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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Oncología > Microambiente tumoral > DA - CIMA - Oncología - Microambiente tumoral - Artículos de revista >

Intratumoral injection of interferon-α and systemic delivery of agonist anti-CD137 monoclonal antibodies synergize for immunotherapy
Authors: Dubrot, J. (Juan)
Palazon, A. (Asís)
Alfaro, C. (Carlos)
Azpilicueta, A. (Arantza)
Ochoa, M.C. (María Carmen)
Rouzaut, A. (Ana)
Martinez-Forero, I. (Iván)
Teijeira, A. (Álvaro)
Berraondo, P. (Pedro)
Bon, A. (Agnes) Le
Hervas-Stubbs, S. (Sandra)
Melero, I. (Ignacio)
Keywords: Type I interferon
4-1BB (CD137)
Combined immunotherapy
Immunostimulatory monoclonal antibodies
Issue Date: 2011
Publisher: Wiley Blackwell
Publisher version: http://onlinelibrary.wiley.com/doi/10.1002/ijc.25333/abstract
ISSN: 1097-0215
Citation: Dubrot J, Palazon A, Alfaro C, Azpilikueta A, Ochoa MC, Rouzaut A, et al. Intratumoral injection of interferon-alpha and systemic delivery of agonist anti-CD137 monoclonal antibodies synergize for immunotherapy. Int J Cancer 2011 Jan 1;128(1):105-118.
Abstract
CD137 artificial costimulation results in complete tumor rejection in several mouse models. Type I interferons (IFN) exert antitumor effects through an array of molecular functions on malignant cells, tumor stroma and immune system cells. The fact that agonist anti-CD137 mAb induce tumor regressions in mice deficient in the unique receptor for Type I IFNs (IFNAR(-/-) ) indicated potential for treatment combinations. Indeed, combination of intratumor injections of mouse IFN-α and intraperitoneal injections of anti-CD137 mAb synergized as seen on subcutaneous lesions derived from the MC38 colon carcinoma, which is resistant to each treatment if given separately. Therapeutic activity was achieved both against lesions directly injected with IFN-α and against distant concomitant tumors. Experiments in bone marrow chimeras prepared with IFNAR(-/-) and WT mice concluded that expression of the receptor for Type I interferons is mainly required on cells of the hematopoietic compartment. Synergistic effects correlated with a remarkable cellular hyperplasia of the tumor draining lymph nodes (TDLNs). Enlarged TDLNs contained more plasmacytoid and conventional dendritic cells (DC) that more readily cross-presented. Importantly, numbers of both DC subtypes inversely correlated with the tumor size. Numbers of CD8 T cells specific for a dominant tumor antigen were increased at TDLNs by each separate treatment but only with slight augments due to the combination. Combined antitumor effects of the therapeutic strategy were also seen on subcutaneous TC-1 tumors established for 24 days before treatment onset. The described strategy is realistic because (i) agents of each kind are clinically available and (ii) equivalent procedures in humans are feasible.
Permanent link: http://hdl.handle.net/10171/20289
Appears in Collections:DA - CIMA - Terapia génica y Hepatología - Terapia génica del cáncer - Artículos de revista
DA - Medicina - Medicina Interna - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Inmunología terapia génica - Artículos de revista
DA - CUN - Área de Terapia Celular - Artículos de revista
DA - Ciencias - Bioquímica y Biología molecular - Artículos de Revista
DA - CIMA - Oncología - Microambiente tumoral - Artículos de revista

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