TCR gene Therapy: Prospects and Limitations
Mirjam H.M. Heemskerk, PhD
Leiden University Medical Center,
Department of Hematology,
Leiden, The Netherlands.
Time: 2009, Monday the 2nd of March, 14.30
Place: "Lille Auditorium", Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev
It would be nice to welcome you all
Per thor Straten
Director
Abstract
TCR gene Therapy: Prospects and Limitations
Mirjam H.M. Heemskerk, PhD
Dept. of Hematology, Leiden University Medical Center, The Netherlands
T cell receptor transfer to engineer tumor specific T cells is being explored as a strategy for adoptive immunotherapy. By retroviral introduction of T cell receptors (TCRs), large numbers of T cells with defined antigen specificity can be obtained. The in vivo efficacy of adoptively transferred TCR engineered T cells has been demonstrated in mouse studies and recently the first clinical trial with TCR engineered T cells was performed in melanoma patients. An attractive strategy to obtain large numbers of leukemia-reactive T cells is retroviral transfer of minor histocompatibility antigen (mHag) specific TCRs. TCR transfer of T cells specific for persistent viruses may enable these T cells to proliferate both after encounter with viral antigens as well as mHags, increasing the possibility of in vivo survival. We analyzed whether the dual specificity of the TCR transferred T cells after repetitive stimulation via either the introduced anti-leukemic TCR or the endogenous virus specific TCR was preserved. Our data imply the persistence of TCR transferred virus specific T cells with both anti-leukemic and anti-virus reactivity in vivo. In addition, we studied the potential drawback of TCR gene transfer, namely the formation of mixed TCR dimers. Chains of the introduced TCR can pair with the endogenous TCR chains, resulting in unknown specificities, and potentially in harmful reactivity against non targeted patient cells. We investigated whether TCR gene transfer leads to the generation of detrimental neoreactivities by creating T cells that expressed mixed TCR dimers. To be able to discriminate between the antigen specificity of the mixed TCR dimers and the introduced as well as the endogenous TCR, we transduced virus specific T cells. The transduced T cells were analyzed for newly acquired specificities against a large HLA-typed EBV-LCL panel covering almost all HLA class I and II molecules. We transduced several polyclonal virus specific T cell populations with the seven different antigen specific TCRs, and showed that in all T cell populations at least one of the seven TCR-transduced populations acquired new alloreactivities. To ascertain that the newly acquired alloreactivities were exerted by mixed TCR dimers, we introduced only TCR alpha or beta chains into antigen specific T cells, and demonstrated that introduced TCR chains acquire potentially dangerous reactivities, both class I and class II restricted. To limit the chance of generating self- or alloreactive T cells, TCRs may be constructed allowing selective pairing of the TCR alpha chain with the corresponding TCR beta chain. Alternatively, we propose to use virus specific T cells as host cells for TCR gene transfer. Since they consist of a restricted TCR repertoire, the number of different mixed TCR dimers formed will be limited. By introducing into these T cells as controls only the alpha or beta chain of the TCR of interest, the reactivity of these T cells and harmful reactivities of the mixed TCR dimers can be tested against different patient derived cell types.
Contact information
Phone: +31-71-5262271
Download invitation and abstract: seminar March 2, 2009 , MS Word, 94 kb
Last update: February 16, 2009
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