BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains.

Checkpoint inhibitors represent a new class of therapeutics in the treatment of cancer that has demonstrated remarkable clinical effectiveness. However, some patients have experienced serious immune-mediated adverse effects including pneumonitis, hepatitis, colitis, nephritis, dermatitis, encephalitis, and adrenal or pituitary insufficiency. These adverse events were not predicted by nonclinical studies. To determine if bone marrow-liver-thymus (BLT) immune humanized mice could demonstrate these adverse effects, we studied the effect of nivolumab on 2 strains of BLT-humanized mice, NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) and NOD.Cg-Prkdcscid Il2rgtm1Sug Tg(SV40/HTLV-IL3, CSF2)10-7Jic/JicTac (NOG-EXL). Mice were treated with 2.5, 5.0, or 10.0 mg/kg nivolumab or saline twice weekly for 28 days. BLT-NOG mice had significantly reduced survival compared with BLT-NOG-EXL mice. In spite of the difference in survival, both BLT-humanized strains showed adverse reactions similar to those reported in humans, including pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also noted in some individuals. Additional histopathologic findings included pancreatic atrophy, myositis, and osteomyelitis in some animals. T-cell activation increased with concomitant loss of PD-1 detection. These findings show that BLT immune humanized mice can demonstrate immune-mediated adverse effects of antiPD1 therapy, and may represent a model that can be used to better understand toxicity of this class of drugs.

[1]  Mamoru Ito,et al.  A Novel Xenogeneic Graft‐Versus‐Host Disease Model for Investigating the Pathological Role of Human CD4+ or CD8+ T Cells Using Immunodeficient NOG Mice , 2017, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  D. Leaf,et al.  Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. , 2016, Kidney international.

[3]  Hussein Tawbi,et al.  Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy , 2016, Journal of Immunotherapy for Cancer.

[4]  G. Freeman,et al.  Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. , 2016, The Journal of clinical investigation.

[5]  A. V. van Bodegraven,et al.  Clinical, Endoscopic, and Histologic Characteristics of Ipilimumab-Associated Colitis. , 2016, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[6]  J. Wolchok,et al.  Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. , 2016, European journal of cancer.

[7]  G. Freeman,et al.  Coinhibitory Pathways in Immunotherapy for Cancer. , 2016, Annual review of immunology.

[8]  L. Riella,et al.  Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma , 2016, Clinical kidney journal.

[9]  Gideon Blumenthal,et al.  FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy , 2016, The oncologist.

[10]  Andreas Wicki,et al.  Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors—an autopsy study , 2016, Journal of Immunotherapy for Cancer.

[11]  J. Wolchok,et al.  Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1 , 2016, Cancer Immunology Research.

[12]  G. Gibney,et al.  Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes , 2015, Clinical Cancer Research.

[13]  M. Boyne,et al.  Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog. , 2015, Toxicology and applied pharmacology.

[14]  M. Hidalgo,et al.  Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rγnull Immunodeficient Mice. , 2015, Cancer research.

[15]  M. Bossard,et al.  Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma , 2015, Journal of Immunotherapy for Cancer.

[16]  F. Cappuzzo,et al.  Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. , 2015, The Lancet. Oncology.

[17]  K. Herold,et al.  Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy , 2014, The Journal of Immunology.

[18]  A. Korman,et al.  In Vitro Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and In Vivo Toxicology in Non-Human Primates , 2014, Cancer Immunology Research.

[19]  Todd M. Allen,et al.  PD-1 Blockade in Chronically HIV-1-Infected Humanized Mice Suppresses Viral Loads , 2013, PloS one.

[20]  H. Suemizu,et al.  Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice , 2013, The Journal of Immunology.

[21]  S. Kenney,et al.  Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[22]  K. Herold,et al.  Analysis of Human Biologics With a Mouse Skin Transplant Model in Humanized Mice , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  M. Greenblatt,et al.  Graft versus Host Disease in the Bone Marrow, Liver and Thymus Humanized Mouse Model , 2012, PloS one.

[24]  C. Ewen,et al.  Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis. , 2011, Journal of autoimmunity.

[25]  T. Okazaki,et al.  PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice , 2011, The Journal of experimental medicine.

[26]  Mamoru Ito,et al.  Highly Sensitive Model for Xenogenic GVHD Using Severe Immunodeficient NOG Mice , 2009, Transplantation.

[27]  Lloyd J. Old,et al.  Adaptive immunity maintains occult cancer in an equilibrium state , 2007, Nature.

[28]  A. Haase,et al.  Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1 , 2006, Nature Medicine.

[29]  Mamoru Ito,et al.  NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. , 2002, Blood.

[30]  R. Schreiber,et al.  Cancer immunoediting: from immunosurveillance to tumor escape , 2002, Nature Immunology.

[31]  T. Honjo,et al.  Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. , 1999, Immunity.

[32]  M. Roncarolo,et al.  Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras , 1994, The Journal of experimental medicine.

[33]  M. Suarez‐Almazor,et al.  Adverse Events in Cancer Immunotherapy. , 2017, Advances in experimental medicine and biology.

[34]  L. Chow.  Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. , 2013, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.