Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2Rγnull immunodeficient mice
Fernandez de Sanmamamed M(1), Lopez Rodriguez I(1), Schalper KA(2), Onate C(3), Azpilikueta A(4), Rodriguez-Ruiz ME(5), Morales-Kastresana A(5), Labiano S(4), Perez-Gracia JL(6), Martin-Algarra S(7), Alfaro C(8), Mazzolini G(9), Sarno F(10), Hidalgo M(11), Korman AJ(12), Jure-Kunkel M(13), Melero I(14).
(1) Oncology and immunotherapy, CIMA and CUN.
(2) Dept of Pathology, Yale University School of Medicine.
(3) Division of immunology, CIMA and clinica Universidad de Navarra. University of Navarra.
(4) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra.
(5) Immunotherapy, CIMA and CUN.
(6) Oncology Department, Clinica Universidad de Navarra. University of Navarra.
(7) Oncology, Clinica UN.
(8) Gene Therapy Unit, CIMA.
(9) Gene Therapy Laboratory, Liver Unit, School of Medicine. Austral University.
(10) oncology, Clara Campal.
(11) Gastrointestinal Cancer Clinical Research Unit, Spanish National Cancer Research Centre.
(12) Biologics Discovery California, Bristol-Myers Squibb.
(13) Bristol Myers Squibb.
(14) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), and University Clinic, University of Navarra.
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 redistributed 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 PBMCs, or with a patient-derived gastric carcinoma and peripheral blood mononuclear cells from the same patient, we found that co-administration 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.
CITATION Cancer Res. 2015 Jun 25. pii: canres.3510.2014.