Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain.
Nat Commun
; 8(1): 1447, 2017 11 13.
Article
em En
| MEDLINE
| ID: mdl-29129918
CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8+ T cells, and an increased ratio of intratumoral CD8+ T cells to CD4+ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Melanoma Experimental
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Neoplasias Encefálicas
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Linfócitos T CD8-Positivos
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Antígenos CD40
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Ligante de CD40
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article