Journal
CANCER RESEARCH
Volume 75, Issue 17, Pages 3466-3478Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-3510
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Funding
- MICINN [SAF2008-03294, SAF2011-22831]
- Departamento de Educacion del Gobierno de Navarra
- Departamento de Salud del Gobierno de Navarra, Redes tematicas de investigacion cooperativa RETIC [RD06/0020/0065]
- RTICC
- European commission VII framework program (project ENCITE)
- European commission VII framework program (project IACT)
- Fundacion Caja Navarra
- Rio Hortega contract
- Fundacion Mutua Madrilena
- Instituto de Salud Carlos III
- ISCIII
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A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4(+) T cell-mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFN gamma and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. (C)2015 AACR.
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