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Methods of making chimeric antigen receptor-expressing cells

A technology of chimeric antigen receptors and cells, applied in receptors/cell surface antigens/cell surface determinants, biochemical equipment and methods, animal cells, etc., can solve problems such as the impact of therapeutic efficacy in the manufacturing process

Pending Publication Date: 2020-08-21
NOVARTIS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, such impurities from the starting materials can negatively affect the manufacturing process, final product quality and therapeutic efficacy of said product

Method used

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  • Methods of making chimeric antigen receptor-expressing cells
  • Methods of making chimeric antigen receptor-expressing cells
  • Methods of making chimeric antigen receptor-expressing cells

Examples

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example

[1241] The present invention is described in further detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and should not be intended to be limiting unless otherwise indicated. Accordingly, the present invention should in no way be construed as limited to the following examples, but rather should be construed to cover any and all variations which become apparent as a result of the teachings provided herein.

example 1

[1242] Example 1: Glycolytic metabolism of CTL019 cells

[1243] Metabolic changes were evaluated in CAR T cell samples from 41 patients with advanced, heavily pretreated, high-risk CLL who received at least one dose of CD19-directed CAR T cells.

[1244] result

[1245] CAR T cells from patients with partial response (PR) or non-response (NR) demonstrated a glycolytic gene signature. CAR-specific stimulation of retroactive cell infusion product samples increased glycolysis and glucose analog uptake ( figure 2 ), which provides evidence that T cells in CLL patients can be metabolically modulated by linking synthetic CARs. CAR-stimulated T cells from PR / NR patients exhibited higher glucose analog uptake relative to CR / PRTD (partial response, transfusion-dependent) patients ( image 3 ), which is consistent with the transcriptional profile of these cells ( Figures 1A to 1D ). Furthermore, blockade of glycolysis using 2-deoxy-D-glucose (2-DG) reduced effector differentiatio...

example 2

[1257] Example 2: STAT3 Pathway Activation in CD19 Expressing Chimeric Antigen Receptor (CAR) T Cells

[1258] CAR T cell samples from patients with advanced, heavily pretreated, high-risk CLL who received at least one dose of CD19-directed CAR T cells were evaluated for STAT3 pathway activation.

[1259] Materials and methods

[1260] patient sample

[1261] Samples were obtained from CLL patients enrolled in the Penn Institutional Review Board (IRB)-approved clinical trial of single-agent CTL019 therapy. All participants provided written informed consent in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.

[1262] These studies are registered with ClinicalTrials.gov (ID numbers: NCT01029366, NCT01747486, and NCT02640209).

[1263] Vector production, T cell isolation and CTL019 cell generation

[1264] A lentiviral vector (GeMCRIS 377 0607-793) containing a transgene encoding a CD19-sp...

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Abstract

The disclosure provides methods of making CAR-expressing immune effector cells (e.g., T cells, or NK cells), and compositions and reaction mixtures comprising the same. The disclosure further providesmethods of using said CAR-expressing immune effector cells.

Description

technical field [0001] The present invention generally relates to methods of making immune effector cells (e.g., T cells or NK cells) expressing chimeric antigen receptors (CARs), and compositions and reactions comprising such immune effector cells expressing chimeric antigen receptors mixture. Background technique [0002] Adoptive cell transfer (ACT) therapy using autologous T cells, especially T cells transduced with a chimeric antigen receptor (CAR), has shown promise in several hematologic cancer trials. [0003] Currently, the manufacture of autologous genetically modified T cells is a complex process that begins with patient material (e.g., from leukapheresis) from which CAR-expressing cells are derived. Engineered therapeutic T cells. Patient leukapheresis material can have high levels of variability in cellular composition. The cellular composition of the starting material can vary widely between different patients and within a disease state. Cellular impurities...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/725C12N5/0783
CPCC07K14/7051C12N5/0636A61K2239/48A61K39/4631A61K39/4611A61K39/464412C12N2501/2306C12N2501/231C12N2501/2317C12N2501/2323A61K39/4613A61P35/00A61K2121/00A61K2300/00C07K14/70503C12N2501/2311C12N2501/2319C12N2501/2322C12N2501/2324C12N2501/2326C12N2501/2328C12Q1/54G01N33/5091G01N2800/52
Inventor J·A·弗拉伊塔J·J·梅勒霍斯特E·奥兰多R·奥康纳C·H·琼
Owner NOVARTIS AG