title: A novel method using blinatumomab for efficient, clinical-grade expansion of polyclonal T cells for adoptive immunotherapy.
abstract: Current treatment of chronic lymphocytic leukemia (CLL) patients often results in life-threatening immunosuppression. Furthermore, CLL is still an incurable disease due to the persistence of residual leukemic cells. These patients may therefore benefit from immunotherapy approaches aimed at immunoreconstitution and/or the elimination of residual disease following chemotherapy. For these purposes, we designed a simple GMP-compliant protocol for ex vivo expansion of normal T cells from CLL patients' peripheral blood for adoptive therapy, using bispecific Ab blinatumomab (CD3 × CD19), acting both as T cell stimulator and CLL depletion agent, and human rIL-2. Starting from only 10 ml CLL peripheral blood, a mean 515 × 10(6) CD3(+) T cells were expanded in 3 wk. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4(+) and CD8(+) and mostly effector and central memory cells. The Th1 subset was slightly prevalent over Th2, whereas Th17 and T regulatory cells were <1%. CMV-specific clones were detected in equivalent proportion before and after expansion. Interestingly, BET cells had normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were cytotoxic against CD19(+) targets in presence of blinatumomab in vitro. In support of their functional capacity, we observed that BET, in combination with blinatumomab, had significant therapeutic activity in a systemic human diffuse large B lymphoma model in NOD-SCID mice. We propose BET as a therapeutic tool for immunoreconstitution of heavily immunosuppressed CLL patients and, in combination with bispecific Ab, as antitumor immunotherapy.
authors.affiliation: Centro di Terapia Cellulare, "G. Lanzani," USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy; jgolay@hpg23.it.
authors.forename: Josée
authors.initials: J
authors.lastname: Golay
authors.affiliation: Centro di Terapia Cellulare, "G. Lanzani," USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: Centro Trapianto Midollo Osseo, USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Borleri
authors.affiliation: Centro di Terapia Cellulare, "G. Lanzani," USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Michela
authors.initials: M
authors.lastname: Bonzi
authors.affiliation: Centro di Terapia Cellulare, "G. Lanzani," USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Rut
authors.initials: R
authors.lastname: Valgardsdottir
authors.affiliation: Nerviano Medical Sciences, 20014 Nerviano, Italy; and.
authors.forename: Rachele
authors.initials: R
authors.lastname: Alzani
authors.affiliation: Nerviano Medical Sciences, 20014 Nerviano, Italy; and.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cribioli
authors.affiliation: Nerviano Medical Sciences, 20014 Nerviano, Italy; and.
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.affiliation: Nerviano Medical Sciences, 20014 Nerviano, Italy; and.
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.affiliation: Centro Trapianto Midollo Osseo, USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Finazzi
authors.affiliation: Centro Trapianto Midollo Osseo, USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Giulia
authors.initials: G
authors.lastname: Quaresmini
authors.affiliation: Global Clinical Development, Amgen, Thousand Oaks, CA 91320.
authors.forename: Dirk
authors.initials: D
authors.lastname: Nagorsen
authors.affiliation: Centro di Terapia Cellulare, "G. Lanzani," USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Martino
authors.initials: M
authors.lastname: Introna
authors.affiliation: Centro Trapianto Midollo Osseo, USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000954:Antigens, Surface / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy; D051379:Mice; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D000954:Antigens, Surface; D007376:Interleukin-2; D061026:Programmed Cell Death 1 Receptor; C510808:blinatumomab