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Analysis of mechanisms of CD19- relapse following novel low affinity CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) in a Phase I clinical study in paediatric ALL: CARPALL

ABSTRACT: Phase I clinical study (CARPALL, NCT02443831) utilizing a novel low affinity CD19CAR CAR in patients age <25 with high risk CD19+ ALL. Seventeen patients were enrolled and 14 received an infusion of CAR T cells. Among those achieving complete remission, 6 subsequently relapsed, 5 with CD19- disease, 1 with CD19+ disease. Whole exome sequencing of bone marrow DNA from patients with CD19- relapse showed mutations in the CD19 gene predicted to result in loss of surface expression in 4/5 patients. These mutations were not detectable prior to CAR T cell therapy. With a median follow-up of 14 months, 5/14 patients (36%) are alive and disease-free. Overall survival was 84% at 6 months and 63% at 12 months and by the criteria used in the ELIANA study, event-free survival was 67% and 46%. Using more stringent criteria where an event is defined as molecular relapse, molecular EFS was 55% and 29 %. The median duration of remission in responding patients was 7.4 months.

PROVIDER: EGAS00001003733 | EGA |

REPOSITORIES: EGA

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Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy

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2020-12-11 | GSE153697 | GEO

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2019-03-29 | PXD012833 | Pride

Regulatory programs of B-cell activation and germinal center reaction allow for B-ALL escape from CD19 CAR T-cell therapy

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Generation of clinical grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of B-cell malignancies

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2016-06-29 | E-GEOD-68003 | biostudies-arrayexpress

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CD19-CAR T cells undergo exhaustion epigenetic programming in patients with acute lymphoblastic leukemia

Project description:Zebley et al. show that CD8+ CD19-CAR T cells undergo genome-wide DNA methylation changes during an anti-tumor response in patients with B-cell acute lymphoblastic leukemia (ALL). Post-infusion CAR T cell differentiation involves acquisition of DNA methylation programs associated with effector function, repression of memory potential, and transition toward exhaustion.

2021-11-08 | GSE188325 | GEO

Allogenic and Autologous anti-CD7 CAR-T cell Therapies in Relapsed or Refractory T-Cell Malignancies

Project description:Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7- 14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.

2023-03-25 | GSE227828 | GEO

Tandem CAR and single CAR T cells have different fates and therapeutic potency

Project description:Chimeric antigen receptor T (CAR T) cells targeting CD19 have achieved breakthroughs in the treatment of haematological malignancies, but many clinical studies have also shown that a proportion of patients relapse after remission. In this study, we designed a series of tandem CARs (TanCARs) and found that TanCAR7 T cells retained relatively potent antitumour activity compared with single CAR T cell upon target antigen recognition. It may be associated with stable immunological synapse formation and rapid degranulation. Our transcriptional analysis underscores the potential of scFv domains binding to direct different T cell fates.

2020-06-30 | GSE134937 | GEO

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Project description:Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical grade tumor-redirected TSCM cells starting from naïve precursors. CD8+CD62L+CD45RA+ naïve T cells enriched by streptamer-based serial positive selection were activated by CD3/CD28 engagement in the presence of IL-7, IL-21 and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions allowed for the generation of CD19-CAR modified TSCM cells that were phenotypically, functionally and transcriptomically equivalent to their naturally occurring counterpart. Compared with T cell products currently under clinical investigation, CD19-CAR modified TSCM cells exhibit enhanced metabolic fitness, persistence and anti-tumor activity against systemic acute lymphoblastic leukemia xenografts. Based on these findings, we have initiated a phase 1 clinical study to evaluate the activity of CD19-CAR modified TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation.

2016-06-29 | GSE68003 | GEO

Single-cell gene expression in CD19-specific and GD2-specific CAR T cells on day 10 in culture.

Project description:Purpose: To compare cell states between CD19-28z and GD2-28z human CAR T cells on day 10 of cell culture. Methods: Human T cells were activated and lentivirally transduced with CD19-28z or GD2-28z CAR constructs and maintained in culture for 10 days, and then delivered to the Stanford Functional Genomics Facility for 3' single-cell RNA-sequencing on the 10X Genomics platform. Results: Comparison of transcription factor profiles by single cell RNA-seq analysis of CD8+ T cells expressing CD19-28z vs. GD2-28z CAR confirmed that the bZIP family members JUN, JUNB, JUND, and ATF4 were among the most differentially expressed and broadly connected in exhausted GD2-28z CAR T cells. Conclusions: This study provides insights into cell states that could explain the underlying differences between highly functional CD19-28z CAR T cells and exhaustion-prone GD2-28z CAR T cells on day 10 in culture.

2019-10-01 | GSE136874 | GEO

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