A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells.
Cancer Res
; 77(6): 1296-1309, 2017 03 15.
Article
em En
| MEDLINE
| ID: mdl-28082401
ABSTRACT
Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNγ and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer. Cancer Res; 77(6); 1296-309. ©2017 AACR.
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Base de dados:
MEDLINE
Assunto principal:
Sarcoma Experimental
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Receptores de Antígenos de Linfócitos T
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Imunoterapia Adotiva
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Neoplasias do Colo
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Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral
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Neoplasias Mamárias Experimentais
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Anticorpos Monoclonais
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article