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Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial

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Abstract

Background

The bone marrow (BM) of breast cancer patients harbors tumor-reactive memory T cells (TCs) with therapeutic potential. We recently described the immunologic effects of adoptive transfer of ex vivo restimulated tumor-reactive memory TCs from the BM of 12 metastasized breast cancer patients in a clinical phase-I study. In this trial, adoptive T cell transfer resulted in the occurrence of circulating tumor antigen-reactive type-1 TCs. We here describe the long-term clinical outcome and its correlation with tumor-specific cellular immune response in 16 metastasized breast cancer patients, including 12 included in the original study.

Methods

Sixteen metastatic breast cancer patients with preexisting tumor-reactive BM memory TCs were included into the study. The study protocol involved one transfusion of TCs which were reactivated in vitro with autologous dendritic cells pulsed with lysates of MCF-7 breast cancer cells as source of tumor antigens. The presence of tumor-reactive memory TCs was analyzed by IFN-γ ELISpot assays.

Results

Tumor-reactive memory TCs in the peripheral blood were induced de novo in 7/16 patients (44 %) after adoptive TC transfer. These patients were considered immunologic responders to the therapy. Positive adoptive immunotherapy (ADI) response was observed significantly more often in patients without bone metastases (p = 0.0051), in patients with high levels of tumor-reactive BM TCs prior to therapy (p = 0.036) and correlated significantly with the estimated numbers of transferred tumor-reactive TCs (p = 0.0021). After the treatment, we observed an overall median survival of 33.8 months in the total cohort with three patients alive at last follow-up and more than 7 years after ADI. Numbers of transferred tumor-reactive TCs correlated significantly with the overall survival of patients (p = 0.017). Patients with an immunologic response to ADI in the peripheral blood had a significantly longer median survival than nonresponders (median survival 58.6 vs. 13.6 months; p = 0.009).

Conclusion

In metastasized breast cancer patients, adoptive transfer of BM TCs can induce the presence of tumor antigen-reactive type-1 TCs in the peripheral blood. Patients with immunologic response after ADI show a significantly longer overall survival. Patients with bone metastases significantly less frequently respond to the treatment and, therefore, might not be optimal candidates for ADI. Although the present study does not yet prove the therapeutic effect of ADI, these findings shed light on the relation between immune response and cancer prognosis and suggest that transfer of reactivated BM TCs might bear therapeutic potential.

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Abbreviations

ADI:

Adoptive immunotherapy

BM/BMTC:

Bone marrow/bone marrow T cell

CD:

Cluster of differentiation

DC:

Dendritic cell

ELISpot:

Enzyme-linked immunosorbent spot

GM-CSF:

Granulocyte macrophage colony-stimulating factor

IFN:

Interferon

IL:

Interleukin

PBMC:

Peripheral blood mononuclear cell

TA:

Tumor antigen

TC:

T cell

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Acknowledgments

This work was supported by grants from Deutsche Forschungsgemeinschaft (SFB 938).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Translational Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany

    Christoph Domschke, Yingzi Ge, Simone Juenger, Mariana Bucur & Philipp Beckhove

  2. Department of Gynecology and Obstetrics, University Hospital of Heidelberg/National Center for Tumor Diseases (NCT), INF 460, Voßstraße 9, 69115, Heidelberg, Germany

    Christoph Domschke, Isa Bernhardt, Sarah Schott, Sophia Keim, Luisa Mayer, Maria Blumenstein, Joachim Rom, Joerg Heil, Christof Sohn, Andreas Schneeweiss & Florian Schuetz

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  1. Christoph Domschke
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  2. Yingzi Ge
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Corresponding author

Correspondence to Philipp Beckhove.

Additional information

Philipp Beckhove and Florian Schuetz contributed equally.

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Domschke, C., Ge, Y., Bernhardt, I. et al. Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial. Cancer Immunol Immunother 62, 1053–1060 (2013). https://doi.org/10.1007/s00262-013-1414-x

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