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(-/-)gammac(-/-) 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(-/-)gammac(-/-) 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.
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 immunodeficientRAG2(-/-)gammac(-/-) 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(-/-)gammac(-/-) 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.
Authors: M Frenquelli; N Caridi; E Antonini; F Storti; V Viganò; M Gaviraghi; M Occhionorelli; S Bianchessi; L Bongiovanni; A Spinelli; M Marcatti; D Belloni; E Ferrero; S Karki; P Brambilla; F Martinelli-Boneschi; S Colla; M Ponzoni; R A DePinho; G Tonon Journal: Leukemia Date: 2019-05-31 Impact factor: 11.528
Authors: Daniel W Sherbenou; Blake T Aftab; Yang Su; Christopher R Behrens; Arun Wiita; Aaron C Logan; Diego Acosta-Alvear; Byron C Hann; Peter Walter; Marc A Shuman; Xiaobo Wu; John P Atkinson; Jeffrey L Wolf; Thomas G Martin; Bin Liu Journal: J Clin Invest Date: 2016-11-14 Impact factor: 14.808
Authors: Emily B Ehlerding; Christopher G England; Dawei Jiang; Stephen A Graves; Lei Kang; Saige Lacognata; Todd E Barnhart; Weibo Cai Journal: Mol Pharm Date: 2017-06-08 Impact factor: 4.939
Authors: Andrei A Postnov; Henk Rozemuller; Viviene Verwey; Henk Lokhorst; Nora De Clerck; Anton C Martens Journal: Calcif Tissue Int Date: 2009-10-09 Impact factor: 4.333
Authors: Subhashis Sarkar; Wilfred T V Germeraad; Kasper M A Rouschop; Elisabeth M P Steeghs; Michel van Gelder; Gerard M J Bos; Lotte Wieten Journal: PLoS One Date: 2013-05-28 Impact factor: 3.240
Authors: Simone S Riedel; Anja Mottok; Christian Brede; Carina A Bäuerlein; Ana-Laura Jordán Garrote; Miriam Ritz; Katharina Mattenheimer; Andreas Rosenwald; Hermann Einsele; Bjarne Bogen; Andreas Beilhack Journal: PLoS One Date: 2012-12-26 Impact factor: 3.240
Authors: Zhihong Ren; Jeong Hyun Ahn; Hequn Liu; Yi-Hsuan Tsai; Natarajan V Bhanu; Brian Koss; David F Allison; Anqi Ma; Aaron J Storey; Ping Wang; Samuel G Mackintosh; Ricky D Edmondson; Richard W J Groen; Anton C Martens; Benjamin A Garcia; Alan J Tackett; Jian Jin; Ling Cai; Deyou Zheng; Gang Greg Wang Journal: Blood Date: 2019-08-05 Impact factor: 25.476