SEP 30, 2015 7:30 AM PDT

Humanized NSGTM Mice for Evaluation of Immuno-Oncology Therapeutics

Speaker
  • Technical Information Scientist, The Jackson Laboratory
    Biography
      Brian has worked at The Jackson Laboratory for 20 years. He conducted research on treatment strategies for a mouse model of human enzyme deficiency. Approaches included enzyme replacement, gene therapy, and neonatal allogeneic bone marrow transplantation. He is currently a Technical Information Services Scientist. Brian's area of expertise is in modeling (and complications associated with) human type 1 and type 2 diabetes, and research with immunodeficient mice.

    Abstract

    Using the NSGTM mouse (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ), JAX In Vivo Pharmacology Services has combined the human CD34+ hematopoietic stem cell engrafted NSGTM (hu-CD34 NSGTM) with human patient derived xenograft (PDX) to create a platform for humanized preclinical studies in immuno-oncology. Non-HLA matched PDX tumors grow well in hu-CD34 NSGTM, despite concerns over transplant rejection. When unmatched human PDX was engrafted in NSGTM or hu-CD34 NSGTM tumor growth rate was similar, indicating the human immune cells did not influence tumor growth. Next, hu-CD34 NSGTM mice were transplanted with a PDX breast or lung tumor in which 56.9% and 89.1% of the cells in the tumor expressed PD-L1, respectively. When PD-L1 is bound to PD1 on T cells, the T cells are rendered anergic. When treated with Keytruda, an antibody that blocks PD1/PD-L1 binding, tumor growth was significantly diminished. This showed human T cells could be induced to respond to PDX following treatment with a check-point inhibitor. Recognizing that CTL’s are not the only cell population important in immuno-oncology, we are now evaluating NSGTM-SGM3 mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ) for humanization and co-engraftment of PDX. These mice express human IL-3, GM-CSF, and KIT ligand that allow improved development of regulatory T cells (Treg) and myeloid cells. Within the tumor, Treg are implicated in suppression of T effector function. Myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) also diminish immune responses. Engraftment kinetics comparing hu-CD34 NSGTM to hu-CD34 NSGTM-SGM3 hosts show more rapid expansion of CD3+ T cells, Treg, and CD33+ myeloid cells in the NSGTM-SGM3 hosts. Several PDX tumors have successfully engrafted in the hu-CD34 NSGTM-SGM3 hosts, enabling further research into both the basic biology and development of therapeutics in human immuno-oncology.


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