Abstract PR02: Humanized mouse melanoma model using patient-derived xenografts

Abstract

Abstract Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical and clinical results with immune checkpoint inhibitors using antibodies directed against CTLA4 and PD1 have re-energized the field of immune-based therapies in melanoma. However, similar to chemo- or targeted-therapies only subsets of melanoma patients respond to immune checkpoint blockade. Currently available immunodeficient mouse xenograft and transgenic mouse melanoma models have a number of short comings and are unable to address the basis of drug resistance and immune non-responsiveness frequently observed in melanoma patients treated either with chemo- and targeted-therapy drugs or immune checkpoint inhibitors. Thus there is an urgent need to establish a mouse model with an immune microenvironment that can address the above issues encountered in melanoma patients. For this, our laboratory has developed a humanized mouse melanoma model using patient-derived xenograft (PDX). Immunodeficient (NOD/Shi-SCID/IL-2Rgnull [NOG; Taconic]/ NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ [NSG; Jackson Laboratory]) mice were reconstituted with human CD34+ cells and after 12 weeks, mature human CD45+ cells are observed in mouse peripheral blood and in the lymphoid organs. Humanized mice with optimum number of mature human CD45+ cells in peripheral blood were challenged with HLA-matched melanoma PDX and the immune response to melanoma associated antigens were monitored. Lymphoid cells derived from humanized mice that are challenged with human leukocyte antigen (HLA) matched melanoma cells in vivo showed enhanced cytokine expression to in vitro stimulation with peptides derived from melanoma antigens. In addition, cytotoxic T-cells were able to functionally lyse tumor cells in vitro, infiltrate and restrict in vivo tumor growth. We are currently refining our model to establish an autologous mouse melanoma model. Our innovative humanized mouse melanoma model will enable one to understand the causes of therapy resistance and immune non-responsiveness in patients. This abstract is also being presented as Poster B33. Citation Format: Clemens Krepler, Michela Perego, Mizuho Kalabis, Marilda Beqiri, Denitsa Hristova, Min Xiao, Nicholas J. Petrelli, Rajasekharan Somasundaram, Meenhard Herlyn. Humanized mouse melanoma model using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR02.