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Cytotherapy Oct 2019Although promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical effect and safety are associated with some controversy, and lack sufficient evidence. Here, we conducted a meta-analysis of 21 clinical trials to better evaluate the efficacy of DC-CIK immunotherapy in clinical practice to treat PC.
METHODS
PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform (WANFANG Data) were searched to identify clinical trials that used DC-CIK immunotherapy for PC. Meta-analysis was performed using RevMan 5.3 and Stata 12.0.
RESULTS
A total of 21 clinical trials involving 1549 patients were included. Compared with traditional treatment, DC-CIK immunotherapy improved and increased the clinical indices such as complete remission, partial remission, overall response rate, disease control rate, overall survival (0.5-y OS, 1-y OS, 1.5-y OS, 2-y OS and 3-y OS), interferon γ and CD3+, CD4+, CD4+/CD8+ and CD3+CD56+ lymphocyte. Additionally, DC-CIK immunotherapy reduced stable disease, progression disease, mortality, CD8+, CD4+CD25+CD127 low lymphocyte and interleukin-4. Furthermore, it showed a low incidence of adverse reactions (22%).
CONCLUSION
In contrast to traditional therapy, DC-CIK immunotherapy not only shows improved short-term effect, long-term effect and immunologic function, but also reduces mortality and negative immunoregulatory index, and shows mild adverse reactions. This is the first study to evaluate the clinical effect and safety of DC-CIK immunotherapy for PC, and it indicated that DC-CIK immunotherapy may be suitable for patients with advanced PC or intolerance to radiotherapy and chemotherapy.
Topics: Adult; Clinical Trials as Topic; Cytokine-Induced Killer Cells; Dendritic Cells; Humans; Immunotherapy, Adoptive; Pancreatic Neoplasms; Treatment Outcome
PubMed: 31462394
DOI: 10.1016/j.jcyt.2019.07.006 -
Bone Marrow Transplantation Apr 2023Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD... (Review)
Review
Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD portends a high risk of death and effective management is not well established. CD19-targeted CAR-T cell therapy has been utilized, but the risks and benefits are unknown. We report the first case of diffuse large B-cell lymphoma (DLBCL) PTLD treated with lisocabtagene maraleucel and present a systematic literature review of SOTRs with PTLD treated with CD19 CAR-T therapy. Our patient achieved a complete response (CR) with limited toxicity but experienced a CD19 relapse 8 months after infusion despite CAR-T persistence. Literature review revealed 14 DLBCL and 2 Burkitt lymphoma PTLD cases treated with CD19 CAR-T cells. Kidney (n = 12), liver (n = 2), heart (n = 2), and pancreas after kidney (n = 1) transplant recipients were analyzed. The objective response rate (ORR) was 82.4% (14/17), with 58.5% (10/17) CRs and a 6.5-month median duration of response. Among kidney transplant recipients, the ORR was 91.7% (11/12). Allograft rejection occurred in 23.5% (4/17). No graft failure occurred. Our analysis suggests that CD19 CAR-T therapy offers short-term effectiveness and manageable toxicity in SOTRs with R/R PTLD. Further investigation through larger datasets and prospective study is needed.
Topics: Humans; Antigens, CD19; Epstein-Barr Virus Infections; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Lymphoproliferative Disorders; Neoplasm Recurrence, Local; Organ Transplantation; Receptors, Chimeric Antigen; Transplant Recipients
PubMed: 36575360
DOI: 10.1038/s41409-022-01907-z -
Transplantation and Cellular Therapy Jun 2024Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory... (Meta-Analysis)
Meta-Analysis Comparative Study
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor T cell (CAR-T) therapies approved for relapsed/refractory aggressive large B cell lymphoma (LBCL). Significant costs and complex manufacturing underscore the importance of evidence-based counseling regarding the outcomes of these treatments. With the aim of examining the efficacy and safety of axi-cel versus tisa-cel in patients with relapsed/refractory aggressive LBCL, we performed a systematic literature search of comparative studies evaluating outcomes in relapsed/refractory aggressive LBCL after treatment with axi-cel or tisa-cel. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for response, progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity. Meta-analysis and meta-regression were used to generate summary statistics. A total of 2372 participants were included in the 8 studies in our analysis. The dropout rate between apheresis and infusion was 13% for axi-cel versus 18% for tisa-cel, and the median time from apheresis to infusion was 32 days versus 45 days. Axi-cel showed higher odds for a complete response (OR, 1.65; P < .001) and was associated with higher odds for PFS at 1 year after infusion (OR, .60; P < .001). OS appeared to be improved with axi-cel (OR, .84; 95% CI, .68 to 1.02; P = .08), whereas the cumulative incidence of nonrelapse mortality (NRM) was 11.5% for axi-cel versus 3.7% for tisa-cel (P = .002). The main predictors for survival were lactate dehydrogenase level, Eastern Cooperative Oncology Group Performance Status, and response to bridging, and axi-cel maintained superior efficacy even in elderly patients. In terms of safety, axi-cel was associated with significantly higher odds of any-grade CRS (OR, 3.23; P < .001), but not of grade ≥3 CRS (P = .92). Axi-cel was associated with significantly higher odds of severe ICANS grade ≥3 (OR, 4.03; P < .001). In terms of hematotoxicity, axi-cel was significantly associated with higher odds of severe neutropenia at 1 month after infusion (OR, 2.06; P = .003). As a result, axi-cel was associated with significantly greater resource utilization, including prolonged hospital stay, more frequent intensive care admission, and use of agents such as tocilizumab for toxicity management. We provide strong evidence of the greater efficacy of axi-cel versus tisa-cel in relapsed/refractory aggressive LBCL. The higher toxicity and NRM seen with axi-cel might not counterbalance the overall results, highlighting the need for timely intervention and careful selection of patients, balancing resource utilization and clinical benefit.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Biological Products; Immunotherapy, Adoptive; Antigens, CD19; Receptors, Antigen, T-Cell; Cytokine Release Syndrome; Treatment Outcome
PubMed: 38281590
DOI: 10.1016/j.jtct.2024.01.074 -
Advanced Drug Delivery Reviews 2020In cancer, lymph nodes (LNs) coordinate tumor antigen presentation necessary for effective antitumor immunity, both at the levels of local cellular interactions and...
In cancer, lymph nodes (LNs) coordinate tumor antigen presentation necessary for effective antitumor immunity, both at the levels of local cellular interactions and tissue-level organization. In this review, we examine how LNs may be engineered to improve the therapeutic outcomes of cancer immunotherapy. At the cellular scale, targeting the LNs impacts the potency of cancer vaccines, immune checkpoint blockade, and adoptive cell transfer. On a tissue level, macro-scale biomaterials mimicking LN features can function as immune niches for cell reprogramming or delivery in vivo, or be utilized in vitro to enable preclinical testing of drugs and vaccines. We additionally review strategies to induce ectopic lymphoid sites reminiscent of LNs that may improve antitumor T cell priming.
Topics: Adoptive Transfer; Animals; Antineoplastic Agents, Immunological; Biocompatible Materials; Cancer Vaccines; Drug Administration Routes; Humans; Hydrogels; Immune Checkpoint Inhibitors; Immunotherapy; Immunotherapy, Adoptive; Lab-On-A-Chip Devices; Lymph Nodes; Nanoparticles; Neoplasms; Tissue Engineering; Tissue Scaffolds
PubMed: 32750376
DOI: 10.1016/j.addr.2020.07.023 -
Current Molecular Medicine 2022Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate...
Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate the malignant transformation and progression of the lesion. Many agents have been attempted, but their cost inefficacy and inadequate outcomes posed a major hindrance in their successful adoption. Retinoid Based Therapy (RBT) though a cheap and effective treatment option, could not achieve much clinical usage because of variable responsiveness in clinical outcomes. Such clinical response variability may be attributed to the repression of retinoid receptors by Preferentially Expressed Antigen of Melanoma (PRAME) protein molecule. Therefore, in order to make RBT successful, targeting PRAME by various immunotherapies is an exciting area of research investigation. This review provides an insight into the various immunotherapeutic strategies targeting PRAME and their usefulness in retinoid-resistant OPMD and OC. Method of data collection: An exhaustive internet-based literature search following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was carried out in PUBMED and Google SCHOLAR database using terms 'Anti-PRAME' OR 'PRAME Immunotherapy' OR 'PRAME Vaccines' AND 'Cancer' AND 'Retinoid resistance'. Only articles in the English language with at least 1 citation, published in a journal with impact factor ≥ 1, having relevance to the context and availability of full text were considered. Results: After an initial search, 342 articles were yielded on the basis of inclusion criteria and, by reading the abstract and availability of full text, a total of 124 articles were selected. Further reading the full texts and considering articles from the references of the selected articles, a total of 65 articles were finally included in the review. Conclusion: Our analysis of the literature suggests that PRAME screening in OC and OPMDs prior to RBT should be done. In PRAME positive cases, approaches like PRAME based immunotherapy in the form of Cancer vaccine therapy [Acellular PRAME vaccine, PRAME pulsed Dendritic Cells (DC)]; Adoptive T Cell therapy/T Cell Receptor-T Cell therapy, Antibody therapy/Chimeric Antigen Receptor-T Cell therapy along with Presented antigen modulation Therapies employing histone deacetylase inhibitors and demethylation agents seem plausible. In the future, a combination therapy employing either PRAME vaccines or antibodies or Adoptive T cell Therapy and ATRA could be used in retinoid resistant OC and OPMDs.
Topics: Antigens, Neoplasm; Humans; Immunotherapy; Mouth Neoplasms; Retinoids
PubMed: 34711164
DOI: 10.2174/1566524021666211027091719 -
Frontiers in Immunology 2021Programmed cell death protein 1 (PD-1) can attenuate chimeric antigen receptor-T (CAR-T) cell-mediated anti-tumoral immune responses. In this regard, co-administration...
BACKGROUND
Programmed cell death protein 1 (PD-1) can attenuate chimeric antigen receptor-T (CAR-T) cell-mediated anti-tumoral immune responses. In this regard, co-administration of anti-PD-1 with CAR-T cells and PD-1 gene-editing of CAR-T cells have been suggested to disrupt this inhibitory axis. Herein, we aim to investigate the advantages and disadvantages of these two approaches and propose a novel strategy to ameliorate the prognosis of glioma patients.
METHODS
Scopus, Embase, and Web of Science were systematically searched to obtain relevant peer-reviewed studies published before March 7, 2021. Then, the current study was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. The random-effect model was applied to evaluate the effect size of administrated agents on the survival of animal models bearing gliomas using RevMan version 5.4. The Cochran Q test and I were performed to assess the possible between-study heterogeneity. Egger's and Begg and Mazumdar's tests were performed to objectively assess potential asymmetry and publication bias using CMA version 2.
RESULTS
Anti-PD-1 can substantially increase the survival of animal models on second-generation CAR-T cells. Also, PD-1 knockdown can remarkably prolong the survival of animal models on third-generation CAR-T cells. Regardless of the CAR-T generations, PD-1 gene-edited CAR-T cells can considerably enhance the survival of animal-bearing gliomas compared to the conventional CAR-T cells.
CONCLUSIONS
The single-cell sequencing of tumoral cells and cells residing in the tumor microenvironment can provide valuable insights into the patient-derived neoantigens and the expression profile of inhibitory immune checkpoint molecules in tumor bulk. Thus, single-cell sequencing-guided fourth-generation CAR-T cells can cover patient-derived neoantigens expressed in various subpopulations of tumoral cells and inhibit related inhibitory immune checkpoint molecules. The proposed approach can improve anti-tumoral immune responses, decrease the risk of immune-related adverse events, reduce the risk of glioma relapse, and address the vast inter-and intra-heterogeneity of gliomas.
Topics: Animals; Brain Neoplasms; Gene Editing; Glioma; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Mice; Precision Medicine; Programmed Cell Death 1 Receptor; Single-Cell Analysis
PubMed: 35126356
DOI: 10.3389/fimmu.2021.788211 -
The Cochrane Database of Systematic... Dec 2021Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For people with localised NSCLC (stages I to... (Review)
Review
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For people with localised NSCLC (stages I to III), it has been speculated that immunotherapy may be helpful for reducing postoperative recurrence rates, or improving the clinical outcomes of current treatment for unresectable tumours. This is an update of a Cochrane Review first published in 2017 and it includes two new randomised controlled trials (RCTs).
OBJECTIVES
To assess the effectiveness and safety of immunotherapy (excluding checkpoint inhibitors) among people with localised NSCLC of stages I to III who received curative intent of radiotherapy or surgery.
SEARCH METHODS
We searched the following databases (from inception to 19 May 2021): CENTRAL, MEDLINE, Embase, CINAHL, and five trial registers. We also searched conference proceedings and reference lists of included trials.
SELECTION CRITERIA
We included RCTs conducted in adults (≥ 18 years) diagnosed with NSCLC stage I to III after surgical resection, and those with unresectable locally advanced stage III NSCLC receiving radiotherapy with curative intent. We included participants who underwent primary surgical treatment, postoperative radiotherapy or chemoradiotherapy if the same strategy was provided for both intervention and control groups.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected eligible trials, assessed risk of bias, and extracted data. We used survival analysis to pool time-to-event data, using hazard ratios (HRs). We used risk ratios (RRs) for dichotomous data, and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). Due to clinical heterogeneity (immunotherapeutic agents with different underlying mechanisms), we combined data by applying random-effects models.
MAIN RESULTS
We included 11 RCTs involving 5128 participants (this included 2 new trials with 188 participants since the last search dated 20 January 2017). Participants who underwent surgical resection or received curative radiotherapy were randomised to either an immunotherapy group or a control group. The immunological interventions were active immunotherapy Bacillus Calmette-Guérin (BCG) adoptive cell transfer (i.e. transfer factor (TF), tumour-infiltrating lymphocytes (TIL), dendritic cell/cytokine-induced killer (DC/CIK), antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25), and targeted natural killer (NK) cells. Seven trials were at high risk of bias for at least one of the risk of bias domains. Three trials were at low risk of bias across all domains and one small trial was at unclear risk of bias as it provided insufficient information. We included data from nine of the 11 trials in the meta-analyses involving 4863 participants. There was no evidence of a difference between the immunotherapy agents and the controls on any of the following outcomes: overall survival (HR 0.94, 95% CI 0.84 to 1.05; P = 0.27; 4 trials, 3848 participants; high-quality evidence), progression-free survival (HR 0.94, 95% CI 0.86 to 1.03; P = 0.19; moderate-quality evidence), adverse events (RR 1.12, 95% CI 0.97 to 1.28; P = 0.11; 4 trials, 4126 evaluated participants; low-quality evidence), and severe adverse events (RR 1.14, 95% CI 0.92 to 1.40; 6 trials, 4546 evaluated participants; low-quality evidence). Survival rates at different time points showed no evidence of a difference between immunotherapy agents and the controls. Survival rate at 1-year follow-up (RR 1.02, 95% CI 0.96 to 1.08; I = 57%; 7 trials, 4420 participants; low-quality evidence), 2-year follow-up (RR 1.02, 95% CI 0.93 to 1.12; 7 trials, 4420 participants; moderate-quality evidence), 3-year follow-up (RR 0.99, 95% CI 0.90 to 1.09; 7 trials, 4420 participants; I = 22%; moderate-quality evidence) and at 5-year follow-up (RR 0.98, 95% CI 0.86 to 1.12; I = 0%; 7 trials, 4389 participants; moderate-quality evidence). Only one trial reported overall response rates. Two trials provided health-related quality of life results with contradicting results. AUTHORS' CONCLUSIONS: Based on this updated review, the current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for people with localised NSCLC (stages I to III). Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights into the role of immunotherapy for people with stages I to III NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Immunotherapy; Lung Neoplasms; Progression-Free Survival; Randomized Controlled Trials as Topic
PubMed: 34870327
DOI: 10.1002/14651858.CD011300.pub3 -
Clinical Lymphoma, Myeloma & Leukemia Jun 2024The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate.
METHODS
In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL.
RESULTS
After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel.
CONCLUSIONS
Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages.
Topics: Humans; Immunotherapy, Adoptive; Lymphoma, Non-Hodgkin; Receptors, Chimeric Antigen
PubMed: 38582666
DOI: 10.1016/j.clml.2024.02.007 -
Clinical Lymphoma, Myeloma & Leukemia Apr 2024Chimeric Antigen Receptor T-cell (CAR T-cell) therapy is an effective treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, patients with... (Meta-Analysis)
Meta-Analysis Review
Chimeric Antigen Receptor T-cell (CAR T-cell) therapy is an effective treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, patients with central nervous system (CNS) lymphoma were excluded in most of the CAR T-cell therapy trials. This meta-analysis assesses the efficacy with CAR T-cell therapy in LBCL patients with CNS involvement. Two reviewers independently searched PubMed and Cochrane Library to identify all published literature associated with United States Food and Drug Administration approved CAR T-cell therapies for LBCL. Patients with CNS LBCL were included. Meta-analysis of proportion was performed to evaluate the overall response (ORR), complete response (CR) for efficacy, and cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome for safety assessment. Nineteen studies were qualified for inclusion with 141 CNS LBCL patients. The ORR and CR rates were 61% and 55% respectively. The median overall survival (OS) was 8.8 months, and the median progression free survival (PFS) was 4.4 months. Severe immune effector cell-associated neurotoxicity syndrome (grade≥3) were reported in 25% (32/130) patients and severe cytokine release syndrome (grade≥3) were found in 10% (13/124) of the patients. The safety and efficacy of CAR T-cell therapy in CNS LBCL patients appears comparable to patients without CNS involvement.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Cytokine Release Syndrome; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neurotoxicity Syndromes; Central Nervous System; Cell- and Tissue-Based Therapy; Antigens, CD19
PubMed: 38267353
DOI: 10.1016/j.clml.2023.12.012 -
Cancer Gene Therapy Jun 2023Chimeric Antigen Receptor (CAR) T cell therapy is an effective treatment approach for patients with relapsed or refractory acute lymphoblastic leukemia (R/R B-ALL).... (Meta-Analysis)
Meta-Analysis
Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis.
Chimeric Antigen Receptor (CAR) T cell therapy is an effective treatment approach for patients with relapsed or refractory acute lymphoblastic leukemia (R/R B-ALL). However, identifying the factors that influence long-term response to this therapy is necessary to optimize patient selection and treatment allocation. We conducted a literature review and meta-analysis to investigate the use of autologous anti-CD19 CAR T cell therapy in both pediatric and adult patients with R/R B-ALL, using several databases including MEDLINE, Cochrane Central, ScienceDirect, Web of Science, Journals@Ovid, Embase, and clinicaltrial.gov. A total of 38 reports were analyzed, which enrolled 2134 patients. Time-to-event endpoints were estimated using reconstructed patient survival data. The study explored key modulators of response, including costimulatory domains, disease status, age, and lymphodepletion. The median overall survival and event-free survival were 36.2 months [95% CI 28.9, NR] and 13.3 months [95% CI 12.2, 17], respectively. The overall response rate was 76% [95% CI 71, 81]. The use of 4-1BB costimulatory domain in the CAR construct, administration of low-dose cyclophosphamide lymphodepletion, and pretreatment morphologic remission were associated with better overall survival, with hazard ratios of 0.72, 0.56, and 0.66, respectively. Morphologic remission and 4-1BB domain were associated with better event-free survival, with hazard ratios of 0.66 and 0.72, respectively. These findings suggest that CAR T cell therapy may offer long-term benefits to patients with R/R B-ALL. However, further research is needed to optimize patient selection and better understand the impact of various factors on the outcome of CAR T cell therapy.
Topics: Adult; Humans; Child; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antigens, CD19; T-Lymphocytes
PubMed: 36750666
DOI: 10.1038/s41417-023-00593-3