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Frontiers in Immunology 2023Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive... (Meta-Analysis)
Meta-Analysis
The benefit and risk of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small-cell lung cancer: a systematic review and single-arm meta-analysis of prospective clinical trials.
BACKGROUND
Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive anti-tumor activities. However, almost all studies on the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer are non-randomized controlled trials with small sample sizes, which might lead to a lack of effective metrics to assess the effectiveness and safety of the therapeutic regimen. Here, this meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer.
METHODS
A single-arm meta-analysis was performed, and published literature from PubMed, Web of Science and Embase databases as of January 13, 2023, was systematically retrieved. We used the Cochrane risk of bias tool and methodological index for non-randomized studies (MINORS) Methodological items to evaluate the quality of eligible clinical trials. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. The random effect model is used to calculate the pooled parameters.
RESULTS
19 studies (16 were non-comparative single-arm clinical trials and 3 were randomized controlled trials) were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.4% (95% CI, 16.6-28.1%) and 76.8% (95% CI, 72.6-81.1%), respectively. With regard to survival analysis, the pooled PFS and OS were 5.20 (95% CI, 4.46-5.93) months and 14.09 (95% CI, 13.20-14.97) months, respectively. The pooled grade ≥3 adverse effect (AE) rate was 47.6% (95% CI, 33.1-62.0%).
CONCLUSION
PD-1/PD-L1 inhibitors plus anti-angiogenic agents has promising efficacy and safety as second or later-line treatment in patients with advanced non-small cell lung cancer.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42023407559.
Topics: Humans; Angiogenesis Inhibitors; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Programmed Cell Death 1 Receptor; Prospective Studies; Clinical Trials as Topic
PubMed: 37614237
DOI: 10.3389/fimmu.2023.1218258 -
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 -
Leukemia & Lymphoma 2023Relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is a challenging disease with low rates of remission and survival in adult patients. Anti-CD19... (Meta-Analysis)
Meta-Analysis
Differences in efficacy and safety among CAR-Ts anti-CD19/CD22, anti-CD19, and anti-CD22, in adult patients with relapse/refractory B-cell acute lymphoblastic leukemia: a meta-analysis and systematic review.
Relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is a challenging disease with low rates of remission and survival in adult patients. Anti-CD19 Chimeric Antigen Receptor T-cells (CAR-Ts) therapies have been approved for these patients. Dual-target CAR-Ts against CD19 and CD22 have recently been developed to improve the efficacy of the single-target therapy; however, extent of the improvement using this dual-target therapy has yet to be determined. We performed a meta-analysis of the outcome and safety of CAR-Ts, comparing anti-CD19 vs anti-CD22 vs dual-target anti-CD19/CD22 CAR-Ts, to elucidate the differences and limitations of these therapies in adult patients with R/R B-ALL. our results suggest that anti-CD19/CD22 CAR-Ts generate lower incidence of relapse and neurotoxicity, but similar results were obtained regarding complete remission, minimal residual disease, overall survival, and cytokine release syndrome compared with single-target anti-CD19 and anti-CD22 CAR-Ts.
Topics: Humans; Adult; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Lymphoma, B-Cell; Antigens, CD19; Acute Disease; Sialic Acid Binding Ig-like Lectin 2
PubMed: 37548560
DOI: 10.1080/10428194.2023.2243357 -
International Journal of Molecular... Sep 2023The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and... (Review)
Review
The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and CAR-T cell therapies in relapsed/refractory (R/R) haematological malignancies. A systematic literature review was performed until 21 November 2022. Inclusion criteria: cohort studies/clinical trials aimed at evaluating the efficacy and/or safety of the combination of CAR-T cell therapy with PD-1/PD-L1 inhibitors in R/R haematological malignancies, which had reported results. Those focusing only on ICI or CAR-T separately or evaluating the combination in other non-hematological solid tumours were excluded. We used a specific checklist for quality assessment of the studies, and then we extracted data on efficacy or efficiency and safety. A total of 1867 articles were identified, and 9 articles were finally included (early phase studies, with small samples of patients and acceptable quality). The main pathologies were B-cell acute lymphoblastic leukaemia (B-ALL) and B-cell non-Hodgkin's lymphoma (B-NHL). The most studied combination was tisagenlecleucel with pembrolizumab. In terms of efficacy, there is great variability: the combination could be a promising option in B-ALL, with modest data, and in B-NHL, although hopeful responses were received, the combination does not appear better than CAR-T cell monotherapy. The safety profile could be considered comparable to that described for CAR-T cell monotherapy.
Topics: Humans; Immune Checkpoint Inhibitors; Receptors, Chimeric Antigen; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Hematologic Neoplasms; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37834228
DOI: 10.3390/ijms241914780 -
Annals of Medicine Dec 2024Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an... (Meta-Analysis)
Meta-Analysis
Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis.
BACKGROUND
Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL.
METHODS
The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
RESULTS
Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles.
CONCLUSION
Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.
Topics: Humans; Immunotherapy, Adoptive; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Antigens, CD19; Sialic Acid Binding Ig-like Lectin 2; Receptors, Chimeric Antigen; Child; Treatment Outcome; Neoplasm, Residual; Cytokine Release Syndrome; Recurrence; Neurotoxicity Syndromes
PubMed: 38738799
DOI: 10.1080/07853890.2024.2349796 -
Journal of Gastrointestinal Cancer Mar 2024T cell exhaustion and activation markers are helpful in determining the therapies and predicting the overall survival in pancreatic cancer (PC) patients. (Review)
Review
BACKGROUND
T cell exhaustion and activation markers are helpful in determining the therapies and predicting the overall survival in pancreatic cancer (PC) patients.
PURPOSE
In this systematic review, we have addressed two questions, how do these markers differ in their expression levels in PC patients and healthy individual and correlating the expression level of these markers with the cancer stage.
METHODS
The systematic review was registered with Prospective Register of Systematic Reviews (PROSPERO) with registration number "CRD42022246780." All the included articles were obtained from three databases, PubMed, MEDLINE, and Cochrane, published from January 2010 to 26th May 2022. Two independent reviewers followed the PRISM protocol and reviewed and extracted data from the included articles.
RESULTS
PD-1 and CTLA-4 were the most studied markers in this field. A clear elevation in the expression of PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT was found in most of the studies. CD69, CD25, and HLA-DR expression was found to be upregulated after chemotherapy and immunotherapy. CD25 was the only marker analyzed against cancer progression, in a single study. No study compared the expression of exhaustion and activation markers (except CD69) with the cancer progression of the tumor stage.
CONCLUSION
Since the exhaustion markers are upregulated in patients, single or multiple markers can be targeted in immunotherapies. Knowledge of the dynamics of these markers at various cancer stages will help in determining the right immunotherapy for pancreatic cancer patients. Stage-wise comparison could also be made possible by developing in vitro models.
Topics: Humans; Pancreatic Neoplasms; Biomarkers, Tumor; T-Lymphocytes; CTLA-4 Antigen; Lymphocyte Activation; T-Cell Exhaustion
PubMed: 37672169
DOI: 10.1007/s12029-023-00965-w -
Frontiers in Immunology 2023Accurate prediction of efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors is of critical importance. To address this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Accurate prediction of efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors is of critical importance. To address this issue, a network meta-analysis (NMA) comparing existing common measurements for curative effect of PD-1/PD-L1 monotherapy was conducted.
METHODS
We searched PubMed, Embase, the Cochrane Library database, and relevant clinical trials to find out studies published before Feb 22, 2023 that use PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), microsatellite instability (MSI), multiplex IHC/immunofluorescence (mIHC/IF), other immunohistochemistry and hematoxylin-eosin staining (other IHC&HE) and combined assays to determine objective response rates to anti-PD-1/PD-L1 monotherapy. Study-level data were extracted from the published studies. The primary goal of this study was to evaluate the predictive efficacy and rank these assays mainly by NMA, and the second objective was to compare them in subgroup analyses. Heterogeneity, quality assessment, and result validation were also conducted by meta-analysis.
FINDINGS
144 diagnostic index tests in 49 studies covering 5322 patients were eligible for inclusion. mIHC/IF exhibited highest sensitivity (0.76, 95% CI: 0.57-0.89), the second diagnostic odds ratio (DOR) (5.09, 95% CI: 1.35-13.90), and the second superiority index (2.86). MSI had highest specificity (0.90, 95% CI: 0.85-0.94), and DOR (6.79, 95% CI: 3.48-11.91), especially in gastrointestinal tumors. Subgroup analyses by tumor types found that mIHC/IF, and other IHC&HE demonstrated high predictive efficacy for non-small cell lung cancer (NSCLC), while PD-L1 IHC and MSI were highly efficacious in predicting the effectiveness in gastrointestinal tumors. When PD-L1 IHC was combined with TMB, the sensitivity (0.89, 95% CI: 0.82-0.94) was noticeably improved revealed by meta-analysis in all studies.
INTERPRETATION
Considering statistical results of NMA and clinical applicability, mIHC/IF appeared to have superior performance in predicting response to anti PD-1/PD-L1 therapy. Combined assays could further improve the predictive efficacy. Prospective clinical trials involving a wider range of tumor types are needed to establish a definitive gold standard in future.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Network Meta-Analysis; Prospective Studies; Biomarkers, Tumor; Gastrointestinal Neoplasms
PubMed: 37822932
DOI: 10.3389/fimmu.2023.1265202 -
Expert Review of Hematology 2024This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab.
METHODS
PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies.
RESULTS
The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy.
CONCLUSIONS
The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.
Topics: Humans; Immunotherapy, Adoptive; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Bispecific; Recurrence; Antigens, CD19
PubMed: 38135295
DOI: 10.1080/17474086.2023.2298732 -
Survey of Ophthalmology 2024Primary vitreoretinal lymphoma is a potentially aggressive intraocular malignancy with poor systemic prognosis and sometimes significant diagnostic delays as it may... (Review)
Review
Primary vitreoretinal lymphoma is a potentially aggressive intraocular malignancy with poor systemic prognosis and sometimes significant diagnostic delays as it may masquerade as chronic uveitis. Despite the variety of diagnostic techniques, it is unclear which modality is most accurate in the diagnosis of PVRL. A systematic literature search was conducted on Ovid MEDLINE, EMBASE and the Cochrane Controlled Register of Trials for studies published between January, 2000, and June, 2023. Randomized controlled trials (RCTs) reporting on the following diagnostic tools used to diagnose patients with PVRL were included: cytology, flow cytometry, MYD88 L265P mutation, CD79B mutation, interleukin 10/interleukin-6 (IL-10/IL-6) ratio, polymerase chain reaction (PCR) for monoclonal immunoglobulin heavy chain (IgH) and immunoglobulin kappa light chain (IgK) rearrangements, and imaging findings. The aggregated sensitivity of each diagnostic modality was reported and compared using the chi-squared (χ2) test. A total of 662 eyes from 29 retrospective studies reporting on patients diagnosed with PVRL were included. An IL-10/IL-6 ratio greater than 1 had the highest sensitivity (89.39%, n = 278/311 eyes, n = 16 studies) for PVRL, where the sensitivity was not significantly different when only vitreous samples were drawn (88.89%, n = 232/261 eyes, n = 13 studies) compared to aqueous samples (83.33%, n = 20/24, n = 2) (p = 0.42). Flow cytometry of vitreous samples gave a positive result in 66/75 eyes (88.00%, n = 6 studies) with PVRL, and monoclonal IgH rearrangements on PCR gave a positive result in 354/416 eyes (85.10%, n = 20 studies) with PVRL. MYD88 L265P and CD79B mutation analysis performed poorly, yielding a positive result in 63/90 eyes (70.00%, n = 8 studies) with PVRL, and 20/57 eyes (35.09%, n = 4 studies) with PVRL, respectively. Overall, our systematic review found that an IL-10/IL-6 ratio greater or equal to one may provide the highest sensitivity in identifying patients with PVRL. Future studies are needed to employ multiple diagnostic tools to aid in the detection of PVRL and to further establish nuanced guidelines when determining the optimal diagnostic tool to use in diverse patient populations.
Topics: Humans; Retinal Neoplasms; Vitreous Body; Interleukin-10; Intraocular Lymphoma; Flow Cytometry; Interleukin-6; Myeloid Differentiation Factor 88; Diagnostic Techniques, Ophthalmological; Biomarkers, Tumor; CD79 Antigens; Polymerase Chain Reaction
PubMed: 38163550
DOI: 10.1016/j.survophthal.2023.12.001 -
Transplantation and Cellular Therapy Jan 2024The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data... (Meta-Analysis)
Meta-Analysis
The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I = 0%) and 5% (95% CI, 0% to 21%; I = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I = 68%) and 40% (95% CI, 3% to 85%; I = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.
Topics: Adult; Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Lymphoma; Organ Transplantation; Adaptor Proteins, Signal Transducing; Antigens, CD19; Cytokine Release Syndrome; Immunosuppressive Agents; Cell- and Tissue-Based Therapy
PubMed: 37279856
DOI: 10.1016/j.jtct.2023.05.018