Zelluläre Immuntherapie beim metastasiertem Mammakarzinom mit reaktivierten T-Gedächtniszellen

Tumor-reactive CD4 and CD8 memory T cells (MTC) can be found in bone marrow (BM) of the majority of primary and metastatic breast cancer patients. In xenotransplant mouse models these cells, upon specific re-activation ex vivo, mediated efficient rejection of autologous breast tumors suggesting that the polyclonal natural MTC repertoire possesses therapeutic potential. In order to clinically exploit these anti-tumor capacities we treated 11 advanced metastasized breast cancer patients with autologous, tumor-reactive, reactivated MTC of BM in a phase-1 trial. Activation of T cells was done by MCF-7 lysate pulsed dendritic cells (DC). After reactivation both, T cells and pulsed DC were injected once intravenously. Peripheral blood was drawn on day 0, 1, 7, 14, 28. BM-re-aspiration was done on day 28 and 84. While TAA-reactive memory T cells were absent in the peripheral blood (PB) before therapy, 5 from 11 patients (=responders) showed TAA-specific PB T cell reactivity 7 days after therapeutic cell application suggesting a massive proliferation and mobilization into the blood of TAA-reactive T cells in these patients. A comparison of responders to adoptive cellular immunotherapy with non-responders revealed differences in the numbers of therapeutic cells that could be generated ex vivo and in the decreased frequency of tumor-reactive MTC in responders´ BM on days 28 and 84 which could be expained by a mobilization due to in situ activation by co-transferred DCs or due to local or systemic cytokine signals by transferred, activated T lymphocytes. Such effect might have contributed to the high numbers of circulating TAA-reactive T cells observed 7 days after the transfer. Furthermore we observed different concentrations of IL-4, IL-10, TNF-a, and INF-g in PB and BM between the two groups leading to the hypothesis of a polarization in T cell responses (T1 type in responders vs. T2 type in non-responders).