title: Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Translational Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany. christoph.domschke@med.uni-heidelberg.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Domschke
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Ge
authors.forename: Isa
authors.initials: I
authors.lastname: Bernhardt
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Sophia
authors.initials: S
authors.lastname: Keim
authors.forename: Simone
authors.initials: S
authors.lastname: Juenger
authors.forename: Mariana
authors.initials: M
authors.lastname: Bucur
authors.forename: Luisa
authors.initials: L
authors.lastname: Mayer
authors.forename: Maria
authors.initials: M
authors.lastname: Blumenstein
authors.forename: Joachim
authors.initials: J
authors.lastname: Rom
authors.forename: Joerg
authors.initials: J
authors.lastname: Heil
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Florian
authors.initials: F
authors.lastname: Schuetz
mesh_terms: D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016219:Immunotherapy, Adoptive; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome