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


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.
Rozemuller
Henk
H
Dept. of Immunology, University Medical Center Utrecht, KC.02.085.2, P.O. Box 85500, 3508 AB Utrecht, The Netherlands.
van der Spek
Ellen
E
Bogers-Boer
Lijnie H
LH
Zwart
Mieke C
MC
Verweij
Vivienne
V
Emmelot
Maarten
M
Groen
Richard W
RW
Spaapen
Robbert
R
Bloem
Andries C
AC
Lokhorst
Henk M
HM
Mutis
Tuna
T
Martens
Anton C
AC
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D020350:Graft vs Tumor Effect; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008164:Luminescent Proteins / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000378:metabolism; D016896:Treatment Outcome
D008164:Luminescent Proteins