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Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Breast cancer patients frequently harbour tumour-reactive memory T cells in their bone marrow (BM) but not in the blood. After reactivation ex-vivo these cells rejected autologous breast tumours in xenotransplanted mice demonstrating therapeutic potential upon reactivation and mobilization into the blood. We conducted a clinical pilot study on metastasized breast cancer patients to investigate if ex-vivo reactivation of tumour-reactive BM memory T cells and their adoptive transfer is feasible and increases the frequencies of tumour-reactive T cells in the blood.

Methods

The study protocol involved one transfusion of T cells which were reactivated in vitro with autologous dendritic cells pulsed with lysate of MCF7 breast cancer cells as source of tumour antigens. Immunomonitoring included characterization of T cell activation in vitro and of tumour-specific T cells in the blood by interferon (IFN)-γ ELISPOT assay, HLA-tetramers and antigen-induced interleukin (IL)-4 secretion.

Results

Twelve patients with pre-existing tumour-reactive BM memory T cells were included into the study. In all cases, the treatment was feasible and well tolerated. Six patients (responders) showed by ELISPOT assay de-novo tumour antigen-specific, IFN-γ-secreting T cells in the blood after 7 days. In contrast, non responders showed in the blood tumour antigen-induced IL-4 responses. All responders received more than 6.5 × 103 tumour-reactive T cells. In contrast, all non responders received lower numbers of tumour antigen-reactive T cells. This was associated with reduced activation of memory T cells in activation cultures, increased amounts of CD4+ CD25high regulatory T cells in the BM and increased tumour antigen-dependent IL-10 secretion. The latter was prevented by preceding depletion of regulatory T cells suggesting that regulatory T cells in the BM can inhibit reactivation of tumour-specific T cells.

Conclusion

Taken together, adoptive transfer of ex-vivo re-stimulated tumour-reactive memory T cells from BM of metastasized breast cancer patients can induce the presence of tumour antigen-reactive type-1 T cells in the peripheral blood.

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Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, The University Hospital of Heidelberg, Heidelberg, Germany

    Florian Schuetz, Andreas Schneeweiss, Joachim Rom, Natalija Inzkirweli & Christoph Sohn

  2. Department of Cellular Immunology, The German Cancer Research Center, INF 280, 69120, Heidelberg, Germany

    Katrin Ehlert, Yingzi Ge, Volker Schirrmacher & Philipp Beckhove

Authors
  1. Florian Schuetz
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  2. Katrin Ehlert
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  3. Yingzi Ge
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  4. Andreas Schneeweiss
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  5. Joachim Rom
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  6. Natalija Inzkirweli
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  7. Christoph Sohn
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  8. Volker Schirrmacher
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  9. Philipp Beckhove
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Corresponding author

Correspondence to Philipp Beckhove.

Additional information

Florian Schuetz and Katrin Ehlert contributed equally to the study.

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Schuetz, F., Ehlert, K., Ge, Y. et al. Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study. Cancer Immunol Immunother 58, 887–900 (2009). https://doi.org/10.1007/s00262-008-0605-3

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  • DOI: https://doi.org/10.1007/s00262-008-0605-3

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