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Adoptive T-Zell-Therapie des Rhabdomyosarkoms

Adoptive T-cell therapy of rhabdomyosarcoma
: Simon-Keller, K.; Paschen, A.; Eichmüller, S.; Gattenlöhner, S.; Barth, S.; Koscielniak, E.; Leuschner, I.; Stöbel, P.; Hombach, A.; Abken, H.; Marx, A.


Der Pathologe 31 (2010), Suppl.2, S.215-220
ISSN: 0172-8113
ISSN: 1432-1963
Fraunhofer IME ()

Aims. To improve survival of patients with advanced rhabdomyosarcomas (RMS), we aimed to adoptively transfer T-cells with redirected specificity for the fetal acetylcholine receptor (AChR), an RMS-specific cell surface antigen.Methods. A "second generation" chimeric antigen receptor (CAR) with a combined CD28-CD3 signaling domain was derived from our previously described chimeric antigen receptor composed of an extracellular human anti-fAChR antibody fragment, an Fc hinge region, and the intracellular T-cell receptor zeta chain. Lymphocytes from the peripheral blood were modified by retroviral transduction and monitored by FACS analysis. Cytotoxicity of modified T-cells towards RMS cells was recorded by MTT-based viability tests; expression of co-stimulatory molecules and anti-apoptotic genes was studied by FACS and qRT-PCR analysis.Results. Co-stimulatory molecules were expressed in low levels on RMS cells giving the rationale to generate a CD28-CD3 signalling CAR (chi meric antigen receptor) for redirecting T-cells. T-cells were successfully engineered with the "second generation" AChR-specific chimeric antigen receptor. Despite of high CAR expression engineered T-cells showed low killing efficiency towards RMS compared to redirected killing of CD20+ lymphoma or CEA-expressing adenocarcinoma cell lines when redirected by CD20- and/or CEA-specific CAR.Conclusions. Data suggest that RMS cells exhibit resistance to a T-cell attack redirected by a fAChR-specific CAR. Inhibition of anti-apoptotic pathways in those cells may improve sensitivity to conventional as well as T-cell-based therapeutics.