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Journal of Clinical Oncology : Official... Sep 2016Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately,... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, only a subgroup of patients responds and shows long-term survival to these therapies. Tumor vaccines and cellular immunotherapies could synergize with checkpoint blockade, but which of these treatments is most efficacious is unknown. In this meta-analysis, we assessed the efficacy of tumor vaccination and cellular immunotherapy in NSCLC.
METHODS
We searched for randomized controlled trials (RCTs) investigating cellular immunotherapy or vaccines in NSCLC. We used random effects models to analyze overall survival (OS) and progression-free survival (PFS), expressed as hazard ratios (HRs), and differences in time (months). The effect of immunotherapy type, disease stage, tumor histology, and concurrent chemotherapy was assessed using subgroup analysis and meta-regression. All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS
We identified 18 RCTs that matched our selection criteria; these included a total of 6,756 patients. Immunotherapy extended NSCLC survival and PFS, expressed as HR (OS: HR, 0.81, 95% CI, 0.70 to 0.94, P = .01; PFS: HR, 0.83, 95% CI, 0.72 to 0.95, P = .006) and month difference (OS: difference, 5.43 months, 95% CI, 3.20 to 7.65, P < .005; PFS: difference, 3.24 months, 95% CI, 1.61 to 4.88, P < .005). Cellular therapies outperformed tumor vaccines (OS as HR: P = .005, month difference: P < .001; PFS as HR: P = .001, month difference: P = .004). There was a benefit of immunotherapy in low-stage compared with high-stage NSCLC and with concurrent administration of chemotherapy only in one of four outcome measures evaluated (PFS in months: P = .01 and PFS as HR: P = .031, respectively). There was no significant effect of tumor histology on survival or PFS.
CONCLUSION
Tumor vaccines and cellular immunotherapies enhanced OS and PFS in NSCLC. Cellular immunotherapy was found to be more effective than tumor vaccination. These findings have implications for future studies investigating combination immunotherapy in NSCLC.
Topics: Cancer Vaccines; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Humans; Immunotherapy, Adoptive; Lung Neoplasms; Neoplasm Staging; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome
PubMed: 27432922
DOI: 10.1200/JCO.2015.66.3955 -
Journal For Immunotherapy of Cancer Apr 2023The number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) is increasing. In many of these trials, CIK therapy was coadministered with conventional cancer therapy. The aim of this review is to systematically assess the available literature, in which the majority were only in Chinese, on CIK therapy for the management of CRC using meta-analysis and to identify parameters associated with successful CIK therapy implementation.
METHODS
Prospective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in patients with CRC were searched for electronically on MEDLINE, Embase, China National Knowledge Infrastructure, and Wanfang Data databases. The clinical endpoints of overall survival (OS), progression-free survival (PFS), OS and PFS rates, overall response rate (ORR), and toxicity were meta-analyzed using HR and relative ratio (RR), and subgroup analyses were performed using chi-square (χ) test and I-squared (I) statistics for study design, disease stage, cotherapy type, and timing of administration.
RESULTS
In total, 70 studies involving 6743 patients were analyzed. CIK therapy was favored over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53 to 0.65), PFS (HR=0.55, 95% CI: 0.47 to 0.63), and ORR (RR=0.65, 95% CI: 0.57 to 0.74) without increasing toxicity (HR=0.59, 95% CI: 0.16 to 2.25). Subgroup analyses on OS and PFS by study design (randomized vs non-randomized study design), disease stage (Stage I-III vs Stage IV), cotreatment with dendritic cells (DCs) (CIK vs DC-CIK therapy), or timing of therapy administration (concurrent vs sequential with coadministered anticancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, cotreatment with DCs did not improve clinical outcomes over CIK therapy alone.
CONCLUSION
Compared with standard therapy, patients who received additional CIK cell therapy had favorable outcomes without increased toxicity, warranting further investigation into CIK therapy for the treatment of CRC.
Topics: Humans; Colorectal Neoplasms; Cytokine-Induced Killer Cells; Immunotherapy, Adoptive; Prospective Studies; Retrospective Studies; Clinical Trials as Topic
PubMed: 37117007
DOI: 10.1136/jitc-2023-006764 -
Expert Review of Pharmacoeconomics &... 2023The new class of chimeric antigen receptor T-cell has emboldened health-care professionals and patients for a more effective treatment of hematological malignancies,... (Review)
Review
INTRODUCTION
The new class of chimeric antigen receptor T-cell has emboldened health-care professionals and patients for a more effective treatment of hematological malignancies, indicatively lymphoma, acute lymphoblastic leukemia, and myeloma. Nevertheless, their burgeoning procurement costs comprise a litmus stress for health systems across the globe. In this context, this systematic review aims to update the current body of evidence assessing CAR-T economic evaluations and elucidate their financial efficiency.
AREAS COVERED
A systematic review of the economic evaluations of tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel and brexucabtagene autoleucel was performed.
EXPERT OPINION
The updated results corroborated the previously reported favorable cost-effectiveness ratio of CAR-T. They also pointed out differences among CAR-T agents. However, their budget impact emerges as a significant barrier in the reimbursement process. Any proposed Managed Entry Agreement must integrate the ingrained uncertainty of long-term efficacy and precede reimbursement decisions.
Topics: Humans; Cost-Benefit Analysis; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Budgets; Cell- and Tissue-Based Therapy
PubMed: 37288738
DOI: 10.1080/14737167.2023.2214731 -
Human Gene Therapy Mar 2023Dual-targeting chimeric antigen receptor (CAR)-T cell therapy has been proposed as a potential solution for overcoming antigen escape during anti-CD19 CAR-T treatment.... (Meta-Analysis)
Meta-Analysis
Dual-targeting chimeric antigen receptor (CAR)-T cell therapy has been proposed as a potential solution for overcoming antigen escape during anti-CD19 CAR-T treatment. We performed this systematic review and meta-analysis to investigate the efficacy and safety of this novel treatment in patients with B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). We systematically searched relevant literature based on databases (PubMed, Web of Science, Embase and Cochrane) and conference abstracts. The primary outcomes measured were the best objective response rate (ORR) or complete response (CR), 12-month overall survival (OS) and progression-free survival (PFS), cytokine release syndrome (CRS), and neurotoxicity. Fifteen registered prospective open-label clinical trials were included. Among the 260 patients with B-NHL, the pooled best ORR and CR were 77% (95% confidence interval [CI]: 0.71-0.82) and 52% (95% CI: 0.40-0.63), respectively, and the pooled 12-month PFS and OS were 54.0% (95% CI: 0.47-0.61) and 66.0% (95% CI: 0.56-0.77), respectively. In the 159 patients with B-ALL, the combined best CR was observed to be 92% (95% CI: 0.82-0.99) and the pooled 12-month PFS and OS were 65.0% (95% CI: 0.51-0.77) and 73.0% (95% CI: 0.56-0.92), respectively. Moreover, in B-NHL patients, grade ≥3 CRS was observed in 14.0% (95% CI: 0.04-0.29) of these patients, and 5.0% (95% CI: 0.02-0.08) showed grade ≥3 neurotoxicity; in the case of B-ALL patients, grade ≥3 CRS and neurotoxicity occurred in 11.0% (95% CI: 0.04-0.19) and 2.0% (95% CI: 0.00-0.06), respectively. This study demonstrates the safety and clinical efficacy of dual-targeting CAR-T cell therapies in B cell malignancies. Further, well-designed randomized controlled trials are required to establish the role of dual-targeting CAR-T cell therapy in patients with B cell malignancies.
Topics: Humans; Receptors, Chimeric Antigen; Prospective Studies; Immunotherapy, Adoptive; B-Lymphocytes; Lymphoma, B-Cell; Antigens, CD19
PubMed: 36734417
DOI: 10.1089/hum.2022.183 -
Cureus Sep 2021Osteosarcoma (OS) is the most common primary bone cancer affecting children and young adults, most often occurring at the metaphysis of long bones. At present, treatment... (Review)
Review
Osteosarcoma (OS) is the most common primary bone cancer affecting children and young adults, most often occurring at the metaphysis of long bones. At present, treatment with combinations of surgery and chemotherapy for the localized OS has only brought minuscule improvements in prognosis. In comparison, the advanced, metastatic, or recurrent forms of OS are often non-responsive to chemotherapy, adding to the dire need to develop new and efficient therapies. The question of interest investigated in this systematic review is whether immunotherapy can play a meaningful role in improving the clinical outcomes of children with OS. This article aims to summarize the preclinical and clinical research conducted thus far on potential therapeutic avenues for pediatric OS using immunotherapy, including methods like checkpoint inhibition, adoptive cellular therapy with T-cells, chimeric antigen receptor T (CAR-T), and natural killer (NK) cells. It also highlights the influence of the innate and adaptive immune system on the tumor microenvironment, allowing for OS progression and metastasis. This systematic review contains 27 articles and analyses of multiple clinical trials employing immunotherapeutic drugs to 785 osteosarcoma participants and over 243 pediatric patients. The articles were obtained through PubMed, PubMed Central, and ClinicalTrials.gov and individually assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist and the Cochrane risk-of-bias tool. The reviews reveal that immunotherapy's most significant impact on pediatric OS includes combining immune checkpoint blockers with traditional chemotherapy and surgery. However, due to the bimodal distribution of this aggressive malignancy, these studies cannot precisely estimate the overall effect and any potential life-threatening adverse events following therapy in children. Further research is required to fully assess the impact of these immunotherapies, including more extensive multinational clinical trials to focus on the pediatric population.
PubMed: 34725602
DOI: 10.7759/cureus.18349 -
Clinical and Experimental Medicine Oct 2023As a novel anticancer therapy, chimeric antigen receptor T (CAR T) cell therapy may lead to cardiotoxic reactions. However, the exact incidence remains unclear. Our... (Meta-Analysis)
Meta-Analysis Review
As a novel anticancer therapy, chimeric antigen receptor T (CAR T) cell therapy may lead to cardiotoxic reactions. However, the exact incidence remains unclear. Our study aimed to preliminarily assess the prevalence of cardiotoxicity after CAR T cell treatment using a systematic review and meta-analysis. PubMed, Embase, Web of Science, and Cochrane databases were searched for potentially relevant studies. All types of relevant clinical studies were screened and assessed for risk bias. In most instances, random-effect models were used for data analysis, and heterogeneity between studies was evaluated. Standard quality assessment tools were used to assess quality. The study was registered with PROSPERO (CRD42022304611). Eight eligible studies comprising 3567 patients, including seven observational studies and one controlled study, were identified. The incidence of cardiovascular events was 16.7% [95% confidence interval (CI) 0.138-0.200, P < 0.01)]. Arrhythmia was the most common disorder, with an incidence of 6.5% (95% CI 0.029-0.115, P < 0.01). The occurrence of cardiotoxicity was associated with cytokine release syndrome (CRS), with a prevalence of 18.7% (95% CI 0.107-0.315, P < 0.01). Moreover, such adverse reactions were more common when CRS > 2 (OR = 0.07, 95% CI 0.02-0.29, P < 0.01). The risk of cardiotoxicity was not notably higher in patients receiving CAR T cell therapy than in those receiving traditional anticancer treatment. However, sufficient attention should be paid to this. And further evidence from large-scale clinical trials are needed.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Cardiotoxicity; T-Lymphocytes; Cytokine Release Syndrome; Cell- and Tissue-Based Therapy
PubMed: 36930381
DOI: 10.1007/s10238-023-01042-z -
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 -
Molecules (Basel, Switzerland) Apr 2021Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic...
Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).
Topics: Antineoplastic Agents, Immunological; Artificial Intelligence; B7-H1 Antigen; Fluorodeoxyglucose F18; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Positron-Emission Tomography; Programmed Cell Death 1 Receptor; Radiopharmaceuticals; Signal Transduction; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Tumor Microenvironment
PubMed: 33920423
DOI: 10.3390/molecules26082201 -
Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies.Immunotherapy May 2013There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic... (Review)
Review
AIMS
There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic hematopoietic cell transplantation. However, it is unclear if and how this benefit varies according to specific diseases. Because administration of DLI is not universally effective and could be associated with significant toxicities resulting in morbidity and mortality, it is imperative to identify cases where benefits outweigh harms of the procedure.
MATERIALS & METHODS
We conducted a systematic review of the published literature and extracted and pooled data independently for each disease cohort: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL).
RESULTS
In summary, 39 studies met inclusion criteria. The pooled proportion (95% CI) for complete response was 27% (16-40) in ALL, 55% (15-92) in CLL, 26% (19-33) in MM, 52% (33-71) in NHL and 37% (20-56) in HL.
CONCLUSION
Complete response rates appear higher when DLI is used for relapsed CLL and lymphomas (NHL and HL), and less pronounced in ALL or MM. Absence of data pertaining to disease-specific prognostic determinants, such as adverse genetic or molecular abnormalities, or quantitative disease burden when applicable, limit our ability to identify cases in whom benefits from DLI outweigh risks associated with the procedure within a particular disease.
Topics: Humans; Immunotherapy, Adoptive; Leukemia; Lymphocyte Transfusion; Lymphoma; Multiple Myeloma; Treatment Outcome
PubMed: 23638742
DOI: 10.2217/imt.13.31 -
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