Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis

Abstract

Chimeric antigen receptor (CAR) modified T cells targeted CD19 showed promising clinical outcomes in treatment of B cell malignances such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) and other indolent lymphomas. However, the clinical benefit varies tremendously among different trials. This meta-analysis investigated the efficacy (response rates and survival time) of CD19-CAR T cells in refractory B cell malignances in Phase I clinical trials. We searched publications between 1991 and 2014 from PubMed and Web of Science. Pooled response rates were calculated using random-effects models. Heterogeneity was investigated by subgroup analysis and meta-regression. Fourteen clinical trials including 119 patients were eligible for response rate evaluation, 62 patients in 12 clinical trials were eligible for progression-free survival analysis. The overall pooled response rate of CD19-CAR T cells was 73% (95% confidence interval [CI]: 46-94%). Significant heterogeneity across estimates of response rates was observed (p < 0.001, I2=88.3%). ALL patients have higher response rate (93%, 95% CI: 65-100%) than CLL (62%, 95% CI: 27-93%) and lymphoma patients (36%, 95% CI: 1-83%). Meta-regression analysis identified lymphodepletion and no IL-2 administrated T cells as two key factors associated with better clinical response. Lymphodepletion and higher infused CAR T cell number were associated with better prognosis. In conclusion, this meta-analysis showed a high clinical response rate of CD19-CAR T cell-based immunotherapy in treatment of refractory B cell malignancies. Lymphodepletion and increasing number of infused CD19-CAR T cells have positive correlations with the clinical efficiency, on the contrary, IL-2 administration to T cells is not recommended.

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

“…The development of highly sensitive MRD techniques standardized for all patients, genetic profiling and identification of other predicting factors are required for better-individualized treatments. Emerging therapies like bi-specific antibodies 23,24 and CAR T cells 25,26 will profoundly modify the landscape of resistant ALLs, but these targeted therapies are still lacking for childhood AML.…”

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

“…CAR T cells with 4-1BB costimulation persisted for more than 6 months in the blood of most patients, whereas CD28 CAR T cells were mostly undetectable beyond 3 months [23]. CD28 CAR T cells show a reprogramming toward CD45RO + CCR7 − effector memory maturation while 4-1BB CAR T cells predominantly show a CD45RO + CCR7…”

“…However, a recent meta-analysis of CD19 CAR T cell trials confirmed lymphodepletion and CAR T cell dose as key factors for successful treatment, while IL-2 co-administration is not recommended [23]. Most patients with 4-1BB-CD3ζ CAR T cell therapy did not receive further treatment; patients treated with CD28-CD3ζ CAR T cells frequently underwent subsequent allogeneic stem cell transplantation; the clinical decision is partly based on the observation that 4-1BB-CD3ζ CAR T cells persist over years while CD28-CD3ζ CAR T cells persist only for a few months.…”

CAR-T Cells and Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

“…The median interval of PFS was 7.0 months. Higher numbers of infused CAR-T cells and lymphodepletion were associated with a better prognosis [36].…”

“…Altogether, approximately 40-90% of patients with refractory/relapsed ALL can reach complete molecular or cellular remission through treatment with CAR-T cells; however, because CAR-T cells survived in the body for only a short time, some of the patients relapsed quickly, which may be related to the different in the costimulatory molecular or vectors used, or variation in the disease burden across treated individuals [36,37] (Table 1). Thus, other treatments should be performed to improve outcomes in the treatment of refractory/relapsed ALL.…”