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

Objective

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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Host institution

TEL AVIV UNIVERSITY

Address

Ramat Aviv
69978 Tel Aviv

Israel

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 496 875

Beneficiaries (1)

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TEL AVIV UNIVERSITY

Israel

EU Contribution

€ 1 496 875

Project information

Grant agreement ID: 759296

Status

Ongoing project

  • Start date

    1 October 2017

  • End date

    30 September 2022

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 496 875

  • EU contribution

    € 1 496 875

Hosted by:

TEL AVIV UNIVERSITY

Israel