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T cell which expresses a gamma-delta t cell receptor (TCR) and a chimeric antigen receptor (CAR)

a technology of chimeric antigen receptor and t cell, which is applied in the direction of specific cell targeting, fusion of specific cells, antibacterial agents, etc., can solve the problems of deeper problem and potential ‘on target-off tumour toxicity’, and achieve the effect of reducing unwanted ‘on target-off tumour’ effects

Inactive Publication Date: 2018-05-10
UCL BUSINESS PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention relates to a type of immune cell called γδ T cells that can target tumors without causing harmful side effects. These cells are specifically designed to recognize and attack cancer cells that express low levels of a specific protein. The unique design of these cells ensures that they are only activated when a danger signal is present, reducing the risk of accidental damage to healthy cells. This approach enhances the safety and effectiveness of γδ T cells as a potential cancer treatment.

Problems solved by technology

A limitation of this technology is potential ‘on target-off tumour toxicity’.
This problem is more profound in solid tumours where there is a dearth of highly selective targets.

Method used

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  • T cell which expresses a gamma-delta t cell receptor (TCR) and a chimeric antigen receptor (CAR)
  • T cell which expresses a gamma-delta t cell receptor (TCR) and a chimeric antigen receptor (CAR)
  • T cell which expresses a gamma-delta t cell receptor (TCR) and a chimeric antigen receptor (CAR)

Examples

Experimental program
Comparison scheme
Effect test

example 1

n of γδ T Cells Expressing a Co-Stimulatory CAR

[0187]PBMCs were extracted from the blood of healthy donors using Ficoll density gradient separation. They were cultured in RPMI 1640 medium supplemented with 10% FCS, 1% penicillin / streptomycin, 100u / ml human IL-2 and 5 μM zoledronic acid for 5 days.

[0188]After 5 days they were transduced with retrovirus containing the CAR construct fused to RQR8, which acts as a marker gene and also provides a Rituximab (αCD20) sensitive suicide gene.

[0189]The illustrative CAR described herein includes aGD2-specific scFv, a linker based on the Fc portion of IgG1, a transmembrane domain derived from CD28 and the endodomain of DAP10 (see FIG. 10).

[0190]A second illustrative CAR includes a CD33-specific scFv, a linker based on the Fc portion of IgG1, a transmembrane domain derived from CD28 and the endodomain of DAP10 (see FIG. 11).

[0191]Co-expression of an anti-GD2-Fc-DAP10 CAR with the endogenous TCR of a γδ T cell was demonstrated (FIG. 4).

example 2

f GD2+ Cell Lines LAN1 and TC71 by Vδ2 γδT Cells Transduced with the aGD2-Fc-DAP10 CAR

[0192]Both the LAN1 and TC71 cells lines are known to express GD2.

[0193]Significant killing of GD2+ neuroblastoma cell line LAN1 was only seen when CAR transduced cells were used and not when non-transduced (NT) Vδ2 cells were used as effectors (FIG. 5A).

[0194]There was an additive effect against the GD2+ Ewing sarcoma cell line TC71 when the aGD2-Fc-DAP10 CAR was used in combination with 24h zoledronic acid treatment (FIG. 5B).

[0195]Addition of the CAR to αβT cells, which lack the signal 1 provided by the γδTCR in response to cellular stress, had no effect on cytotoxicity, unlike the effect of the CAR in Vδ2+γδT cells (FIG. 5C). This indicates that the CAR signal alone is insufficient for T-cell activation.

[0196]Expression of the aGD2-Fc-DAP10 CAR in γδ T cells did not result in GD2-specific killing of GD2 negative SK-N-SH cells (FIG. 6).

example 3

ion of CAR Expression Following Prolonged Co-Culture and GD2 Specific Expansion

[0197]Co-culture was started 24 days after transduction and serial analyses of cells for the presence of CAR and TCRVδ2 were taken in the presence of irradiated GD2+(LAN1) and GD2− (SK-N-SH) neuroblastoma cells (FIG. 7A).

[0198]The expansion of aGD2-Fc-DAP10 transduced Vδ2+ cells was only seen in the presence of irradiated GD2+ target cells (FIG. 7B).

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Abstract

The present invention provides a T cell which expresses a gamma-delta T cell receptor (TCR) and a chimeric antigen receptor (CAR), wherein the CAR comprises: an antigen binding domain; a transmembrane domain; and a co-stimulatory intracellular signalling domain; wherein the intracellular signalling domain provides a co-stimulatory signal to the T cell following binding of antigen to the antigen binding domain.

Description

FIELD OF THE INVENTION[0001]The present invention relates to immunotherapeutic T cells. In particular, the invention provides immunotherapeutic gamma-delta T cells comprising a chimeric antigen receptor (CAR).BACKGROUND TO THE INVENTION[0002]Chimeric antigen receptors (CARs) developed for cancer immunotherapy combine an extracellular antigen recognition domain with signalling domains specific for effector cells within a single molecule. The most common CAR system involves an antigen recognition domain derived from a monoclonal antibody fused to signalling domains which provide activating signals for T cells.[0003]Typically, the signalling domains of a CAR provides cytotoxicity, proliferation and survival signals to activate the effector cell upon binding of antigen to the antigen recognition domain (Signals 1 and 2).[0004]A limitation of this technology is potential ‘on target-off tumour toxicity’. This toxicity is caused by the recognition of low levels of a cancer-associated antig...

Claims

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Application Information

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IPC IPC(8): A61K35/17C07K14/725C12N5/0783A61P31/04A61P31/12A61P35/00
CPCA61K35/17C07K14/7051C12N5/0638A61P31/04A61P31/12A61P35/00C12N2501/599C12N2510/00C12N5/0636C07K2319/33C07K2319/02C07K2319/00A61K39/464402A61K39/4611A61K2239/29A61K2239/28A61K39/464471A61K39/4631
Inventor ANDERSON, JOHNFISHER, JONATHANPULE, MARTINGUSTAFSSON, KENTH
Owner UCL BUSINESS PLC
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