title: Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rγnull Immunodeficient Mice.
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 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 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.
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Sanmamed
authors.affiliation: Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Oñate
authors.affiliation: Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Rodriguez-Ruiz
authors.affiliation: Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Aizea
authors.initials: A
authors.lastname: Morales-Kastresana
authors.affiliation: Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Labiano
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Pérez-Gracia
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Martín-Algarra
authors.affiliation: Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.affiliation: Gene Therapy Laboratory, Department of Medicine, Universidad Austral, Pilar, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sarno
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain. Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.affiliation: Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain. imelero@unav.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C499308:Rag2 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000077594:Nivolumab