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: Josée Golay, Anna D'Amico, Gianmaria Borleri, Michela Bonzi, Rut Valgardsdottir, Rachele Alzani, Sabrina Cribioli, Clara Albanese, Enrico Pesenti, Maria Chiara Finazzi, Giulia Quaresmini, Dirk Nagorsen, Martino Introna, Alessandro Rambaldi
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 9 Pg. 4739-47 (Nov 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25267972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Antibodies, Bispecific
• Antigens, Surface
• Interleukin-2
• Programmed Cell Death 1 Receptor
• blinatumomab

Topics

• Animals
• Antibodies, Bispecific (pharmacology)
• Antigens, Surface (metabolism)
• Cell Culture Techniques
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Disease Models, Animal
• Female
• Humans
• Immunophenotyping
• Immunotherapy, Adoptive
• Interleukin-2 (pharmacology)
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology, mortality, therapy)
• Mice
• Phenotype
• Programmed Cell Death 1 Receptor (metabolism)
• T-Lymphocyte Subsets (drug effects, immunology, metabolism)