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

Henk Rozemuller; Ellen van der Spek; Lijnie H. Bogers-Boer; Mieke C. Zwart; Vivienne Verweij; Maarten Emmelot; Richard W. Groen; Robbert Spaapen; Andries C. Bloem; Henk M. Lokhorst; Tuna Mutis; Anton C. Martens

doi:https://doi.org/10.3324/haematol.12349

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

Henk Rozemuller, Ellen van der Spek, Lijnie H. Bogers-Boer, Mieke C. Zwart, Vivienne Verweij, Maarten Emmelot, Richard W. Groen, Robbert Spaapen, Andries C. Bloem, Henk M. Lokhorst, Tuna Mutis, Anton C. Martens

Research output: Contribution to journal › Article › Academic › peer-review

35 Citations (Scopus)

Abstract

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. 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. 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. 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

Original language	English
Pages (from-to)	1049-1057
Number of pages	9
Journal	Haematologica
Volume	93
Issue number	7
DOIs	https://doi.org/10.3324/haematol.12349
Publication status	Published - Jul 2008

Keywords

Animals
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Disease Progression
Graft vs Tumor Effect
Humans
Immunotherapy/methods
Luminescent Proteins/chemistry
Mice
Mice, Transgenic
Multiple Myeloma/immunology
Neoplasm Transplantation
Retroviridae/metabolism
Treatment Outcome

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https://doi.org/10.3324/haematol.12349

Cite this

Rozemuller, H., van der Spek, E., Bogers-Boer, L. H., Zwart, M. C., Verweij, V., Emmelot, M., Groen, R. W., Spaapen, R., Bloem, A. C., Lokhorst, H. M., Mutis, T., & Martens, A. C. (2008). A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect. Haematologica, 93(7), 1049-1057. https://doi.org/10.3324/haematol.12349

@article{488c3691eea543f5944b6135204a7063,

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

abstract = "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. 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. 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. 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",

keywords = "Animals, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Disease Progression, Graft vs Tumor Effect, Humans, Immunotherapy/methods, Luminescent Proteins/chemistry, Mice, Mice, Transgenic, Multiple Myeloma/immunology, Neoplasm Transplantation, Retroviridae/metabolism, Treatment Outcome",

author = "Henk Rozemuller and {van der Spek}, Ellen and Bogers-Boer, {Lijnie H.} and Zwart, {Mieke C.} and Vivienne Verweij and Maarten Emmelot and Groen, {Richard W.} and Robbert Spaapen and Bloem, {Andries C.} and Lokhorst, {Henk M.} and Tuna Mutis and Martens, {Anton C.}",

year = "2008",

month = jul,

doi = "https://doi.org/10.3324/haematol.12349",

language = "English",

volume = "93",

pages = "1049--1057",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "7",

}

Rozemuller, H, van der Spek, E, Bogers-Boer, LH, Zwart, MC, Verweij, V, Emmelot, M, Groen, RW, Spaapen, R, Bloem, AC, Lokhorst, HM, Mutis, T & Martens, AC 2008, 'A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect', Haematologica, vol. 93, no. 7, pp. 1049-1057. https://doi.org/10.3324/haematol.12349

TY - JOUR

T1 - A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect

AU - Rozemuller, Henk

AU - van der Spek, Ellen

AU - Bogers-Boer, Lijnie H.

AU - Zwart, Mieke C.

AU - Verweij, Vivienne

AU - Emmelot, Maarten

AU - Groen, Richard W.

AU - Spaapen, Robbert

AU - Bloem, Andries C.

AU - Lokhorst, Henk M.

AU - Mutis, Tuna

AU - Martens, Anton C.

PY - 2008/7

Y1 - 2008/7

N2 - 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. 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. 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. 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

AB - 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. 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. 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. 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

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Disease Models, Animal

KW - Disease Progression

KW - Graft vs Tumor Effect

KW - Humans

KW - Immunotherapy/methods

KW - Luminescent Proteins/chemistry

KW - Mice

KW - Mice, Transgenic

KW - Multiple Myeloma/immunology

KW - Neoplasm Transplantation

KW - Retroviridae/metabolism

KW - Treatment Outcome

U2 - https://doi.org/10.3324/haematol.12349

DO - https://doi.org/10.3324/haematol.12349

M3 - Article

C2 - 18492693

SN - 0390-6078

VL - 93

SP - 1049

EP - 1057

JO - Haematologica

JF - Haematologica

IS - 7

ER -