Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice

Miguel F. Sanmamed, Inmaculada Rodriguez, Kurt A. Schalper, Carmen Oñate, Arantza Azpilikueta, Maria E. Rodriguez-Ruiz, Aizea Morales-Kastresana, Sara Labiano, Jose L. Pérez-Gracia, Salvador Martín-Algarra, Carlos Alfaro, Guillermo Mazzolini, Francesca Sarno, Manuel Hidalgo, Alan J. Korman, Maria Jure-Kunkel, Ignacio Melero

Research output: Contribution to journalArticle

Abstract

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 cellsurface 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 patientderived 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 IFNγ 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.

Original languageEnglish (US)
Pages (from-to)3466-3478
Number of pages13
JournalCancer Research
Volume75
Issue number17
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

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Human Activities
T-Lymphocytes
Heterografts
Neoplasms
Lymphocytes
Carcinoma
HT29 Cells
Regulatory T-Lymphocytes
Drug Combinations
Allergy and Immunology
nivolumab
Blood Cells
Stomach
Histology
Monoclonal Antibodies
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Sanmamed, M. F., Rodriguez, I., Schalper, K. A., Oñate, C., Azpilikueta, A., Rodriguez-Ruiz, M. E., ... Melero, I. (2015). Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice. Cancer Research, 75(17), 3466-3478. https://doi.org/10.1158/0008-5472.CAN-14-3510

Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice. / Sanmamed, Miguel F.; Rodriguez, Inmaculada; Schalper, Kurt A.; Oñate, Carmen; Azpilikueta, Arantza; Rodriguez-Ruiz, Maria E.; Morales-Kastresana, Aizea; Labiano, Sara; Pérez-Gracia, Jose L.; Martín-Algarra, Salvador; Alfaro, Carlos; Mazzolini, Guillermo; Sarno, Francesca; Hidalgo, Manuel; Korman, Alan J.; Jure-Kunkel, Maria; Melero, Ignacio.

In: Cancer Research, Vol. 75, No. 17, 01.09.2015, p. 3466-3478.

Research output: Contribution to journalArticle

Sanmamed, MF, Rodriguez, I, Schalper, KA, Oñate, C, Azpilikueta, A, Rodriguez-Ruiz, ME, Morales-Kastresana, A, Labiano, S, Pérez-Gracia, JL, Martín-Algarra, S, Alfaro, C, Mazzolini, G, Sarno, F, Hidalgo, M, Korman, AJ, Jure-Kunkel, M & Melero, I 2015, 'Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice', Cancer Research, vol. 75, no. 17, pp. 3466-3478. https://doi.org/10.1158/0008-5472.CAN-14-3510
Sanmamed, Miguel F. ; Rodriguez, Inmaculada ; Schalper, Kurt A. ; Oñate, Carmen ; Azpilikueta, Arantza ; Rodriguez-Ruiz, Maria E. ; Morales-Kastresana, Aizea ; Labiano, Sara ; Pérez-Gracia, Jose L. ; Martín-Algarra, Salvador ; Alfaro, Carlos ; Mazzolini, Guillermo ; Sarno, Francesca ; Hidalgo, Manuel ; Korman, Alan J. ; Jure-Kunkel, Maria ; Melero, Ignacio. / Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice. In: Cancer Research. 2015 ; Vol. 75, No. 17. pp. 3466-3478.
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