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VDJtargeting

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Cerrado

Engineering T cells and B cells for Immunotherapy using V D J recombination

T cell engineering has shown clinical success mainly in haematological cancers, but scaling up is challenging due to reliance on ex vivo manipulations. In addition, B cell engineering has not shown therapeutic efficacy to date. He... ver más

30/09/2022

TAU

1M€

Presupuesto del proyecto: 1M€

Líder del proyecto

TEL AVIV UNIVERSITY No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Ver 2 Participantes

Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2022-09-30

ERC-2017-STG: ERC Starting Grant

I+D

Cerrada hace 8 años

0% 100% 100%

Información adicional privada

No hay información privada compartida para este proyecto. Habla con el coordinador.

2 Participantes

TAU

1.50M€ | Lider

EUROCIR

872.18K€ | Participante

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Duración del proyecto: 60 meses Fecha Inicio: 2017-09-08
Fecha Fin: 2022-09-30

Líder del proyecto

TEL AVIV UNIVERSITY No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 1M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto T cell engineering has shown clinical success mainly in haematological cancers, but scaling up is challenging due to reliance on ex vivo manipulations. In addition, B cell engineering has not shown therapeutic efficacy to date. Here, we propose a novel immunotherapy approach, allowing safe and efficient engineering of B cells and T cells, both ex vivo and in vivo. We will use adeno associated vectors (AAV) to integrate chimeric antigen receptor (CAR) or T cell receptor (TCR) genes into loci coding TCR chains and to integrate antibody (Ab) genes into loci coding Ab chains. Previously, we used AAV facilitated gene targeting in vivo to ameliorate genetic diseases in mice. For lymphocytes we develop VDJ targeting: A promoterless receptor/Ab gene flanked by recognition signal sequences (RSS) will be inserted into the endogenous locus by the recombination activating gene (RAG) complex during V(D)J recombination. Only developing lymphocytes, expressing RAG, will incorporate the receptor/Ab gene, which will thus be expressed in potent naïve cells from the strong endogenous promoter. Targeted developing cells are subjected to negative selection, thus reducing risk of adverse autoimmunity. Lack of promoter reduces spurious expression and oncogenic risk upon rare off-target integration. Targeting endogenous loci may allow allelic exclusion. In B cells it may allow utilizing the endogenous constant region to express a B cell receptor and, upon activation, a secreted Ab. Activation may be accompanied by proliferation and affinity maturation, including somatic hypermutation and class switching, to allow a potent immune response, memory retention and diminished antigenic escape. Where controlled autoimmunity is desired, we will engineer B cells to inducibly secret an auto-Ab. We will demonstrate efficacy in cancer and autoimmune disease models implanted with lymphocytes that we engineered while ex vivo differentiated and in mice injected with vectors for in vivo VDJ targeting.

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