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ABSTRACT: The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated Ag by T cell-based immunotherapeutical strategies such as cancer vaccines and adoptive T cell transfer. The prerequisite for a successful T cell-based therapy is the induction of T cells capable of recognizing the HER2-expressing tumor cells. In this study, we generated human cytotoxic T cell clones directed against the HER2(369-377) epitope known to be naturally presented with HLA-A*0201. Those HER2-reactive CTLs, which were also tumor lytic, exhibited a similar lysis pattern dividing the targets in lysable and nonlysable tumor cells. Several HER2-expressing tumor cells became susceptible to CTL-mediated lysis after IFN-gamma treatment and, in parallel, up-regulated molecules of the Ag-presenting machinery, indicating that the tumor itself also contributes to the success of CTL-mediated killing. Some of the HER2(369-377)-reactive T cells specifically cross-reacted with the corresponding peptides derived from the family members HER3 and/or HER4 due to a high sequence homology. The epitopes HER3(356-364) and HER4(361-369) were endogenously processed and contributed to the susceptibility of cell lysis by HER cross-reacting CTLs. The principle of "double" or "triple targeting" the HER Ags by cross-reacting T cells will impact the further development of T cell-based therapies.
The Journal of Immunology 06/2008; 180(12):8135-45. · 5.79 Impact Factor
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ABSTRACT: The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated antigen by immunotherapeutical approaches based on HER2-directed monoclonal antibodies and cancer vaccines. We describe the adoptive transfer of autologous HER2-specific T-lymphocyte clones to a patient with metastatic HER2-overexpressing breast cancer. The HLA/multimer-based monitoring of the transferred T lymphocytes revealed that the T cells rapidly disappeared from the peripheral blood. The imaging studies indicated that the T cells accumulated in the bone marrow (BM) and migrated to the liver, but were unable to penetrate into the solid metastases. The disseminated tumor cells in the BM disappeared after the completion of adoptive T-cell therapy. This study suggests the therapeutic potential for HER2-specific T cells for eliminating disseminated HER2-positive tumor cells and proposes the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.
Cancer Immunology and Immunotherapy 03/2008; 57(2):271-80. · 3.70 Impact Factor
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Julia Neudorfer,
Burkhard Schmidt,
Katharina M Huster,
Florian Anderl,
Matthias Schiemann,
Gerd Holzapfel,
Thomas Schmidt,
Lothar Germeroth,
Hermann Wagner,
Christian Peschel,
Dirk H Busch,
Helga Bernhard
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ABSTRACT: The development of MHC/peptide multimers has facilitated the visualization and purification of antigen-specific T cells. However, the persistence of multimers leads to prolonged T cell receptor signaling and subsequently to altered T-cell function. We have recently developed a new type of MHC/peptide multimers, which can be dissociated from the T cell. Herein, we have generated and tested for the first time reversible HLA/peptide multimers, termed Streptamers, for the isolation of human T cells. The Streptamer technique demonstrates the specificity and sensitivity of conventional HLA/peptide tetramers with regards to the sorting of human T lymphocytes. This is shown for T cells directed against immunogenic peptides derived from viral and tumor-associated antigens. We show that antigen-specific cytotoxic T cells remain functionally active following Streptamer dissociation, whereas lytic function and proliferation of the T cells is impaired in the presence of conventional tetramers. These novel HLA/peptide Streptamer reagents allow the isolation of antigen-specific T cells with preserved function and, therefore, facilitate the development of adoptive T cell transfer regimens for the treatment of patients with cancer or infectious diseases.
Journal of Immunological Methods 04/2007; 320(1-2):119-31. · 2.20 Impact Factor
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Daniel Sommermeyer, Julia Neudorfer,
Monika Weinhold,
Matthias Leisegang,
Boris Engels,
Elfriede Noessner,
Mirjam H M Heemskerk,
Jehad Charo,
Dolores J Schendel,
Thomas Blankenstein,
Helga Bernhard,
Wolfgang Uckert
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ABSTRACT: T cell receptor (TCR) gene transfer is a convenient method to produce antigen-specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong--in terms of cell surface expression--and replace weak TCR on the cell surface, resulting in exchange of antigen specificity. Two strong TCR are co-expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCRalpha/beta combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering.
European Journal of Immunology 12/2006; 36(11):3052-9. · 5.10 Impact Factor
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ABSTRACT: Adoptive T-cell therapy is based on specificity and efficacy, two essentials known to be necessary for successful cancer therapy.
Tumor-reactive T-cells potentially display both characteristics in terms of antigen recognition and antitumor activity. In
recent years, novel technologies have been established for the identification, isolation, activation, and expansion of human
T-cells, which have greatly facilitated the further development of adoptive T-cell transfer regimens. Lessons learned from
the first clinical trials revealed that the complexity of the in vivo environment interferes with the efficacy of transferred
T-cells, such as tolerance induction and outgrowth of tumor escape variants. The results from these studies can be concluded
by the following critical, but nevertheless encouraging, statement: “Tumor regressions observed after adoptive Tcell transfer
are too frequent to be spontaneous.” As these trials are not solely conducted for treating cancer patients, but also for research
on human beings, the resulting scientific observations have increased our understanding of T-cell activation, homing, and
survival, as well as of the possibility of disrupting regulatory mechanisms. The knowledge drawn from the first generation
of transfer studies can be implemented in the next generation of clinical trials. T-cell-based immunotherapy regimens are
currently being combined with other immunological strategies in order to coordinate an effective attack against tumors. Further
development of combinatorial therapies involving immunological and molecular technologies will offer the means to tailor adoptive
transfer of T-cell immunity for each cancer patient.
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