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A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect

¹ Dept. of Immunology
² Haematology
³ Clinical Chemistry and Haematology of the University Medical Center Utrecht, Utrecht
⁴ Dept. of Pathology, University of Amsterdam, Amsterdam Medical Center, Amsterdam, The Netherlands

Correspondence: Anton C. Martens, PhD, University Medical Center Utrecht, Dept. of Immunology KC.02.085.2, P.O. Box 85500, 3508 AB Utrecht, The Netherlands. E-mail:a.martens{at}umcutrecht.nl

Background: The development and preclinical testing of novel immunotherapy strategies for multiple myeloma can benefit substantially from a humanized animal model that enables quantitative real-time monitoring of tumor progression. Here we have explored the feasibility of establishing such a model in immunodeficient RAG2^–/–c^–/– mice, by utilizing non-invasive bioluminescent imaging for real-time monitoring of multiple myeloma cell growth.

Design and Methods: Seven multiple myeloma cell lines, marked with a green fluorescent protein firefly luciferase fusion gene, were intravenously injected into RAG2^–/–c^–/– mice. Tumor localization and outgrowth was monitored by bioluminescent imaging. The sensitivity of this imaging technique was compared to that of free immumoglobulin light chain -based myeloma monitoring. Established tumors were treated with radiotherapy or with allogeneic peripheral blood mononuclear cell infusions to evaluate the application areas of the model.

Results: Five out of seven tested multiple myeloma cell lines progressed as myeloma-like tumors predominantly in the bone marrow; the two other lines showed additional growth in soft tissues. In our model bioluminescent imaging appeared superior to free light chain-based monitoring and also allowed semi-quantitative monitoring of individual foci of multiple myeloma. Tumors treated with radiotherapy showed temporary regression. However, infusion of allogeneic peripheral blood mononuclear cells resulted in the development of xenogeneic graft-versus-host-disease and a powerful cell dose-dependent graft-versus-myeloma effect, resulting in complete eradication of tumors, depending on the in vitro immunogenicity of the inoculated multiple myeloma cells.

Conclusions: Our results indicate that this new model allows convenient and sensitive real-time monitoring of cellular approaches for immunotherapy of multiple myeloma-like tumors with different immunogenicities. This model, therefore, allows comprehensive preclinical evaluation of novel combination therapies for multiple myeloma.

Key words: molecular imaging, bioluminescence, luciferase gene marking, cellular immunotherapy, multiple myeloma, graft versus multiple myeloma.