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Transfusion Medicine Reviews Apr 2019Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize... (Meta-Analysis)
Meta-Analysis
Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception - November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of patients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.
Topics: Antigens, CD19; Hematologic Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Risk Assessment; T-Lymphocytes; Treatment Outcome
PubMed: 30948292
DOI: 10.1016/j.tmrv.2019.01.005 -
PloS One 2016Adoptive immunotherapy (AI) has been applied in the treatment of non-small-cell lung cancer (NSCLC) patients, but the value of postoperative AI has been inconclusive... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Adoptive immunotherapy (AI) has been applied in the treatment of non-small-cell lung cancer (NSCLC) patients, but the value of postoperative AI has been inconclusive largely as a result of the small number of patients included in each study. We performed a systematic review and meta-analysis to address this issue for patients with postoperative NSCLC.
METHODS
Pubmed, Embase, Cochrane Library were searched for randomized controlled trials comparing adoptive immunotherapy with control therapies in postoperative NSCLC patients. The primary endpoint was overall survival. Hazard ratio (HR) was estimated and 95% confidence intervals (CI) were calculated using a fixed-effect model.
RESULTS
Compared with control therapies, analyses of 4 randomized controlled trials (472 patients) showed a significant benefit of adoptive immunotherapy on survival (hazard ratio [HR] 0.61, 95% CI 0.45-0.84, p = 0.002), and a 39% reduction in the relative risk of death (no evidence of a difference between trials; p = 0.16, I² = 42%). In subgroup analyses by treatment cycles and treatment regimen, significant OS benefit was found in combination therapy of AI with chemotherapy, regardless of whether or not the treatment cycles were more than 10 cycles.
CONCLUSION
Adoptive immunotherapy has the potential to improve overall survival in postoperative NSCLC. The findings suggest this is a valid treatment option for these patients. Further randomized clinical trials are urgently needed.
Topics: Carcinoma, Non-Small-Cell Lung; Female; Humans; Immunotherapy, Adoptive; Lung Neoplasms; Male; Middle Aged; Postoperative Period; Survival Rate
PubMed: 27618180
DOI: 10.1371/journal.pone.0162630 -
Cancer Research and Treatment Jul 2023We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis. (Meta-Analysis)
Meta-Analysis
Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis.
PURPOSE
We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis.
MATERIALS AND METHODS
R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and chimeric antigen receptor (CAR) T-cell therapy was used as reference treatment.
RESULTS
Twenty-six ASCT-eligible cohorts from 17 studies comprising 2,924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3,617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval [CI], 0.15 to 0.65) for the CAR T-cell group and 0.34 (95% CI, 0.30 to 0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI, 0.35 to 0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI, 0.37 to 0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment.
CONCLUSION
Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Salvage Therapy; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Lymphoma, Large B-Cell, Diffuse
PubMed: 36915243
DOI: 10.4143/crt.2022.1658 -
Transplantation and Cellular Therapy Jan 2024Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients... (Meta-Analysis)
Meta-Analysis
Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.
Topics: Humans; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Neurotoxicity Syndromes; Observational Studies as Topic; Pathologic Complete Response; Receptors, Chimeric Antigen; Retrospective Studies; T-Lymphocytes
PubMed: 37890589
DOI: 10.1016/j.jtct.2023.10.017 -
Gynecologic Oncology Jun 2022Adoptive cell therapy (ACT) has shown promise in hematologic and solid tumors. While data supports immunogenicity of gynecologic cancers, the benefit of ACT is not yet... (Meta-Analysis)
Meta-Analysis Review
Adoptive cell therapy (ACT) has shown promise in hematologic and solid tumors. While data supports immunogenicity of gynecologic cancers, the benefit of ACT is not yet clear. To address this question, we performed a comprehensive systematic review and meta-analysis. Eligible studies included those reporting oncologic response or toxicity data in at least one patient with any gynecologic cancer treated with ACT. Chi-square test and multivariable logistic regression were performed to identify predictors of response. We retrieved 281 articles, and 28 studies met our inclusion criteria. These comprised of 401 patients including 238 patients with gynecologic cancers (61.8% ovarian, 34.0% cervical, 2.9% endometrial, and 1.2% other). In patients with gynecologic cancers, response rates to ACT were 8.1% complete response, 18.2% partial response, and 31.4% stable disease, for an objective response rate (ORR) of 26.3%, disease control rate (DCR) of 57.6%, and median response duration of 5.5 months. Patients in studies reporting ≤1 median line of prior therapy had a higher ORR (52.9% vs. 22.6% for >1, p < 0.001), although DCR in the >1 group was still 53.2%. ORRs by ACT type were tumor infiltrating lymphocytes (TIL) 41.4%, natural killer cells 26.7%, peripheral autologous T-cells 18.4%, T-cell receptor-modified T-cells 15.4%, and chimeric antigen receptor T-cells 9.5% (p = 0.001). ORR was significantly improved with inclusion of lymphodepletion (34.8% vs. 15.4% without, p = 0.001). On multivariable analysis controlling for cancer type and lymphodepletion, TIL therapy was predictive of objective response (odds ratio 2.6, p = 0.011). The rate of grade 3 or 4 toxicity was 46.0%. All grade adverse events included fever, hypotension, dyspnea, confusion, hematologic changes, nausea/vomiting, fatigue, and diarrhea. In conclusion, ACT is a promising treatment modality in gynecologic cancer. We observed a particular benefit of TIL therapy and suggest inclusion of lymphodepletion in future trials.
Topics: Cell- and Tissue-Based Therapy; Female; Genital Neoplasms, Female; Humans; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Receptors, Antigen, T-Cell
PubMed: 35400527
DOI: 10.1016/j.ygyno.2022.03.013 -
Critical Reviews in Oncology/hematology Dec 2023A registered (PROSPERO - CRD42022346462) systematic review and meta-analysis was conducted of all-grade infections amongst adult patients receiving CAR-T therapy for... (Meta-Analysis)
Meta-Analysis Review
A registered (PROSPERO - CRD42022346462) systematic review and meta-analysis was conducted of all-grade infections amongst adult patients receiving CAR-T therapy for haematological malignancy. Meta-analysis of pooled incidence, using random effects model, was conducted. Cochran's Q test examined heterogeneity. 2678 patients across 33 studies were included in the primary outcome. Forty-percent of patients (95% CI: 0.33 - 0.48) experienced an infection of any grade. Twenty-five percent of infection events (95% CI: 0.16 - 0.34) were severe. Late infections were as common as early infections (IRR = 0.86, 95% CI: 0.38 - 1.98). All-grade infections, bacterial and viral infections were highest in myeloma patients at 57%, 37% and 28% respectively. Patients with NHL more commonly experienced late infections. Pooled rate of invasive candidiasis/yeast infections was 2% in studies utilizing anti-yeast prophylaxis. This review identified a high rate of all-grade infections, moderate rate of severe infections, and myeloma as a high-risk haematological group.
Topics: Adult; Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Hematologic Neoplasms; Hematology
PubMed: 37739146
DOI: 10.1016/j.critrevonc.2023.104134 -
Cancers Jan 2022To systematically review the current body of evidence on the efficacy and safety of immunotherapy for cervical cancer (CC). (Review)
Review
PURPOSE
To systematically review the current body of evidence on the efficacy and safety of immunotherapy for cervical cancer (CC).
MATERIAL AND METHODS
Medline, the Cochrane Central Register of Controlled Trials and Web of Science were searched for prospective trials assessing immunotherapy in CC patients in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Full-text articles in English and German reporting outcomes of survival, response rates or safety were eligible.
RESULTS
Of 4655 screened studies, 51 were included (immune checkpoint inhibitors (ICI) =20; therapeutic vaccines = 25; adoptive cell transfer therapy =9). Of these, one qualified as a phase III randomized controlled trial and demonstrated increased overall survival following treatment with pembrolizumab, chemotherapy and bevacizumab. A minority of studies included a control group ( = 7) or more than 50 patients ( = 15). Overall, response rates were low to moderate. No response to ICIs was seen in PD-L1 negative patients. However, few remarkable results were achieved in heavily pretreated patients. There were no safety concerns in any of the included studies.
CONCLUSION
Strong evidence on the efficacy of strategies to treat recurrent or metastatic cervical cancer is currently limited to pembrolizumab in combination with chemotherapy and bevacizumab, which substantiates an urgent need for large confirmatory trials on alternative immunotherapies. Overall, there is sound evidence on the safety of immunotherapy in CC.
PubMed: 35053603
DOI: 10.3390/cancers14020441 -
Frontiers in Immunology 2023Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been FDA-approved, CAR T-cells targeting CD22, as well as dual-targeting CD19/CD22 CAR T-cells, are currently being evaluated in clinical trials. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of CD22-targeting CAR T-cell therapies. We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to March 3rd 2022 for full-length articles and conference abstracts of clinical trials employing CD22-targeting CAR T-cells in acute lymphocytic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The primary outcome was best complete response (bCR). A DerSimonian and Laird random-effects model with arcsine transformation was used to pool outcome proportions. From 1068 references screened, 100 were included, representing 30 early phase studies with 637 patients, investigating CD22 or CD19/CD22 CAR T-cells. CD22 CAR T-cells had a bCR of 68% [95% CI, 53-81%] in ALL (n= 116), and 64% [95% CI, 46-81%] in NHL (n= 28) with 74% and 96% of patients having received anti-CD19 CAR T-cells previously in ALL and NHL studies respectively. CD19/CD22 CAR T-cells had a bCR rate of 90% [95% CI, 84-95%] in ALL (n= 297) and 47% [95% CI, 34-61%] in NHL (n= 137). The estimated incidence of total and severe (grade ≥3) CRS were 87% [95% CI, 80-92%] and 6% [95% CI, 3-9%] respectively. ICANS and severe ICANS had an estimated incidence of 16% [95% CI, 9-25%] and 3% [95% CI, 1-5%] respectively. Early phase trials of CD22 and CD19/CD22 CAR T-cells show high remission rates in ALL and NHL. Severe CRS or ICANS were (1)rare and dual-targeting did not increase toxicity. Variability in CAR construct, dose, and patient factors amongst studies limits comparisons, with long-term outcomes yet to be reported.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier CRD42020193027.
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Lymphoma, Non-Hodgkin; B-Lymphocytes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sialic Acid Binding Ig-like Lectin 2
PubMed: 37180149
DOI: 10.3389/fimmu.2023.1178403 -
European Radiology Experimental Jan 2020A wide range of cancer immunotherapy approaches has been developed including non-specific immune-stimulants such as cytokines, cancer vaccines, immune checkpoint...
A wide range of cancer immunotherapy approaches has been developed including non-specific immune-stimulants such as cytokines, cancer vaccines, immune checkpoint inhibitors (ICIs), and adoptive T cell therapy. Among them, ICIs are the most commonly used and intensively studied. Since 2011, these drugs have received marketing authorisation for melanoma, lung, bladder, renal, and head and neck cancers, with remarkable and long-lasting treatment response in some patients. The novel mechanism of action of ICIs, with immune and T cell activation, leads to unusual patterns of response on imaging, with the advent of so-called pseudoprogression being more pronounced and frequently observed when compared to other anticancer therapies. Pseudoprogression, described in about 2-10% of patients treated with ICIs, corresponds to an increase of tumour burden and/or the appearance of new lesions due to infiltration by activated T cells before the disease responds to therapy. To overcome the limitation of response evaluation criteria in solid tumors (RECIST) to assess these specific changes, new imaging criteria-so-called immune-related response criteria and then immune-related RECIST (irRECIST)-were proposed. The major modification involved the inclusion of the measurements of new target lesions into disease assessments and the need for a 4-week re-assessment to confirm or not confirm progression. The RECIST working group introduced the new concept of "unconfirmed progression", into the irRECIST. This paper reviews current immunotherapeutic approaches and summarises radiologic criteria to evaluate new patterns of response to immunotherapy. Furthermore, imaging features of immunotherapy-related adverse events and available predictive biomarkers of response are presented.
Topics: Diagnostic Imaging; Humans; Immunotherapy; Neoplasms; Response Evaluation Criteria in Solid Tumors
PubMed: 31900689
DOI: 10.1186/s41747-019-0134-1 -
Gastroenterology Research Dec 2020The utilization of immunotherapy is increasing to the point of becoming the fifth pillar of management alongside surgical intervention, chemotherapy, radiotherapy and... (Review)
Review
The utilization of immunotherapy is increasing to the point of becoming the fifth pillar of management alongside surgical intervention, chemotherapy, radiotherapy and targeted therapy. However, gastrointestinal adverse effects and toxicities have been frequently cited with its use. As per literature, the most common adverse effect of immune checkpoint inhibitors is watery and non-bloody diarrhea. Adoptive cell therapy can lead to delayed, on-target but off-tumor adverse effects which are unknown and may be life-threatening. The use of anti-angiogenic monoclonal antibodies can lead to bowel perforations, whereas epidermal growth factor receptor inhibitors and anti-HER2 agents are frequently associated with diarrhea. Minimal adverse effects have been associated with therapeutic cancer vaccines; however, additional studies are needed to determine their efficacy and potential toxicities. To provide an in-depth review of the gastrointestinal side effects of immunotherapeutic agents, we performed a thorough literature search using multiple online search engines such as PubMed, Google Scholar and Ovid MEDLINE, along with a review of the guidelines from the United States Food and Drug Administration (FDA) and the Cancer Research Institute on immunotherapy. In this systematic review, we detail the gastrointestinal adverse effects of immunotherapy and describe their management. With the advent of newer immunotherapeutic agents and the consistent approval of current agents by FDA for a wide spectrum of cancers, it is vital for physicians to familiarize themselves with their adverse effects for prompt diagnosis and early intervention to decrease adverse outcomes.
PubMed: 33447301
DOI: 10.14740/gr1340