TMOD-37. IN VIVO SYNERGISTIC EFFECT OF CHECKPOINT BLOCKADE AND RADIATION THERAPY AGAINST CHORDOMAS IN A HUMANIZED MOUSE MODEL. (5th November 2018)

• Record Type: Journal Article
• Authors: Ishida, Wataru; McCormick, Kyle; Mahajan, Aayushi; Feldstein, Eric; Lim, Michael; Bruce, Jeffrey; Canoll, Peter; Lo, Sheng-fu
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi276
• Page End: vi276
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.1149
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Currently, there are no murine chordoma cell lines nor transgenic mouse models of chordomas, which prevents us from investigating the interaction between murine chordomas and murine immune cells. Thus, to scrutinize immunotherapy (IT) against chordomas, the development of a humanized mouse model of chordomas, where human thymus, CD34+ stem cells, and chordomas are co-transplanted to engraft human immune system into mice, is imperative. We aimed to investigate synergistic effect between IT and radiation therapy (RT) against chordomas using this model. METHODS: Fifteen 10-12-week-old NSG mice were sub-lethally irradiated and then implanted with human fetal thymic tissue and CD34+ stem cells, whose HLA-type is partially-matched with that of the U-CH1 chordoma cell line. Reconstitution of immune cells in NSG mice was confirmed eight weeks post-transplantation, and then each animal was injected with U-CH1 subcutaneously. Next, they were treated for four weeks as follows: (A) control (n=3), (B) anti-human-PD-1 antibodies (n=4), (C) RT + isotype antibodies (n=3, 8Gy x 4), (D) anti-human-PD-1 antibodies and RT (n=5). Anti-tumor activities were monitored via tumor size, flow cytometry, immunohistochemistry, and qRT-PCR. RESULTS: One week after the treatment, on the irradiated side, (D) demonstrated lowest tumor volume, highest number of human peripheral blood mononuclear cells, highest percentages of CD8+ human T cells and CD45RO+CD4+ human T cells, and lowest percentage of PD-1+CD8+ human T cells in the tumors via flow cytometry and immunohistochemistry, and highest mRNA level of IFN-gamma in the tumors via qRT-PCR, amongst the four groups with statistical significance. CONCLUSIONS: We demonstrated that this humanized mouse model could be a revolutionary platform to investigate IT against rare cancers such as chordomas, where murine equivalents are unavailable. The direct synergistic effect between IT and RT against chordoma was observed, evidenced by lowest tumor volume, highest cytotoxic T cells, and memory T cells.