Kurzfassung

The Graft-versus-Leukaemia/Tumour effect (GvT) is the mainstay of immunotherapy of radiation- and chemotherapy-resistant malignant diseases by allogeneic stem cell transplantation (ASCT). Despite improved outcomes, ineffective GvT resulting in disease relapse still is a major cause of death following ASCT. From current understanding, antigen-specific cytotoxic T cells (CTL) and natural killer (NK) cells inducing tumour cell apoptosis are the major effectors of GvT. To understand the mechanism...The Graft-versus-Leukaemia/Tumour effect (GvT) is the mainstay of immunotherapy of radiation- and chemotherapy-resistant malignant diseases by allogeneic stem cell transplantation (ASCT). Despite improved outcomes, ineffective GvT resulting in disease relapse still is a major cause of death following ASCT. From current understanding, antigen-specific cytotoxic T cells (CTL) and natural killer (NK) cells inducing tumour cell apoptosis are the major effectors of GvT. To understand the mechanism underlying resistance versus susceptibility of malignant cells in response to cytolytic immune effectors, we have established experimental systems for the study of CTL- or NK cell-mediated tumour cell eradication in vitro and in vivo. Using oncogene-expressing transgenic murine embryonic fibroblasts (MEF) as tumour model, we have analysed the pathways of CTL-induced tumour cell apoptosis by retrovirus-based expression of several anti-apoptotic genes. We found that the expression of BCL-XL as well as the expression of dominant-negative mutants of FADD or caspase-9 conferred resistance against CTL-mediated tumour cell lysis in vitro. Moreover, BCL-XL-expressing MEF grown in NOD/SCID mice proved to be protected against rejection by adoptively transplanted CTL in vivo. These experimental systems provide the basis for the investigational plan of the present grant proposal.
The first part of the project is dedicated to a systematic study of the impact of a set of resistance genes on the anti-tumoural efficacy of adoptively transplanted CTL, including murine CTL as well as tumour-specific, T cell receptor (TCR)-transduced human T cells, and NK cells. We will primarily focus on receptors and kinases, such as Her2/Neu, ALK, BCR-ABL, AKT, or RAF1, which are frequently deregulated in human malignancies. In the second part of the project, pharmacological strategies to modulate cancer cell resistance against adoptively transplanted CTL or NK cells will be explored. This includes “proof-of-concept” studies using conditionally expressed resistance genes, as well as small drugs, such as imatinib and additional kinase inhibitors.
In the light of the increasing application of ASCT in solid tumour and additional patient populations with high probability of disease relapse, the study of resistance mechanisms and their therapeutic circumvention will become a matter of growing relevance to the field. Results from our proposed preclinical investigations will set the stage for the design of innovative clinical trials of ASCT in patients with increased risk for disease relapse.

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