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Method for in situ inhibition of regulatory t cells

a technology of regulatory t cells and in situ inhibition, which is applied in the field of engineered t cells, can solve the problems of inability to provide prolonged expansion and anti-tumor activity in vivo, hinder the induction of an immune response against cancer, and systemic administration of inhibitors directed against cancer

Inactive Publication Date: 2018-07-26
CELLECTIS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]By “inhibitor of regulatory T-cells” is meant a molecule or precursor of said molecule secreted by the T-cells and which allow T-cells to escape the down regulation activity exercised by the regulatory T-cells thereon. In general, such inhibitor of regulatory T-cell activity has the effect of reducing FoxP3 transcriptional activity in said cells.

Problems solved by technology

First generation CARs have been shown to successfully redirect T cell cytotoxicity, however, they failed to provide prolonged expansion and anti-tumor activity in vivo.
Because of their immune regulatory function, the presence of regulatory T-cells at a cancer or infection site may hinder the induction of an immune response against cancer or infectious pathogens (Aandahl E. M. et al.
Dysfunction of FOXP3 is however associated with serious autoimmune disorders such as systemic lupus erythematosus or X-lined IPEX syndrome, such that systemic administration of inhibitors directed against, e.g, FoxP3, is currently not deemed a suitable option in immune therapy.
The release of such inhibitors in the blood stream or even locally may lead to toxic effects by unleashing autoimmune reactions in organs not affected by the primary disease.

Method used

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  • Method for in situ inhibition of regulatory t cells
  • Method for in situ inhibition of regulatory t cells
  • Method for in situ inhibition of regulatory t cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

bition Test

[0174]Human primary T cells were activated with anti-CD3 / CD28 beads. At day 3, they were transfected with a messenger RNA coding for foxp3 inhibitory peptide p60 (SEQ ID NO: 1) fused to a mutated Chicken lysozyme signal peptide (3R CLSP—SEQ ID NO: 12) (alternative SEQ ID NO. 13 to 17 displayed in Table 1 may also be used). At day four, the transfected T cells were mixed with human regulatory T cells (Treg) and their proliferation was followed according to the assay described by Collison, L. W et al. (In vitro Treg suppression assays, Methods Mol. Biol., 2011, 707:21-37). This assay shows that the T-cells transfected with the p60 messenger RNAs, proliferate faster than those transfected with the mock RNA (scrambled p60—SEQ ID NO: 9), upon contact with the regulatory T cells. It resulted that p60 peptide expression allowed T cells to resist Treg inhibition.

example 2

Activity Test

[0175]Human primary T cells is activated with anti-CD3 / CD28 beads. At day 3, the activated T cells are transduced with a lentiviral vector encoding the chimeric antigen receptor anti-CD19 set forth as SEQ ID NO: 5 along with the Foxp3 inhibitory peptide p60 (SEQ ID NO: 1) fused to a mutated Chicken lysozyme signal peptide (3R CLSP—SEQ ID NO: 12) (alternative SEQ ID NO. 13 to 17 displayed in Table 1 may also be used). At day 5, the cytotoxic activity of the transduced T cells are assayed according to the method described by Yang, Z. Z. et al. (Attenuation of CD8(+) T cell function by CD4(+)CD25(+)regulatory T cells in B-cell non-Hodgkin's lymphoma, 2006, Cancer Res.) against a relevant target cell line in the presence or absence of Tregs.

The assay shows that regulatory T cells usually have an inhibitory effect on the cytotoxic capacity of CAR+ T cells, whereas p60 peptide expression by the T cell restores cytotoxic activity by lifting this inhibition.

TABLE 1Sequences use...

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Abstract

The present invention pertains to engineered T-cells, method for their preparation and their use as medicament, particularly for immunotherapy. The engineered T-cells of the invention are designed to express both a Chimeric Antigen Receptor (CAR) directed against at least one antigen expressed at the surface of a malignant or infected cell, and a secreted inhibitor of regulatory T-cells (Treg). Preferably, such secreted inhibitor is a peptide inhibitor of forkhead / winged helix transcription factor 3 (FoxP3), a specific factor involved into the differentiation of T-cells into regulatory T-cells. The engineered T-cells of the invention direct their immune activity towards specific malignant or infected cells, while at the same time will prevent neighbouring regulatory T-cells from modulating the immune response. The invention opens the way to standard and affordable adoptive immunotherapy strategies, especially for treating or preventing cancer, and bacterial or viral infections.

Description

FIELD OF THE INVENTION[0001]The present invention pertains to engineered T-cells, method for their preparation and their use as medicament, particularly for immunotherapy. The engineered T-cells of the invention are designed to express locally a secreted inhibitor of regulatory T-cells (Treg). Preferably, such secreted inhibitor is a peptide inhibitor of forkhead / winged helix transcription factor 3 (FoxP3), a specific factor involved into the differentiation of T-cells into regulatory T-cells. Said T-cells are preferably endowed with Chimeric Antigen Receptors (CAR) directed against at least one antigen expressed at the surface of a malignant or infected cell. The engineered T-cells of the invention thereby direct their immune activity towards specific malignant or infected cells, while at the same time prevent neighbouring regulatory T-cells from modulating the immune response. The invention opens the way to standard and affordable adoptive immunotherapy strategies, especially for ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N5/0783C07K14/715C07K16/28A61K35/17C12N9/16C07K14/47C07K14/725
CPCC12N5/0638C07K14/7155C07K16/2803C07K16/2866C12N2501/60C07K2317/622A61K35/17C12N9/16C07K14/4703C12N2510/00C12N5/0636C07K14/7051C07K2319/74A61P31/12A61P35/00A61P35/02
Inventor POIROT, LAURENTDUCHATEAU, PHILIPPE
Owner CELLECTIS SA
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