scholarly journals Efficacy and safety of CD22 chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies: a protocol for a systematic review and meta-analysis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Komal Adeel ◽  
Nathan J. Fergusson ◽  
Risa Shorr ◽  
Harold Atkins ◽  
Kevin A. Hay
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background Chimeric antigen receptor (CAR) T cell therapy has had great success in treating patients with relapsed or refractory B cell malignancies, with CD19-targeting therapies now approved in many countries. However, a subset of patients fails to respond or relapse after CD19 CAR T cell therapy, in part due to antigen loss, which has prompted the search for alternative antigen targets. CD22 is another antigen found on the surface of B cells. CARs targeting CD22 alone or in combination with other antigens have been investigated in several pre-clinical and clinical trials. Given the heterogeneity and small size of CAR T cell therapy clinical trials, systematic reviews are needed to evaluate their efficacy and safety. Here, we propose a systematic review of CAR T cell therapies targeting CD22, alone or in combination with other antigen targets, in B cell malignancies. Methods We will perform a systematic search of EMBASE, MEDLINE, Web of Science, Cochrane Register of Controlled Trials, clinicaltrials.gov, and the International Clinical Trials Registry Platform. Ongoing and completed clinical trials will be identified and cataloged. Interventional studies investigating CD22 CAR T cells, including various multi-antigen targeting approaches, in patients with relapsed or refractory B cell malignancies will be eligible for inclusion. Only full-text articles, conference abstracts, letters, and case reports will be considered. Our primary outcome will be a complete response, defined as absence of detectable cancer. Secondary outcomes will include adverse events, overall response, minimal residual disease, and relapse, among others. Quality assessment will be performed using a modified Institute of Health Economics tool designed for interventional single-arm studies. We will report a narrative synthesis of clinical studies, presented in tabular format. If appropriate, a meta-analysis will be performed using a random effects model to synthesize results. Discussion The results of the proposed review will help inform clinicians, patients, and other stakeholders of the risks and benefits of CD22 CAR T cell therapies. It will identify gaps or inconsistencies in outcome reporting and help to guide future clinical trials investigating CAR T cells. Systematic review registration PROSPERO registration number: CRD42020193027

scholarly journals Efficacy and Safety of CD22 Chimeric Antigen Receptor (CAR) T-cell Therapy in Patients With B-cell Malignancies: A Protocol for a Systematic Review and Meta-analysis

2020 ◽  
Author(s):  
Komal Adeel ◽  
Nathan Fergusson ◽  
Risa Shorr ◽  
Harry Atkins ◽  
Kevin Anthony Hay
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Chimeric antigen receptor (CAR) T-cell therapy has had great success in treating patients with relapsed or refractory B-cell malignancies, with CD19-targeting therapies now approved in many countries. However, a subset of patients fail to respond or relapse after CD19 CAR T-cell therapy, in part due to antigen loss, which has prompted the search for alternative antigen targets. CD22 is another antigen found on the surface of B-cells. CARs targeting CD22 alone or in combination with other antigens have been investigated in several pre-clinical and clinical trials.Given the heterogeneity and small size of CAR T-cell therapy clinical trials, systematic reviews are needed to evaluate their efficacy and safety. Here, we propose a systematic review of CAR T-cell therapies targeting CD22, alone or in combination with other antigen targets, in B-cell malignancies.Methods:We will perform a systematic search of EMBASE, MEDLINE, Web of Science, Cochrane Register of Controlled Trials, clinicaltrials.gov, and the International Clinical Trials Registry Platform. Ongoing and completed clinical trials will be identified and catalogued. Interventional studies investigating CD22 CAR T-cells, including various multi-antigen targeting approaches, in patients with relapsed or refractory B-cell malignancies will be eligible for inclusion. Only full-text articles, conferences abstracts, letters and case reports will be considered. Our primary outcome will be a complete response, defined as absence of detectable cancer. Secondary outcomes will include adverse events, overall response, minimal residual disease, and relapse, among others. Quality assessment will be performed using a modified Institute of Health Economics tool designed for interventional single-arm studies. We will report a narrative synthesis of clinical studies, presented in tabular format. If appropriate a meta-analysis will be performed using a random effects model to synthesize results.Discussion:The results of the proposed review will help inform clinicians, patients and other stakeholders of the risks and benefits of CD22 CAR T-cell therapies. It will identify gaps or inconsistencies in outcome reporting and help to guide future clinical trials investigating CAR T-cells.PROSPERO Registration Number: CRD42020193027.

scholarly journals Outcomes with "Off the Shelf" Allogeneic CD19 Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4831-4831
Author(s):  
Muhammad Umair Mushtaq ◽  
Moazzam Shahzad ◽  
Ali Hussain ◽  
Amna Y Shah ◽  
Raheel S Siddiqui ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Chimeric antigen receptor T cell (CAR-T) therapy is an adoptive T cell immunotherapy that employs the genetically modified T cell to attack the cancer cell. It is widely studied across various hematological and solid organ malignancies. Several autologous CD19 CAR-T cell therapy constructs are now approved for various B cell lymphomas, including aggressive B cell lymphomas, indolent follicular lymphoma and mantle cell lymphoma, and acute lymphoblastic leukemia (ALL). Autologous CD19 CAR-T cell therapy has unprecedented success in relapsed and refractory disease. Long time to manufacture (2-5 weeks) and manufacture failure are challenges associated with risk of interim death and deterioration of CAR-T candidates with rapidly progressive disease. T cell fitness of the autologous product in heavily pretreated patients is also potentially compromised. To overcome these shortcomings, universal "off the shelf" allogeneic CAR-T cell therapy constructs are being developed and studied. Donor sources include healthy donors and cord or induced pluripotent stem cells (iPSCs). These CAR-T constructs have additional gene modifications to mitigate the risk of rejection and graft versus host disease (GVHD). We performed a systematic review and meta-analysis to assess the safety and efficacy of allogeneic CD19 CAR-T cell therapy. Methods: Four databases (Web of Science/MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) were searched for this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using MeSH terms and keywords for "Receptors, Chimeric antigen" OR "Artificial-T-cell receptor" OR "immunotherapy, adoptive" OR "CD-19". Our search produced 3506 articles and after removing duplicates, 2243 records were screened. After excluding reviews and irrelevant articles, we included 8 prospective trials of allogeneic CD-19 CAR-T cell therapy enrolling two or more than two patients from Jan 2013 to Nov 2020. We also searched ASH 2020 abstracts to include any additional trials. The methodological quality of the included studies was evaluated using NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results: A total of 68 patients from 8 studies were evaluated. Median age was 22.5 (4.8-64) years. (Table 1) The median follow-up time was 10 (2-18) months with median number of prior therapies of 3.2 (2-11) as reported by 5 studies. Underlying diagnosis was acute lymphocytic lymphoma (n=49, 72%), chronic lymphocytic leukemia (n=6, 9%), and non-Hodgkin lymphoma (n=13, 19%). The pooled overall response rate (ORR) was 77% (95% CI 0.63-0.89, I 2 =22%, n=68) with a complete response (CR) of 75% (95% CI 0.57-0.90, I 2 =48%, n=65). The pooled incidence of cytokine release syndrome grade I/II and grade III/IV was 53% (95% CI 0.16-0.89, I 2 =89%, n=65) and 10% (95% CI 0.01-0.25, I 2 =50%, n=65) respectively. Neurotoxicity grade I/II was 12% (95%CI 0.01-0.30, I 2 =47%, p=0.09, n=47) and GVHD grade I/II was 8% (95%CI 0.01-0.19, I 2 =0%, p=0.57 n=53). None of the clinical trials reported the duration of response. Conclusion: "Off the shelf" universal CAR-T therapy is early in development. Our available data suggest that allogeneic CD19 CAR-T constructs offer high ORR and CR rates with acceptable safety profiles. GVHD was mainly low grade (grade I-II). Given these findings, allogeneic CAR-T cell therapy is an attractive option to improve timely access compared to available autologous therapy. Extensive preclinical research to develop novel constructs and several phase I/II clinical trials are ongoing to shape the future of "off the shelf" CAR-T cell therapy. Figure 1 Figure 1. Disclosures Hoffmann: Pharmcyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding.

Updates on CAR T-cell therapy in B-cell malignancies

2019 ◽  
Vol 290 (1) ◽  
pp. 39-59 ◽  
Author(s):  
Elad Jacoby ◽  
Shilpa A. Shahani ◽  
Nirali N. Shah
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Real-World Experiences of CAR T-Cell Therapy for Large B-Cell Lymphoma: How Similar Are They to the Prospective Studies?

2021 ◽  
Vol 4 (3) ◽  
pp. 150-159
Author(s):  
Kevin Tang ◽  
Loretta J. Nastoupil
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Real World ◽  
Response Rates ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

ABSTRACT Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment option for highly aggressive B cell malignancies. Clinical trials of CD19 CAR T cells for the management of relapsed and/or refractory non-Hodgkin lymphoma (NHL) have shown markedly improved survival and response rates. The goal of this review is to evaluate whether the results from these clinical trials are reflective of real-world practices through the analysis of published literature of the commercially available CAR T cell products. We have found that despite the significantly different patient characteristics, the adverse events and response rates of real-world patients were similar to those of the clinical trials. Of interest, several groups excluded from the clinical trials, such as patients with HIV infection, chronic viral hepatitis, and secondary CNS (central nervous system) lymphoma, had case reports of promising outcomes.

scholarly journals Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies

2019 ◽  
Vol 20 (20) ◽  
pp. 5010 ◽  
Author(s):  
Moo-Kon Song ◽  
Byeong-Bae Park ◽  
Ji-Eun Uhm
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Hematologic Malignancies ◽  
Resistance Mechanisms ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.

Anti-CD 19 and Anti- CD 20 Chimeric Antigen Receptor-Modified T Cells for B-Cell Malignancies: A Systematic Review and Meta-Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5163-5163 ◽  
Author(s):  
Irbaz Bin Riaz ◽  
Muhammad Husnain ◽  
Muhammad Umar Kamal ◽  
Ali McBride ◽  
Anh Hua ◽  
...  
Keyword(s):  
Systematic Review ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Hematological Malignancies ◽  
Meta Analysis ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: Chimeric antigen receptor (CAR) modified T cells targeting CD19 and CD20 have shown activity in Phase I, II trials of patients with hematological malignancies. CD19 and CD20 targeted CAR constructs from several different institutions have demonstrated consistently high anti-tumor efficacy in children and adults with relapsed B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL). We conducted a systematic review and meta-analysis of all published clinical trials studying the role of efficacy as well as safety of CD-19 and CD-20 CAR-T therapy for B-cell hematologic malignancies. Methods: Literature search was performed using MEDLINE (Ovid SP and PubMed), EMBASE, The Cochrane Library, Scopus and Web of Science. We conducted meta-analysis using random effects model using Comprehensive Metaanalysis 3.0. Heterogeneity was assessed using Q-statistic and it was quantified using I2statistic. Results: After a comprehensive literature search 4476 studies were identified and finally 15 eligible studies involving 121 patients were included in the final systematic review. The infused CAR T-cell dose was in the range of 0.76 x 106 to 3 x 107 cells/kg in seven trials and in the range of 0.8 x 107 cells to 3.3 x 109 cells/m2in 6 trials. Among 106 patients, the overall response to treatment after CAR T-cell infusion were 33% complete remission (CR), 30 % partial remission (PR), 21% stable disease (SD), and 8% progressive disease (PD). Three studies described response to immunotherapy as minimal residual disease negative (MRD-) and as no evidence of disease (NED) and after including it, the overall CR was 38%. Major adverse events included fever (38%), hypotension (23%), chills (29%), rigor (28%), fatigue 17% and dyspnea 10%. One patient died from cytokine release syndrome, which is potentially serious complication. Neurological symptoms require prompt recognition and management. Conclusion: CAR T cell therapy is a promising treatment for refractory and relapsed hematological malignancies. The durable responses of CAR T cell therapy help integrate it in standard treatment protocols. Patients who are refractory to standard salvage chemotherapy or relapse after allo - HSCT have overall poor prognosis and can potentially achieve remission again with CAR T cell therapy. Disclosures McBride: Sanofi: Research Funding. Anwer:Seattle Genetics: Other: Advisory Board Participant; Incyte: Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document