Topics: Humans; Glioblastoma; Immune Checkpoint Inhibitors; Cancer Vaccines; Neoplasm Recurrence, Local; Glioma; Immunotherapy; Immunotherapy, Adoptive; Brain Neoplasms; Tumor Microenvironment
PubMed: 37894718
DOI: 10.3390/ijms242015037 -
Transplantation and Cellular Therapy Jan 2024Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients... (Meta-Analysis)
Meta-Analysis
Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.
Topics: Humans; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Neurotoxicity Syndromes; Observational Studies as Topic; Pathologic Complete Response; Receptors, Chimeric Antigen; Retrospective Studies; T-Lymphocytes
PubMed: 37890589
DOI: 10.1016/j.jtct.2023.10.017 -
Leukemia Dec 2023In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory...
In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL), the objective was to compare the efficacy of tisagenlecleucel with historical controls from multiple disease registries using patient-level adjustment of the historical controls. The analysis is based on patient-level data of three tisagenlecleucel studies (ELIANA, ENSIGN and CCTL019B2001X) vs. three registries in Germany/Austria. Statistical analyses were fully pre-specified and propensity score weighting of the historical controls by fine stratification weights was used to adjust for relevant confounders identified by systematic literature review. Results showed high comparability of cohorts after adjustment with absolute SMD ≤ 0.1 for all pre-specified confounders and favorable outcomes for tisagenlecleucel compared to SOC for all examined endpoints. Hazard ratios for OS, EFS and RFS were 0.54 (95% CI: 0.41-0.71, p < 0.001), 0.67 (0.52-0.86, p = 0.001) and 0.77 (0.51-1.18, p = 0.233). The OS, EFS and RFS survival probability at 2 years was 59.49% for tisagenlecleucel vs. 36.16% for SOC population, 42.31% vs. 30.23% and 59.60% vs. 54.57%, respectively. Odds ratio for ORR was 1.99 (1.33-2.97, p < 0.001). Results for OS and ORR were statistically significant after adjustment for confounders and provide evidence supporting a superiority of tisagenlecleucel in r/r ALL given the good comparability of cohorts after adjustment for confounders.
Topics: Humans; Child; Young Adult; Standard of Care; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Austria; Immunotherapy, Adoptive
PubMed: 37880478
DOI: 10.1038/s41375-023-02042-4 -
Journal of Autoimmunity Nov 2023This systematic review aimed to characterise the cognitive outcomes of patients who received chimeric antigen receptor T-cell therapy. (Review)
Review
BACKGROUND
This systematic review aimed to characterise the cognitive outcomes of patients who received chimeric antigen receptor T-cell therapy.
METHODS
A systematic search of the literature was performed using PubMed, PsycINFO, SCOPUS, EMBASE, Medline, and CINAHL (February 2023). Risk of bias was assessed using the JBI Checklist for Case Reports and the Risk of Bias Assessment Tool for Non-randomised Studies.
RESULTS
Twenty-two studies met inclusion criteria with a total of 1104 participants. There was considerable methodological heterogeneity with differing study designs (e.g., cohort studies, clinical trials, case studies, a qualitative interview, and a focus group), measures of cognition (e.g., self-report, neuropsychological measures, clinician assessed/neurological examinations), and longest follow-up time points (i.e., five days to five years).
DISCUSSION
Results of the studies were heterogenous with studies demonstrating stable, improved, or reduced cognition across differing time points. Overall, cognitive symptoms are common particularly in the acute stage (<2 weeks) post-infusion. Most deficits that arise in the acute stage resolve within one to two weeks, however, there is a subset of patients who continue to experience and self-report persistent deficits in the subacute and chronic stages. Future studies are needed to comprehensively analyse cognition using a combination of self-report and psychometric measures following chimeric antigen receptor T-cell therapy in the acute, subacute, and chronic settings.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Cognition; Treatment Outcome
PubMed: 37837807
DOI: 10.1016/j.jaut.2023.103126