ImmTAC/Anti-PD-1 antibody combination to enhance killing of cancer cells by reversing regulatory T-cell-mediated immunosuppression.
Immunology
; 155(2): 238-250, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-29791021
ABSTRACT
Recently, bi-functional molecules that can redirect immune effectors to tumour cells have emerged as potentially robust mediators of tumour regression in clinical trials. Two modalities in particular, bi-specific antibodies for T-cell redirection and activation (BiTe) and immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC), are being evaluated in efficacy studies as 'off-the-shelf' reagents. Optimal therapy will require an understanding and means to address regulatory mechanisms of limiting efficacy. In light of this, we evaluated the impact of induced regulatory T (iTreg) cells on the efficacy of tumour cell killing redirected by ImmTAC and demonstrated down-regulation of T-cell proliferation and expression of CD25, CD107a, Granzyme B and Perforin by ImmTAC-redirected T cells. Significant recovery of ImmTAC potency, however, could be achieved when combined with an anti-programmed cell death protein 1 monoclonal antibody. Furthermore, we found that among lung cancer patients failing to respond to ImmTAC therapy, there was a significantly higher fraction of Treg cells in the peripheral blood mononuclear cells of lung cancer patients than in healthy donors. These results provide in vitro evidence for an iTreg cell-mediated immunosuppression of ImmTAC-redirected T-cell responses. Whilst immune checkpoint blockade can reverse the Treg cell suppression, it forms a rational basis for a combination of the blockade with ImmTAC in clinical trials.
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Base de dados:
MEDLINE
Assunto principal:
Ativação Linfocitária
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Terapia de Imunossupressão
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Linfócitos T Reguladores
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Citotoxicidade Imunológica
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Receptor de Morte Celular Programada 1
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Anticorpos Monoclonais
Limite:
Humans
Idioma:
En
Revista:
Immunology
Ano de publicação:
2018
Tipo de documento:
Article