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

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 fr