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Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

Maciocia, Paul M ; Wawrzyniecka, Patrycja A ; Philip, Brian ; Ricciardelli, Ida ; Akarca, Ayse U ; Onuoha, Shimobi C ; Legut, Mateusz ; Cole, David K ; Sewell, Andrew K ; Gritti, Giuseppe ; Somja, Joan ; Piris, Miguel A ; Peggs, Karl S ; Linch, David C ; Marafioti, Teresa ; Pule, Martin A

Nature medicine, 2017-12, Vol.23 (12), p.1416-1423 [Periódico revisado por pares]

United States

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Título:
Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
Autor: Maciocia, Paul M ; Wawrzyniecka, Patrycja A ; Philip, Brian ; Ricciardelli, Ida ; Akarca, Ayse U ; Onuoha, Shimobi C ; Legut, Mateusz ; Cole, David K ; Sewell, Andrew K ; Gritti, Giuseppe ; Somja, Joan ; Piris, Miguel A ; Peggs, Karl S ; Linch, David C ; Marafioti, Teresa ; Pule, Martin A
Assuntos: Animals ; Antineoplastic Agents, Immunological - therapeutic use ; Cells, Cultured ; HEK293 Cells ; Humans ; Immunotherapy, Adoptive - methods ; Jurkat Cells ; K562 Cells ; Leukemia, T-Cell - immunology ; Leukemia, T-Cell - therapy ; Male ; Mice ; Molecular Targeted Therapy - methods ; Receptors, Antigen, T-Cell, alpha-beta - immunology ; T-Lymphocytes - immunology
É parte de: Nature medicine, 2017-12, Vol.23 (12), p.1416-1423
Descrição: Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1 and TRBC2 compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1 , but not TRBC2 , T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.
Editor: United States
Idioma: Inglês

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Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

Maciocia, Paul M ; Wawrzyniecka, Patrycja A ; Philip, Brian ; Ricciardelli, Ida ; Akarca, Ayse U ; Onuoha, Shimobi C ; Legut, Mateusz ; Cole, David K ; Sewell, Andrew K ; Gritti, Giuseppe ; Somja, Joan ; Piris, Miguel A ; Peggs, Karl S ; Linch, David C ; Marafioti, Teresa ; Pule, Martin A

United States

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