The Study of Autologous T Cells Expressing CD19 Chimeric Antigen Receptors Treatment of Minimal Residual Disease(MRD) of B Cell Malignancies and Then Autologous Hematopoietic Stem Cell Transplantation(Auto-HSCT)

The clinical study of CART19 Cells treatment for MRD of B Cell Malignancies and then auto-HSCT

Start Date01 Jun 2018

Sponsor / Collaborator

Shenzhen Second People's Hospital

NCT03146533 / Unknown statusPhase 1/2IIT

Phase I/II Study of CD19 CART Cells for Patients With Relapse and Refractory CD19+ B-cell Lymphoma.

This is a clinical study to observe the maximum tolerated dose (MTD) and the safety and feasibility of chimeric antigen receptor 19 (CD19 CART) cells in relapsed and refractory patients with CD19+ B cell lymphoma.

Start Date01 May 2017

Sponsor / Collaborator

Shenzhen Second People's Hospital

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100 Clinical Results associated with CART19 Cells(Shenzhen Second People's Hospital)

100 Translational Medicine associated with CART19 Cells(Shenzhen Second People's Hospital)

100 Patents (Medical) associated with CART19 Cells(Shenzhen Second People's Hospital)

Literatures (Medical) associated with CART19 Cells(Shenzhen Second People's Hospital)

08 Mar 2022·JNCI: Journal of the National Cancer InstituteQ1 · MEDICINE

Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

Q1 · MEDICINE

Article

Author: Castro de Moura, Manuel ; Delgado, Julio ; Quintarelli, Concetta ; Esteller, Manel ; Avigdor, Abraham ; Juan, Manel ; Ortiz-Maldonado, Valentín ; Itzhaki, Orit ; Garcia-Prieto, Carlos A ; Fernandez, Agustin F ; Davalos, Veronica ; Sinibaldi, Matilde ; Urbano-Ispizua, Álvaro ; Besser, Michal J ; Jacoby, Elad ; Ferrer, Gerardo ; Urdinguio, Rocio G ; Meir, Amilia ; Fraga, Mario F ; del Bufalo, Francesca ; Villanueva, Lorea ; Soler, Marta ; Bar, Diana ; González-Navarro, Europa Azucena ; Locatelli, Franco ; Bueno-Costa, Alberto

AbstractBackgroundChimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course.MethodsWe recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided.ResultsWe identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02).ConclusionsWe show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.

01 Jun 2020·JACC: CardioOncologyQ2 · MEDICINE

Cardiovascular Effects of CAR T Cell Therapy

Q2 · MEDICINE

ArticleOA

Author: Frey, Noelle V ; Lefebvre, Bénédicte ; Kang, Yu ; Scherrer-Crosbie, Marielle ; Carver, Joseph R ; Smith, Amanda M

BACKGROUNDAnti-CD19 chimeric antigen receptor (CAR) T cell (CART19) therapy holds great promise in the treatment of hematological malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CART19 therapy.OBJECTIVESWe aimed to define the occurrence of major cardiovascular events (MACE) in adult patients treated with CART19 cells and assess the relationships between clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes.METHODSBaseline clinical, laboratory and echocardiographic parameters were collected in 145 adult patients undergoing CART19 cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis.RESULTSThirty-one patients had MACE (41 events) at a median time of 11 days (Q1-Q3:6-151 days) after CART19 cell infusion. The median follow-up period was 456 days (Q1-Q3: 128-1214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (Q1-Q3: 1-8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53% respectively. The KM estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and Grade 3 or 4 CRS were independently associated with MACE.CONCLUSIONPatients treated with CART19 are at an increased risk of MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.

01 Nov 2019·Current Opinion in HematologyQ3 · MEDICINE

Mechanisms of failure of chimeric antigen receptor T-cell therapy

Q3 · MEDICINE

Review

Author: Li, Xiaoqing ; Chen, Weihong

Purpose of reviewAlthough chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate.Recent findingsWe firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive receptors, PD-1, CTLA4, TIGIT, LAG-3, CD244, CD160, TIM3, which might be solved by some external pharmacological intervention methods [for instance, the use of FC (Fludarabine, Cyclophosphamide) lymphodepletion regimen, lenalidomide, PD-1 inhibitor, ibrutinib and humanized CD19-CART cells. Secondly, mechanism of CD19 relapse can be attributed to the preexisting of CD19- subclone, the loss or alternative RNA splicing on exon 2 of chromosome 16 on which CD19 gene is located, B-cell transcript factors – paired-box 5 (PAX5) and early B-cell factor 1 (EBF1) are down-regulated to cause lineage-switch from lymphoid to myeloid.SummaryAlthough different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system.Video abstractAlthough Chimeric Antigen Receptor T (CART) cell therapy is best recognized for its antitumor effect in Relapsed/Refractory B-cell hematological cancers, it still shows a high relapse rate. We review mechanisms of failure of CART therapy. http://links.lww.com/COH/A18.

100 Deals associated with CART19 Cells(Shenzhen Second People's Hospital)

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Leukemia	Phase 1	CN	Shenzhen Second People's Hospital	01 Jun 2018
B-Cell Lymphoma	Phase 1	CN	Shenzhen Second People's Hospital	01 Jun 2018
B-Cell Malignant Neoplasm	Phase 1	CN	Shenzhen Second People's Hospital	01 Jun 2018

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