Abstract LB-050: Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy

Abstract

Mouse models are frequently used to test the therapeutic efficacy of anti-cancer drugs. However, the translation of murine experimental data to treatments for patients with cancer often fails due to significant differences between the species, including the differences in the immune system. Our goal is to bridge this gap and to establish an in vivo preclinical model of human tumor immunotherapy by engrafting immunodeficient mice expressing a partial human immune system with human tumor implants. Humanized NOD-scid IL2Rγ (null) (hu-NSG) mice were initially generated by transplanting NSG mice with human CD34+ hematopoietic stem and progenitor cells (HSPCs) which support human hematopoietic and immune system development. Hu-NSG mice develop functional human T cells and B cells with high levels of TCR excision circles, complex TCR repertoire diversity and antigen-specific T cell proliferative responses. Several types of patient-derived tumors (non small cell lung cancer, sarcoma, triple negative breast cancer and invasive bladder cancer) were successfully implanted into HLA mismatched hu-NSG mice. Tumor growth curves show a delay in tumor growth in hu-NSG compared to non-humanized NSG mice. In a colon cancer xenograft model, treatment with chemotherapy agent (5-FU) or with a therapeutic antibody directed against VEGF (Avastin) resulted in decreased tumor growth. In addition to PDX tumors we have also tested human cancer cell lines. Tumor growth was observed in all hu-NSG mice implanted with human ovarian tumor cell line SKOV3-Luc-D3 cells at different time points post HSPC engraftment, showing no evidence of tumor rejection. Thus, our model of humanized mice bearing tumor-derived xenografts provides opportunities to study both the safety and efficacy of current cancer therapies. Citation Format: Minan Wang, James G. Keck, Mingshan Cheng, Danying Cai, Leonard Shultz, Karolina Palucka, Jacques Banchereau, Carol Bult, Rick Huntress. Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-050. doi:10.1158/1538-7445.AM2015-LB-050

Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models

“…This situation of partially matched HLA typing between hNSG mice and the PDXs may have contributed to lower tumor immunogenic rejection while simultaneously resulting in reduced percentages of engraftment and slower growing tumors (Fig. 2 ), as previously observed in similar studies showing that human PDX tumors can grow in hNSG with partially HLA-matched allogeneic human immune systems [ 36 , 37 ].

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“…As was the case with TNBC PDXs, melanoma cell xenograft growth also appeared to be delayed in hNSG animals when compared with nonhumanized NSG mice (Fig. 2b ), highlighting the potential role of humanization and acquisition of a competent immunological status in affecting the growth of a tumor [ 35 ], as previously shown in similar models [ 36 , 37 ]. To further investigate these observations, human leukocyte antigen (HLA) subtyping was performed in both the original hCD34 + HSCs and two of the PDXs used in this study by using standard protocols used at the Department of Pathology & Genomic Medicine, Immunobiology & Transplant Science Center, Houston Methodist Hospital (Houston, TX, USA).…”

“…Our observations showed some differences in the PDX growth rate based on whether the mice were humanized or not, most likely owing to the incipient presence of an active immune system. However, as also shown by others, including the case of commercially available humanized PDX models [ 36 , 37 ], no signs of graft-versus-host reaction were found. Furthermore, on the basis of the fact that the HLA typing of HSCs did not conclusively demonstrate compatibility with more than one pattern, it is plausible to postulate that the slower growth of PDXs may have resulted from partially HLA-matched hNSG/PDX engraftment, which allowed a seemingly regular tumor engraftment.…”