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P72. Transgenic expression of a chimeric signaling receptor to facilitate T cell costimulation in the tumour environment
  1. R Schlenker1,
  2. M Leisegang2,
  3. W Uckert2 and
  4. E Noessner1
  1. Aff1 grid.4567.00000 0004 0483 2525Helmholtz Zentrum MuenchenInstitute of Molecular Immunology Munich Germany
  2. Aff2 grid.419491.00000 0001 1014 0849Max Delbrueck Center for Molecular MedicineMolecular Cell Biology and Gene Therapy Berlin Germany

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Meeting abstracts

Tumour therapy with T cell receptor (TCR) engineered T cells is reported to induce clinical responses but shortcomings regarding poor in vivo persistence and loss of function in the tumour milieu have been observed. Providing costimulation to adoptively transferred T cells may improve these shortcomings. However, human T effector cells are largely CD28 negative and epithelial tumours do not express CD80 or CD86. Therefore, costimulation of human CD8 T effector cells cannot be triggered via the classical way of CD28 ligation. We propose to facilitate costimulation of CD8 T effector cells in the tumour milieu through retroviral engineering of T cells with a chimeric signaling molecule (CSM). This CSM is consisted of an intracellular costimulatory domain fused to an extracellular domain with binding capacity for a ligand expressed by a great variety of tumours.

Human activated PBL retrovirally transduced to express the CSM exhibited a survival advantage during in vitro expansion according to clinical protocol. The effect of the chimeric molecule on T cell function was analyzed using T cells expressing a tumour antigen specific TCR alone or in combination with the CSM. Transduced T cells were stimulated with target cells positive or negative for the CSM ligand (CSM-L). CSM expressing T cells responded better to CSM-L+ target cells showing higher phosphorylation of ERK and RPS6 compared to stimulation with CSM-L- target cells. CSM- T cells responded equally to both target cells. Accordingly, CSM+ but not CSM- T cells secreted more IL-2 and IFN-γ upon co-culture with CSM-L+ target cells. In summary, transduction of PBL with the chimeric signaling molecule supported T cell survival and TCR induced signaling leading to enhanced T cell function.