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Therapeutic Advances in Hematology 2023Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to... (Review)
Review
BACKGROUND
Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia.
OBJECTIVES
This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies.
DESIGN
A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
DATA SOURCES AND METHODS
Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022.
RESULTS
We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs ( = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30-1.93); = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37-0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI ( = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low.
CONCLUSION
So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free survival, but no overall survival, in patients with R/R B-cell lymphoma. Despite one-arm trials have already facilitated approval of CAR-T cell treatments, additional evidence from large comparative studies is still needed to better characterize the benefit-harm ratio of the use of CAR-T in a variety of patient populations with hematological malignancies.
REGISTRATION
https://doi.org/10.12688/openreseurope.14390.1.
PROSPERO/OSF PREREGISTRATION
10.17605/OSF.IO/V6HDX.
PubMed: 37138698
DOI: 10.1177/20406207231168211 -
Viruses May 2023Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a... (Review)
Review
Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a role in this phenomenon. This systematic review investigates the role of CTLA-4 in the development of T cell exhaustion in CHB. A systematic literature search was conducted on PubMed and Embase on 31 March 2023 to identify relevant studies. Fifteen studies were included in this review. A majority of the studies investigating CD8 T cells demonstrated increased expression of CTLA-4 in CHB patients, though one study found this only in HBeAg-positive patients. Three out of four studies investigating the expression of CTLA-4 on CD4 T cells found upregulation of CTLA-4. Several studies showed constitutive expression of CLTA-4 on CD4 regulatory T cells. CTLA-4 blockade resulted in heterogeneous responses for all T cell types, as it resulted in increased T cell proliferation and/or cytokine production in some studies, while other studies found this only when combining blockade of CTLA-4 with other inhibitory receptors. Although mounting evidence supports a role of CTLA-4 in T cell exhaustion, there is still insufficient documentation to describe the expression and exact role of CTLA-4 in T cell exhaustion in CHB.
Topics: Humans; CTLA-4 Antigen; Hepatitis B, Chronic; CD8-Positive T-Lymphocytes; T-Cell Exhaustion; T-Lymphocytes, Regulatory; Hepatitis B virus
PubMed: 37243227
DOI: 10.3390/v15051141 -
Cells Aug 2023Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC.
METHODS
Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible.
RESULTS
A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs-15 studies), perihilar-distal CCAs (p/dCCAs-7 studies), and gallbladder cancer (GBC-5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively.
CONCLUSION
From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.
Topics: Humans; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Biliary Tract Neoplasms; Immunotherapy; Biomarkers; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37626908
DOI: 10.3390/cells12162098 -
Frontiers in Endocrinology 2023Second-generation androgen receptor inhibitors (ARIs) have been developed and approved for treating castration-resistant prostate cancer (CRPC). There is a lack of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Second-generation androgen receptor inhibitors (ARIs) have been developed and approved for treating castration-resistant prostate cancer (CRPC). There is a lack of direct comparison of the therapeutic effects and adverse events between the conventional ARI (bicalutamide) and three second-generation ARIs (enzalutamide, apalutamide and darolutamide).
METHODS
Our network meta-analysis evaluated therapeutic effects and adverse events of the conventional ARI (bicalutamide) and the second-generation ARIs in treating CRPC. We systematically searched the Pubmed, Cochrane library and Embase databases for studies published until October 2022 and only randomized clinical trials (RCTs) were included. The progression-free survival, prostate-specific antigen (PSA) progression-free survival, overall survival (PFS/PSA-PFS/OS), PSA response rate and relative adverse events (AEs) of CRPC patients were collected and synthesized. We then performed subgroup analysis. The non-metastatic and metastatic CRPC (nm/mCRPC) observations were analyzed separately. Data analyses were performed using R software (4.2.1) based on Bayesian framework.
RESULTS
6,993 subjects from seven eligible RCTs were analyzed. Enzalutamide, apalutamide and darolutamide were more effective than bicalutamide in treating CRPC, and the performance of darolutamide was slightly worse than the other two second-generation ARIs. Similar adverse events rate were observed among the second-generation ARIs and bicalutamide. Apalutamide showed a slightly higher rate of Grade 3+ AEs, percentages of AE-related drug withdrawals and AE-related mortality. Patients receiving enzalutamide had significantly higher rate of hypertension and fatigue. In subgroup analysis, enzalutamide showed better therapeutic effects compared with bicalutamide in both nmCRPC and mCRPC groups. In nmCRPC group, enzalutamide and apalutamide had more benefits on PFS and PSA-PFS compared with darolutamide. We displayed the probability ranking map of PFS, PSA-PFS, OS, time to cytotoxic chemotherapy, PSA response rate and relative AE outcomes.
CONCLUSION
The current network meta-analysis indicated that the second-generation ARIs were superior to the conventional ARI, bicalutamide. The three second-generation ARIs showed incomplete equivalence on CRPC treatment. The darolutamide was slightly less effective compared with enzalutamide and apalutamide. The adverse events of apalutamide were worse than the others, but no statistical significance was observed among these vital AEs. All ARIs were generally well-tolerated. These results may provide reference to clinical decision and further direct comparison trials.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022370842.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Prostate-Specific Antigen; Network Meta-Analysis; Treatment Outcome; Androgen Receptor Antagonists
PubMed: 36843606
DOI: 10.3389/fendo.2023.1131033 -
Cureus Aug 2022Chimeric Antigen Receptor (CAR)-T cell therapy has been one of the most important breakthroughs for treating hematologic malignancies. On the other hand, the therapy had... (Review)
Review
Chimeric Antigen Receptor (CAR)-T cell therapy has been one of the most important breakthroughs for treating hematologic malignancies. On the other hand, the therapy had many toxicities. One of the toxicities of the CAR-T therapy is cardiotoxicity. The goal of the systematic review is to elaborate on the cardiotoxicities related to CAR-T therapy for hematologic malignancies. The systematic review is following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines. The systematic search was done using PubMed, PubMed Central (PMC), Google Scholar, Cochrane Library, ScienceDirect, and clinicaltrial.gov. The search and selection of studies were done on April 28, 2022, and May 6, 2022, respectively. The studies were selected based upon participants, intervention, and outcomes (PIO) elements and the articles that were included were, full-text articles published within the last ten years, clinical trials, meta-analyses, randomized controlled trial, review, and systematic review. The exclusion criteria were non-hematologic malignancy, non-English-language articles. The initial search had 2,159 publications. The publications were assessed with assessment tools of Scale of the Assessment of Narrative Review Articles (SANRA), Newcastle-Ottawa Scale (NCOS), and Cochrane Collaboration Risk of Bias Tool (CCRBT), which led to selection of eight publications. The systematic review concludes that cardiotoxicity happened in adults and pediatric patients receiving the CAR-T cell therapy and that those cardiac adverse events had many risk factors. Therefore, monitoring these cardiotoxicities is highly essential.
PubMed: 36148204
DOI: 10.7759/cureus.28162 -
Frontiers in Pharmacology 2023Chimeric antigen receptor T cells treatment targeting B cell maturation antigen (BCMA) is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM)...
Effectiveness and safety of anti-BCMA chimeric antigen receptor T-cell treatment in relapsed/refractory multiple myeloma: a comprehensive review and meta-analysis of prospective clinical trials.
Chimeric antigen receptor T cells treatment targeting B cell maturation antigen (BCMA) is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) and has demonstrated outstanding outcomes in clinical studies. The aim of this comprehensive review and meta-analysis was to summarize the effectiveness and safety of anti-BCMA CAR-T treatment for patients with relapsed/refractory multiple myeloma (RRMM). Our research identifies variables influencing outcome measures to provide additional evidence for CAR-T product updates, clinical trial design, and clinical treatment guidance. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard was followed for conducting this comprehensive review and meta-analysis, which was submitted to PROSPERO (CRD42023390037). From the inception of the study until 10 September 2022, PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and WanFang databases were searched for eligible studies. Stata software (version 16.0) was used to assess effectiveness and safety outcomes. Out of 875 papers, we found 21 relevant trials with 761 patients diagnosed as RRMM and were given anti-BCMA CAR-T treatment. The overall response rate (ORR) for the entire sample was 87% (95% CI: 80-93%) complete response rate (CRR) was 44% (95% CI: 34-54%). The minimal residual disease (MRD) negativity rate within responders was 78% (95% CI: 65-89%). The combined incidence of cytokine release syndrome was 82% (95% CI: 72-91%) and neurotoxicity was 10% (95% CI: 5%-17%). The median progression-free survival (PFS) was 8.77 months (95% CI: 7.48-10.06), the median overall survival (OS) was 18.87 months (95% CI: 17.20-20.54) and the median duration of response (DOR) was 10.32 months (95% CI: 9.34-11.31). According to this meta-analysis, RRMM patients who received anti-BCMA CAR-T treatment have demonstrated both effectiveness and safety. Subgroup analysis confirmed the anticipated inter-study heterogeneity and pinpointed potential factors contributing to safety and efficacy, which may help with the development of CAR-T cell studies and lead to optimized BCMA CAR-T-cell products. Clinicaltrials.gov, PROSPERO, CRD42023390037.
PubMed: 37408760
DOI: 10.3389/fphar.2023.1149138 -
Value in Health : the Journal of the... Apr 2024This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. (Review)
Review
OBJECTIVES
This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer.
METHODS
Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars.
RESULTS
Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects.
CONCLUSIONS
CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.
PubMed: 38641057
DOI: 10.1016/j.jval.2024.04.004 -
European Urology Open Science Aug 2023Identifying malignant tissue and leaving adjacent structures undisturbed constitute an ongoing challenge in prostate cancer (PCa) surgery. Image and radioguided surgical... (Review)
Review
CONTEXT
Identifying malignant tissue and leaving adjacent structures undisturbed constitute an ongoing challenge in prostate cancer (PCa) surgery. Image and radioguided surgical technologies targeting the prostate-specific membrane antigen (PSMA) receptor may facilitate identification and removal of diseased tissue.
OBJECTIVE
To perform a systematic review of the clinical studies on PSMA-targeted surgery.
EVIDENCE ACQUISITION
The MEDLINE (OvidSP), Embase.com, and Cochrane Library databases were searched. Identified reports were critically appraised according to the Idea, Development, Exploration, Assessment, Long-term framework criteria. The risk of bias (RoB) was assessed as per the Risk Of Bias In Non-randomized Studies-of Interventions tool. The strengths and limitations of the techniques and corresponding oncological outcomes were extracted as areas of interest. Data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
EVIDENCE SYNTHESIS
In total, 29 reports were selected, including eight prospective studies, 12 retrospective analyses, and nine case reports, all with a high or an unclear RoB. In 72.4% of studies, PSMA targeting was achieved via radioguided surgery (RGS), predominantly using Tc-PSMA-I&S (66.7%). Hybrid approaches that complement RGS with optical guidance are emerging. The majority of studies retrieved were pilot studies with a short follow-up. In 13 reports, salvage lymph node surgery was discussed (44.8%). In 12 more recent reports (41.4%), PSMA targeting was studied in primary PCa surgery (50.0% lymph nodes and 50.0% surgical margins), and four studied both primary and salvage surgery (13.8%). Overall, specificity was higher than sensitivity (median 98.9% and 84.8%, respectively). Oncological outcomes were discussed only in reports on the use of Tc-PSMA-I&S in salvage surgery (median follow-up of 17.2 mo). A decline in prostate-specific antigen level of >90% ranged from 22.0% to 100.0%, and biochemical recurrence ranged from 50.0% to 61.8% of patients.
CONCLUSIONS
In PSMA-targeted surgery, most studies address salvage PSMA-RGS using Tc-PSMA-I&S. Available evidence suggests that the specificity of intraoperative PSMA targeting is higher than the sensitivity. The studies that included follow-up did not yet objectify a clear oncological benefit. Lacking solid outcome data, PSMA-targeted surgery remains investigational.
PATIENT SUMMARY
In this paper, we review recent advances in prostate-specific membrane antigen (PSMA)-targeted surgery, which is used to help identify and remove prostate cancer. We found good evidence to suggest that PSMA targeting helps identify prostate cancer during surgery. The oncological benefits have yet to be investigated further.
PubMed: 37361200
DOI: 10.1016/j.euros.2023.05.014 -
JAMA Network Open Jul 2021Hundreds of chimeric antigen receptor (CAR) therapies are under investigation for hematologic malignant cancers and solid malignant tumors. As the field of modern CAR...
IMPORTANCE
Hundreds of chimeric antigen receptor (CAR) therapies are under investigation for hematologic malignant cancers and solid malignant tumors. As the field of modern CAR therapy enters its second decade, clinical trials that demonstrate the efficacy of CAR therapies using randomized clinical trials (RCTs) and/or investigate methods to optimize patient outcomes with commercially available CAR therapies are increasingly important.
OBJECTIVE
To analyze the landscape of registered CAR-related trials with dual focuses on trial methods and intent.
EVIDENCE REVIEW
This systematic review identified 1304 ongoing or upcoming CAR-related trials registered at ClinicalTrials.gov as of December 22, 2020, and excluded 513 trials that did not pertain to cell-based therapy. Both CAR-related and trial-related variables, including target antigens and countries of origin, were recorded. Trials were categorized as non-RCTs that compared CAR with non-CAR therapies or RCTs in which every arm received CAR therapy. Trial intent was separately categorized as demonstrating the efficacy of a CAR therapy, optimizing patient outcomes with established CAR therapies using adjunctive non-CAR modalities, or miscellaneous.
FINDINGS
Of 778 relevant trials, 587 (75%) involved blood cancers, whereas 182 (23%) involved solid tumor cancers; the remaining 9 (1%) involved nonmalignant diseases. A total of 433 trials (56%) were from China and 288 from the US (37%). Ten RCTs (1%) compared CAR therapies with non-CAR therapies, including phase 3 RCTs for 4 of 5 CAR therapies (80%) that are currently commercially available. Twenty-eight studies (4%) sought to optimize outcomes with established CAR therapies using non-CAR drugs or radiotherapy, whereas 3 studies (0.4%) sought to optimize supportive care during CAR therapy.
CONCLUSIONS AND RELEVANCE
This systematic review found that randomized and optimization-focused trials are comparatively rare within the landscape of ongoing and upcoming CAR-related trials. As the field of modern CAR therapy enters its second decade, additional studies of these characteristics are necessary to strengthen the evidence base for CAR therapy and improve patient outcomes.
Topics: Humans; Immunotherapy, Adoptive; Research
PubMed: 34236412
DOI: 10.1001/jamanetworkopen.2021.15668 -
Frontiers in Immunology 2023The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in cancer patients. However, the safety of these combination regimens remains conflicting in former researches. Therefore, in order to address this issue, we performed a systematic review and network meta-analysis (NMA) to evaluate and compare the safety profile.
METHODS
We performed a systematic review by searching randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science up to August 15, 2022. The primary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) immune-related adverse events (irAEs). Secondary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) irAEs of subgroups of ICIs.
RESULTS
There were 22 RCTs included in the NMA, involving a total of 15 963 patients diagnosed with any type of cancer. ICIs+nab-PTX was associated with a noticeably decreased risk of grade 3-5 pneumonitis (odds ratio [OR]=0.28, 95% credible interval [CrI]: 0.09,0.90) compared to ICI monotherapy; ICIs+PTX showed a lower risk of grade 1-5 hyperthyroidism (OR=0.46, 95% CrI: 0.22-0.96) and grade 1-5 hypothyroidism (OR=0.49, 95% CrI: 0.26-0.93) than ICIs. Compared with PD-1, PD-1+PTX was associated with a statistically significantly lower risk of grade 1-5 pneumonitis (OR=0.32, 95% CrI: 0.11-0.92). PD-L1 resulted in a noticeably lower risk of grade 1-5 hypothyroidism (OR=0.34, 95% CrI: 0.12-1.00) than PD-L1+PTX. Nearly all treatment regimens containing ICIs demonstrated significantly higher risks of irAEs compared to the standard chemotherapy groups.
CONCLUSION
Nab-PTX/PTX+ICIs demonstrated an approach leading to decreased risk of irAEs compared with ICI monotherapy. This finding supports that ICIs+nab-PTX/PTX may be a safer treatment strategy. Moreover, we also found that the combination regimens containing ICIs had a higher risk of irAEs than standard chemotherapy. Additionally, ICIs+nab-PTX demonstrated a decreased risk of irAEs compared to ICIs+PTX. PD-1 inhibitors were associated with a higher risk of irAEs than PD-L1 inhibitors.
Topics: Humans; Immune Checkpoint Inhibitors; B7-H1 Antigen; Antineoplastic Agents, Immunological; Programmed Cell Death 1 Receptor; Network Meta-Analysis; Neoplasms; Paclitaxel; Hypothyroidism; Pneumonia
PubMed: 37520574
DOI: 10.3389/fimmu.2023.1175809