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Frontiers in Immunology 2022We aimed to compare the efficacy of chimeric antigen receptor T (CAR-T) cell therapy with that of autologous stem cell transplantation (auto-HSCT) in relapsed/refractory...
BACKGROUND
We aimed to compare the efficacy of chimeric antigen receptor T (CAR-T) cell therapy with that of autologous stem cell transplantation (auto-HSCT) in relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL).
RESEARCH DESIGN AND METHODS
We searched eligible publications up to January 31st, 2022, in PubMed, Cochrane Library, Springer, and Scopus. A total of 16 publications with 3484 patients were independently evaluated and analyzed using STATA SE software.
RESULTS
Patients who underwent CAR-T cell therapy showed a better overall response rate (ORR) and partial response (PR) than those treated with auto-HSCT (CAR-T vs. auto-HSCT, ORR: 80% vs. 73%, HR:0.90,95%CI:0.76-1.07, = 0.001; PR: 20% vs. 14%, HR:0.65,95%CI:0.62-0.68, = 0.034). No significant difference was observed in 6-month overall survival (OS) (CAR-T vs. auto-HSCT, six-month OS: 81% vs. 84%, HR:1.23,95%CI:0.63-2.38, = 0.299), while auto-HSCT showed a favorable 1 and 2-year OS (CAR-T vs. auto-HSCT, one-year OS: 64% vs. 73%, HR:2.42,95%CI:2.27-2.79, P < 0.001; two-year OS: 54% vs. 68%, HR:1.81,95%CI:1.78-1.97, P < 0.001). Auto-HSCT also had advantages in progression-free survival (PFS) (CAR-T vs. auto-HSCT, six-month PFS: 53% vs. 76%, HR:2.81,95%CI:2.53-3.11, < 0.001; one-year PFS: 46% vs. 61%, HR:1.84,95%CI:1.72-1.97, < 0.001; two-year PFS: 42% vs. 54%, HR:1.62,95%CI:1.53-1.71, < 0.001). Subgroup analysis by age, prior lines of therapy, and ECOG scores was performed to compare the efficacy of both treatment modalities.
CONCLUSION
Although CAR-T cell therapy showed a beneficial ORR, auto-HSCT exhibited a better long-term treatment superiority in R/R DLBCL patients. Survival outcomes were consistent across different subgroups.
Topics: Humans; Receptors, Chimeric Antigen; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Stem Cell Transplantation
PubMed: 36733398
DOI: 10.3389/fimmu.2022.1041177 -
International Journal of Molecular... May 2024Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell)... (Meta-Analysis)
Meta-Analysis Review
An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis.
Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.
Topics: Multiple Myeloma; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Treatment Outcome; Quality of Life; Neoplasm Recurrence, Local; Cytokine Release Syndrome
PubMed: 38732213
DOI: 10.3390/ijms25094996 -
Cancers Jan 2019Chimeric antigen receptors T cells (CAR T) had been used for treating various tumor patients in clinic, and owned an incredible efficacy in part of malignancies.... (Review)
Review
Chimeric antigen receptors T cells (CAR T) had been used for treating various tumor patients in clinic, and owned an incredible efficacy in part of malignancies. However, CAR T therapy remains controversial due to doubts about its efficacy and safety in the clinical treatment of various malignancies. A total of 997 tumor patients from 52 studies were included in this review. Eligible studies were searched and reviewed from the databases of PubMed, Web of Science, Wanfang and Clinicaltrials.gov. Then meta-analysis and subgroup analysis were used to investigate the overall response rate (ORR), complete response rate (CRR), common side effect rate (CSER) and relapse rate (RR) of CAR T therapy for patients in clinical researches, respectively. The results further confirmed that CAR T therapy had a higher response rate for hematologic malignancies. More importantly, CAR T therapy had a higher CSER in patients with hematologic malignancies, and it had a similar RR in patients with different malignancies. Cell cultured without the addition of IL-2 and total administration less than 10⁸ cells were recommended. This study offers a reference for future research regarding the application in solid and hematologic malignancies, side effects and relapse, and even the production processes of CAR T cells.
PubMed: 30621018
DOI: 10.3390/cancers11010047 -
Experimental Hematology & Oncology Aug 2023Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It is based on genetically modified T cells to express a CAR,... (Review)
Review
Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It is based on genetically modified T cells to express a CAR, which enables the recognition of the specific tumour antigen of interest. To date, CAR-T cell therapies approved for commercialisation are designed to treat haematological malignancies, showing impressive clinical efficacy in patients with relapsed or refractory advanced-stage tumours. However, since they all use the patient´s own T cells as starting material (i.e. autologous use), they have important limitations, including manufacturing delays, high production costs, difficulties in standardising the preparation process, and production failures due to patient T cell dysfunction. Therefore, many efforts are currently being devoted to contribute to the development of safe and effective therapies for allogeneic use, which should be designed to overcome the most important risks they entail: immune rejection and graft-versus-host disease (GvHD). This systematic review brings together the wide range of different approaches that have been studied to achieve the production of allogeneic CAR-T cell therapies and discuss the advantages and disadvantages of every strategy. The methods were classified in two major categories: those involving extra genetic modifications, in addition to CAR integration, and those relying on the selection of alternative cell sources/subpopulations for allogeneic CAR-T cell production (i.e. γδ T cells, induced pluripotent stem cells (iPSCs), umbilical cord blood T cells, memory T cells subpopulations, virus-specific T cells and cytokine-induced killer cells). We have observed that, although genetic modification of T cells is the most widely used approach, new approaches combining both methods have emerged. However, more preclinical and clinical research is needed to determine the most appropriate strategy to bring this promising antitumour therapy to the clinical setting.
PubMed: 37605218
DOI: 10.1186/s40164-023-00435-w -
Frontiers in Immunology 2023Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been FDA-approved, CAR T-cells targeting CD22, as well as dual-targeting CD19/CD22 CAR T-cells, are currently being evaluated in clinical trials. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of CD22-targeting CAR T-cell therapies. We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to March 3rd 2022 for full-length articles and conference abstracts of clinical trials employing CD22-targeting CAR T-cells in acute lymphocytic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The primary outcome was best complete response (bCR). A DerSimonian and Laird random-effects model with arcsine transformation was used to pool outcome proportions. From 1068 references screened, 100 were included, representing 30 early phase studies with 637 patients, investigating CD22 or CD19/CD22 CAR T-cells. CD22 CAR T-cells had a bCR of 68% [95% CI, 53-81%] in ALL (n= 116), and 64% [95% CI, 46-81%] in NHL (n= 28) with 74% and 96% of patients having received anti-CD19 CAR T-cells previously in ALL and NHL studies respectively. CD19/CD22 CAR T-cells had a bCR rate of 90% [95% CI, 84-95%] in ALL (n= 297) and 47% [95% CI, 34-61%] in NHL (n= 137). The estimated incidence of total and severe (grade ≥3) CRS were 87% [95% CI, 80-92%] and 6% [95% CI, 3-9%] respectively. ICANS and severe ICANS had an estimated incidence of 16% [95% CI, 9-25%] and 3% [95% CI, 1-5%] respectively. Early phase trials of CD22 and CD19/CD22 CAR T-cells show high remission rates in ALL and NHL. Severe CRS or ICANS were (1)rare and dual-targeting did not increase toxicity. Variability in CAR construct, dose, and patient factors amongst studies limits comparisons, with long-term outcomes yet to be reported.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier CRD42020193027.
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Lymphoma, Non-Hodgkin; B-Lymphocytes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sialic Acid Binding Ig-like Lectin 2
PubMed: 37180149
DOI: 10.3389/fimmu.2023.1178403 -
Frontiers in Immunology 2022Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy,...
Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have been used successfully against both hematological tumors and solid tumors. Although several problems have reduced engineered CAR-T cell therapeutic outcomes in clinical trials for the treatment of thoracic malignancies, including the lack of specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, off-target toxicity, and other safety issues, CAR-T cell treatment is still full of bright future. In this review, we outline the basic structure and characteristics of CAR-T cells among different period, summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for thoracic malignancies, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for preclinical experiments and clinical trials of CAR-T cell therapy for thoracic malignancies.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Thoracic Neoplasms; Tumor Microenvironment
PubMed: 35911706
DOI: 10.3389/fimmu.2022.871661 -
Annals of Translational Medicine May 2022As a successful treatment for hematological malignancy, chimeric antigen receptor T cells (CAR-T cells) have been expanded to solid tumors to demonstrate their safety...
BACKGROUND
As a successful treatment for hematological malignancy, chimeric antigen receptor T cells (CAR-T cells) have been expanded to solid tumors to demonstrate their safety and efficacy, especially for digestive system cancer (DSC). Various CAR-T cell constructs used in different types of DSCs result in heterogeneous responses. Thus, we aimed to systematically summarize the clinical response of DSCs treated with CAR-T cells and investigate factors associated with heterogeneity in outcomes.
METHODS
Clinical studies of DSC patients treated with CAR-T cell therapy were selected from the PubMed, Cochrane, Embase, Web of Science databases before October 1, 2020. "CAR-T cell", "solid tumor" and their synonymous terms were used to construct the search strategy. Duplicates, reviews, non-English literature, articles not related to clinical studies or CAR-T cells used for digestive tumors were excluded. The included studies were assessed by the Institute of Health Economics (IHE) risk of bias tool to check the methodological quality. The inverse variance method was used to perform data pooling and subgroup analysis to clarify the causes of heterogeneity. Publication bias was examined by funnel plots and Egger's test.
RESULTS
Twelve studies were included, and the risk of bias evaluation was demonstrated as plots using Review Manager 5.3. The pooled overall response rate (ORR) was 2% (95% CI: 0-6%), and the clinical benefit rate (CBR) was 42% (95% CI: 24-61%). According to subgroup analysis, costimulation (P=0.0449), lymphodepletion (P=0.0002), persistence of CAR-T cells (P=0.0443) and transduction method (P=0.0165) were factors contributing to heterogeneity. For adverse effects, pyrexia was the most frequent (35%, 95% CI: 24-61%). No publication bias was found, and the major results were robust within a slight fluctuation for each removal of one of the 12 studies.
DISCUSSION
CAR-T cell therapy is generally beneficial for patients with DSCs though the ORR was still poor. Modified construction with more specific tumor antigens, costimulatory domain and lentiviral vectors is necessary to obtain a better antitumor response of CAR-T cell therapy. Information of survival data are needed for a more comprehensive analysis.
PubMed: 35928759
DOI: 10.21037/atm-21-5019 -
American Journal of Hematology Sep 2021Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To... (Meta-Analysis)
Meta-Analysis
Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse-drug reactions (ADR) associated with CAR-T. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta-analysis of data from CAR-T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR-T (axicabtagene-ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility-interval of information component (IC , significance > 0). We also performed a systematic-review and meta-analysis of CAR-T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR-T: Cytokine release syndrome (CRS, n = 1378, IC = 4.24), neurological disorders (n = 963, IC = 2.42), hematological disorders (n = 532, IC = 3.32), infections (n = 287, IC = 2.38), cardiovascular disorders (n = 256, IC = 2.81), pulmonary disorders (n = 186, IC = 3.80), reno-metabolic disorders (n = 123, IC = 1.89), hemophagocytic-lymphohistiocytosis (n = 36, IC = 5.01) and hepatic disorders (n = 32, IC = 2.49). ADR-related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all-cause mortality. These ADR-related fatalities were associated with hemophagocytic-lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta-analyses, the most frequent any-grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR-T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic-lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.
Topics: Antigens, CD19; Bayes Theorem; Biological Products; Cytokine Release Syndrome; Drug-Related Side Effects and Adverse Reactions; Hematologic Diseases; Humans; Immunotherapy, Adoptive; Incidence; Nervous System Diseases; Pharmacovigilance; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 34057232
DOI: 10.1002/ajh.26259 -
Frontiers in Pharmacology 2022To investigate the effectiveness and safety of using chimeric antigen receptor (CAR) T cell therapies targeting CD19 in patients with diffuse large B-cell lymphoma...
Effectiveness and Safety of Anti-CD19 Chimeric Antigen Receptor-T Cell Immunotherapy in Patients With Relapsed/Refractory Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis.
To investigate the effectiveness and safety of using chimeric antigen receptor (CAR) T cell therapies targeting CD19 in patients with diffuse large B-cell lymphoma (DLBCL). PubMed, Embase, and the Cochrane Library were searched for reports published from database inception up to July 2021. The present meta-analysis included clinical response outcomes, survival outcomes, and safety analyses. For qualitative analysis that could not be combined, the data were presented in a tabular form. Subgroup analyses were also performed according to the costimulatory domains, generic names, and study designs. Twenty-seven studies (1,687 patients) were included. The pooled 12-months overall survival (OS) rate was 63% (95%CI: 56-70%). The pooled best overall response (BOR) was 74.0% (95%CI: 67-79%), with a best complete response (BCR) of 48% (95%CI: 42-54%) and a 3-months CR rate (CRR) of 41% (95%CI: 35-47%). The subgroup analyses by costimulatory domain suggested statistically significant differences in BOR and BCR, whereas not in the 12-months OS rate and 3-months CRR. Among the patients evaluable for safety, 78% (95%CI: 68-87%), 6% (95%CI: 3-10%), 41% (95%CI: 31-52%), and 16% (95%CI: 10-24%) experienced cytokine release syndrome (CRS), severe CRS, neurotoxicity, and severe neurotoxicity, respectively. Compared with the CD28 costimulatory domain, the 4-1BB-based products showed a better safety profile on any-grade CRS ( < 0.01), severe CRS ( = 0.04), any-grade neurotoxicity ( < 0.01), and severe neurotoxicity ( < 0.01). Anti-CD19 CAR-T cell immunotherapy has promising effectiveness and tolerable severe AE profile in DLBCL patients. 4-1BB-based CAR-T cells have a similar 12-months OS rate and 3-months CRR with CD28-based products but a better safety profile. The costimulatory domain might not affect the survival outcomes.
PubMed: 35548364
DOI: 10.3389/fphar.2022.834113 -
Translational Cancer Research Mar 2022Multiple myeloma (MM) is a malignant tumor originating from plasma cells in the bone marrow. The existing treatment methods can prolong the survival time of patients,...
Efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy in the treatment of relapsed and refractory multiple myeloma: a systematic-review and meta-analysis of clinical trials.
BACKGROUND
Multiple myeloma (MM) is a malignant tumor originating from plasma cells in the bone marrow. The existing treatment methods can prolong the survival time of patients, but they still face the problems of myeloma relapse and refractory disease. Chimeric antigen receptor (CAR)-T cell therapy is a new cellular immunotherapy that can target and recognize antigens and kill tumor cells but the efficacy and safety data varied in different studies. We performed this systematic review and meta-analysis to understand its efficacy and safety.
METHODS
Literature published from January 2015 to November 2021 was obtained by searching the keywords "CAR-T", "CAR-T Cell", and "Multiple Myeloma" by computer using the Embase, PubMed, Web of Science, and Cochrane library databases according to the PICOS (Participants, Interventions, Comparisons, Outcomes, Study type) criteria. The quality of the literature was assessed by the Joanna Briggs Institute (JBI) Critical Appraisal Tool for prevalence studies. The complete response rate, the incidence of cytokine release syndrome (CRS) above grade 3, and the overall incidence of adverse reactions were used as the outcome indicators. The pooled rates were performed and analyzed using the R language toolkit.
RESULTS
A total of 10 studies including 353 study cases were included. Meta-analysis showed that the pooled complete response rate of CAR-T therapy in the treatment of MM was 0.55, 95% confidence interval (CI): (0.50, 0.60), the pooled incidence of CRS was 0.55, 95% CI: (0.50, 0.60), and the pooled incidence of serious adverse reactions was 0.92, 95% CI: (0.88, 0.95). Subgroup analysis was performed based on antigen types or costimulatory molecules, and there was no significant difference in the efficacy of CAR-T and the incidence of CRS between the two subgroups (P>0.05).
CONCLUSIONS
As a new immunotherapy strategy with great potential, CAR-T has a significant effect in the treatment of MM, but its safety needs to be further improved. The types of costimulatory molecules and CAR-T antigens can affect its efficacy and safety.
PubMed: 35402175
DOI: 10.21037/tcr-22-344