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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 -
World Journal of Surgical Oncology Nov 2023The effectiveness and safety of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors is controversial. This systematic review and meta-analysis aimed to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The effectiveness and safety of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors is controversial. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors as neoadjuvant therapy for malignant solid tumors.
METHODS
This study has been registered with the number CRD42023407275 on PROSPERO. Systematic searches were conducted in PubMed, Embase, Web of Science and Cochrane Library databases until March 17, 2023. In addition, manual searches were performed. The inclusion criteria encompassed randomized controlled trials (RCTs) that assessed the utilization of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors PD-1/PD-L1 inhibitors for patients with solid malignancies. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials (ROB1) were used. Risk ratios (RRs), hazared ratios (HRs) and their respective 95% confidence intervals were calculated using Stata17.0 MP and Review Manager 5.4 software.
RESULTS
A total of 2780 records were identified, and ultimately 10 studies involving 273 patients were included. The meta-analysis showed that the addition of CTLA-4 inhibitors to PD-1/PD-L1 inhibitors did not demonstrate a significant effect on overall response rate, main pathological response, pathological complete response, surgical resection, radical resection, overall survival, progression-free survival, recurrence-free survival, grade 3-4 adverse events, all-cause mortality, and completed treatment (P > 0.05). However, further subgroup analysis indicated that the combination of PD-1 with CTLA-4 inhibitors significantly increased the occurrence of grade 3-4 adverse events in patients (P < 0.05).
CONCLUSIONS
As neoadjuvant therapy for malignant solid tumors, the addition of CTLA-4 inhibitors to PD-1/PD-L1 inhibitors does not appear to enhance efficacy.Moreover, there is a potential increase in the risk of grade 3-4 adverse events associated with this combination. However, it is important to note that the studies included in this analysis suffer from limitations such as small samples and single-center designs, which are inherent constrains with the available published literature. Further research involving large-sample and multicenter RCTs are warranted to obtain more reliable results.
Topics: Humans; Immune Checkpoint Inhibitors; Neoadjuvant Therapy; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Neoplasms; Multicenter Studies as Topic
PubMed: 37926852
DOI: 10.1186/s12957-023-03212-5 -
Frontiers in Immunology 2022Chimeric antigen receptor (CAR)-based therapies are presented as innovative treatments for multiple malignancies. Despite their clinical success, there is scientific...
Chimeric antigen receptor (CAR)-based therapies are presented as innovative treatments for multiple malignancies. Despite their clinical success, there is scientific evidence of the limitations of these therapies mainly due to immunogenicity issues, toxicities associated with the infusion of the product, and relapses of the tumor. As a result, novel approaches are appearing aiming to solve and/or mitigate the harmful effects of CAR-T therapies. These include strategies based on the use of ligands as binding moieties or ligand-based CAR-T cells. Several proposals are currently under development, with some undergoing clinical trials to assess their potential benefits. In addition to these, therapies such as chimeric autoantibody receptor (CAAR), B-cell receptor antigen for reverse targeting (BAR), and even chimeric human leukocyte antigen (HLA) antibody receptor (CHAR) have emerged, benefiting from the advantages of antigenic ligands as antibody-binding motifs. This review focuses on the potential role that ligands can play in current and future antitumor treatments and in other types of diseases, such as autoimmune diseases or problems associated with transplantation.
Topics: Humans; Ligands; Neoplasms; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 36172370
DOI: 10.3389/fimmu.2022.932559 -
International Journal of Molecular... Nov 2023Behçet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's... (Review)
Review
Behçet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that is the primary genetic risk factor, but non-HLA genes (, , ), as well as innate immunity genes (, , ), also contribute. Genome-wide studies emphasize the significance of and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, γδ T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.
Topics: Humans; Behcet Syndrome; Antigen Presentation; Genetic Predisposition to Disease; HLA-B Antigens; Risk Factors; Aminopeptidases; Minor Histocompatibility Antigens
PubMed: 38003572
DOI: 10.3390/ijms242216382 -
Value in Health : the Journal of the... Jan 2022The objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies,...
OBJECTIVES
The objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel and axicabtagene ciloleucel, evaluated by health technology assessment (HTA) agencies, focusing on young compared with older patients.
METHODS
HTA evaluations in pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL) were included from Australia, Canada, England, Norway, and the United States. Key clinical evidence, economic approach, and outcomes (costs, quality-adjusted life-years [QALYs] and incremental cost-effectiveness ratios) were summarized.
RESULTS
Fourteen HTA evaluations were identified (5 ALL, 9 DLBCL [4 tisagenlecleucel, 5 axicabtagene]). Analyses were naive comparisons of prospective single-arm studies for the CAR-Ts with retrospective cohort studies for the comparators. Key clinical evidence and economic model approaches were generally consistent by CAR-T and indication, although outcomes varied. Notably, incremental QALYs varied substantially in ALL (3.67-10.6 QALYs gained), whereas variation in DLBCL was less (1.21-1.97 [tisagenlecleucel], 1.97-3.40 [axicabtagene]). Discounting of costs and outcomes varied, with the highest QALYs generated for tisagenlecleucel in ALL (10.95) associated with the lowest discount rate (1.5%) and vice versa (4.97 QALYs; 5% discount rate). The approach to extrapolation of overall survival data varied, even where the same empirical data were used.
CONCLUSION
Modeled, long-term treatment benefit in young patients may be associated with greater uncertainty compared with adults because of potential life-long benefits with cell and gene therapies. This reflects the methodological challenges identified by HTA agencies associated with single-arm, short-term studies.
Topics: Adult; Age Factors; Child; Cost-Benefit Analysis; Humans; Lymphoma, Large B-Cell, Diffuse; Models, Economic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quality-Adjusted Life Years; Receptors, Chimeric Antigen; Technology Assessment, Biomedical
PubMed: 35031099
DOI: 10.1016/j.jval.2021.07.008 -
Systematic Review of PD-1/PD-L1 Inhibitors in Oncology: From Personalized Medicine to Public Health.The Oncologist Oct 2021To review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)-1 and PD-ligand 1 blocking antibodies (collectively referred to as... (Review)
Review
BACKGROUND
To review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)-1 and PD-ligand 1 blocking antibodies (collectively referred to as PD-[L]1 inhibitors) over a 6-year period and corresponding companion/complementary diagnostic assays.
MATERIALS AND METHODS
To determine the indications and pivotal trials eligible for inclusion, approval letters and package inserts available on Drugs@FDA were evaluated for approved PD-[L]1 inhibitors to identify all new indications granted from the first approval of a PD-[L]1 inhibitor on September 4, 2014, through September 3, 2020. The corresponding FDA drug and device reviews from the marketing applications for the approved indications were identified through FDA internal records. Two reviewers independently extracted information for the endpoints, efficacy data, basis for approval, type of regulatory approval, and corresponding in vitro diagnostic device test. The results were organized by organ system and tumor type.
RESULTS
Of 70 Biologic Licensing Application or supplement approvals that resulted in new indications, 32 (46%) were granted based on response rate (ORR) and durability of response, 26 (37%) on overall survival, 9 (13%) on progression-free survival, 2 (3%) on recurrence-free survival, and 1 (1%) on complete response rate. Most ORR-based approvals were granted under the accelerated approval provisions and were supported with prolonged duration of response. Overall, 21% of approvals were granted with a companion diagnostic. Efficacy results according to tumor type are discussed.
CONCLUSION
PD-[L]1 inhibitors are an effective anticancer therapy in a subset of patients. This class of drugs has provided new treatment options for patients with unmet need across a wide variety of cancer types. Yet, the modest response rates in several tumor types signal a lack of understanding of the biology of these diseases. Further preclinical and clinical investigation may be required to identify a more appropriate patient population, particularly as drug development continues and additional treatment alternatives become available.
IMPLICATIONS FOR PRACTICE
The number of PD-[L]1 inhibitors in drug development and the associated companion and complementary diagnostics have led to regulatory challenges and questions regarding generalizability of trial results. The interchangeability of PD-L1 immunohistochemical assays between PD-1/PD-L1 drugs is unclear. Furthermore, robust responses in some patients with low levels of PD-L1 expression have limited the use of PD-L1 as a predictive biomarker across all cancers, particularly in the setting of diseases with few alternative treatment options. This review summarizes the biomarker thresholds and assays approved as complementary and companion diagnostics and provides regulatory perspective on the role of biomarkers in oncology drug development.
Topics: B7-H1 Antigen; Humans; Immune Checkpoint Inhibitors; Neoplasms; Precision Medicine; Programmed Cell Death 1 Receptor; Public Health
PubMed: 34196068
DOI: 10.1002/onco.13887 -
Vaccines Apr 2022As the coronavirus disease 2019 (COVID-19) pandemic is ongoing, and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging,... (Review)
Review
As the coronavirus disease 2019 (COVID-19) pandemic is ongoing, and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, vaccines are needed to protect individuals at high risk of complications and to potentially control disease outbreaks by herd immunity. After SARS-CoV-2 vaccination, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presenting with a pulmonary hemorrhage has been described. Previous studies suggested that monocytes upregulate major histocompatibility complex (MHC) II cell surface receptor human leukocyte antigen receptor (HLA-DR) molecules in granulomatosis with polyangiitis (GPA) patients with proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA seropositivity. Here, we present a case of new-onset AAV after booster vaccination with the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine. Moreover, we provide evidence that the majority of monocytes express HLA-DR in AAV after SARS-CoV-2 booster vaccination. It is possible that the enhanced immune response after booster vaccination and presence of HLA-DR monocytes could be responsible for triggering the production of the observed MPO- and PR3-ANCA autoantibodies. Additionally, we conducted a systematic review of de novo AAV after SARS-CoV-2 vaccination describing their clinical manifestations in temporal association with SARS-CoV-2 vaccination, ANCA subtype, and treatment regimens. In light of a hundred million individuals being booster vaccinated for SARS-CoV-2 worldwide, a potential causal association with AAV may result in a considerable subset of cases with potential severe complications.
PubMed: 35632410
DOI: 10.3390/vaccines10050653 -
PloS One 2024Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results.... (Meta-Analysis)
Meta-Analysis
Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.
Topics: Meningioma; Humans; Biomarkers, Tumor; Prognosis; Meningeal Neoplasms; DNA Topoisomerases, Type II; Ki-67 Antigen; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Immunohistochemistry; Poly-ADP-Ribose Binding Proteins
PubMed: 38758750
DOI: 10.1371/journal.pone.0303337 -
PLoS Neglected Tropical Diseases Sep 2022T cells recognize their ligand, the peptide major histocompatibility complex (MHC), via the T-cell receptor (TCR), which is composed of covalently linked α and β or γ... (Review)
Review
T cells recognize their ligand, the peptide major histocompatibility complex (MHC), via the T-cell receptor (TCR), which is composed of covalently linked α and β or γ and δ chains. This recognition is critical for T-cell ontogeny and controls the selection, activation, and function of T lymphocytes. Specific TCR αβ variable regions have been associated with immunopathogenesis of Chagas disease. Here, we present a systematic review that compiles experimental in vivo and human data regarding the preferential expression of variable alpha (Vα) and variable beta (Vβ) chain regions in Trypanosoma cruzi infection. The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. The analysis showed that expression of TCR Vα subfamilies were evaluated in one human study, and, unlike TCR Vβ, TCR Vα presented a more restricted usage. Despite the great variability in the usage of TCR Vβ regions in human Chagas disease, a down-regulation of TCR Vβ5 expression by T cells from patients in the acute phase of the disease was shown. Opposingly, this TCR region was found overly expressed in CD4+ T cells from chronic Chagas patients. It was also demonstrated that murine Vβ9+ T cells derived from nonlymphoid organs of T. cruzi-infected animals had a modulatory profile, while splenic Vβ9+ T cells produced inflammatory cytokines, indicating that although they display the same TCR Vβ region usage, these cells are functionally distinct. Despite the limitations of few papers and year of publication of the studies, compiling the data derived from them reveals that further investigation of TCR usage will point to their potential role in protective or pathogenic responses, as biomarkers of disease progression, and in the search for dominant peptides potentially useful for the development of vaccines or therapies.
Topics: Animals; Chagas Disease; Cytokines; Humans; Ligands; Mice; Peptides; Receptors, Antigen, T-Cell
PubMed: 36107855
DOI: 10.1371/journal.pntd.0010546 -
Annals of Medicine Dec 2023We performed an umbrella meta-analysis to explore the factors that influence the efficacy of immune checkpoint inhibitor (ICI) therapy. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We performed an umbrella meta-analysis to explore the factors that influence the efficacy of immune checkpoint inhibitor (ICI) therapy.
MATERIALS AND METHODS
We systematically searched three databases (PubMed, Web of Science and Embase) up to 20 February 2023. Extracting the effect size and 95% confidence intervals for overall survival (OS), progression-free survival (PFS) and the objective response rate (ORR).
RESULTS
A total of 65 articles were included. We identified the following factors that benefit ICI therapy: smoking status (PFS: 0.72 [0.62, 0.84], < .001), chemotherapy (PFS: 0.68 [0.58, 0.79], < .001), expression of programmed cell death ligand 1(PD-L1) (≥1%, ≥5%, or ≥10%) (≥1%: 0.76 [0.71,0.82], < .001; ≥5%: 0.62 [0.52, 0.74], < .001; ≥10%: 0.42 [0.30, 0.59], < .001). We also identified three adverse factors: epidermal growth factor receptor mutations (OS: 1.57 [1.06, 2.32], = .02), with liver metastases (OS: 1.16 [1.02,1.32], = .02) and antibiotics (OS: 3.13 [1.25,7.84], < .001; PFS: 2.54 [1.38, 4.68], = .003).
CONCLUSION
The results of this umbrella meta-analysis first supported pre-existing understandings of the relationship between beneficial and adverse factors with the efficacy of ICI therapy. In addition, the overexpression of PD-L1 may adversely affect patients.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; B7-H1 Antigen; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological; Randomized Controlled Trials as Topic
PubMed: 37212453
DOI: 10.1080/07853890.2023.2215543