Delving into the Latest Updates on CART19 Cells(Shenzhen Second People's Hospital) with Synapse

Overview

Basic Info

Drug Type

Autologous CAR-T

Synonyms-

Target

CD19

Mechanism

CD19 inhibitors(B-lymphocyte antigen CD19 inhibitors), Cell replacements, Gene transference

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

B-Cell LeukemiaB-Cell Malignant NeoplasmCD19 Expressing Malignancies+ [1]

Originator Organization

Shenzhen Second People's Hospital

Active Organization-

Inactive Organization

Shenzhen Second People's Hospital

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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

Abstract:

Background:

Chimeric 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.

Methods:

We 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.

Results:

We 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).

Conclusions:

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

BACKGROUND:

Anti-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.

OBJECTIVES:

We 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.

METHODS:

Baseline 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.

RESULTS:

Thirty-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.

CONCLUSION:

Patients 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 review:

Although 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 findings:

We 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.

Summary:

Although different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system.

Video abstract:

Although 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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R&D Status

10 top R&D records.

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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 Malignant Neoplasm	Phase 1	CN	Shenzhen Second People's Hospital	01 Jun 2018
CD19 Expressing Malignancies	Phase 1	CN	Shenzhen Second People's Hospital	01 Jun 2018
Residual Neoplasm	Phase 1	CN	Shenzhen Second People's Hospital	01 Jun 2018