Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study.
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)-gamma 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-gamma-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 x 10(3) 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(+) CD25(high) 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.


CONCLUSIONS
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.
Schuetz
Florian
F
Department of Gynecology and Obstetrics, The University Hospital of Heidelberg, Heidelberg, Germany.
Ehlert
Katrin
K
Ge
Yingzi
Y
Schneeweiss
Andreas
A
Rom
Joachim
J
Inzkirweli
Natalija
N
Sohn
Christoph
C
Schirrmacher
Volker
V
Beckhove
Philipp
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000276:immunology*; D001859:Bone Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008875:Middle Aged; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
D016207:Cytokines; D015847:Interleukin-4