Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche.
Animals
Bone Marrow
/ immunology
CD8-Positive T-Lymphocytes
/ immunology
Cell Line, Tumor
Coculture Techniques
Cytokines
/ immunology
Cytotoxicity, Immunologic
Female
Humans
Killer Cells, Natural
/ immunology
Male
Mice, Inbred C57BL
Multiple Myeloma
/ immunology
Oncolytic Virotherapy
Oncolytic Viruses
/ immunology
Reoviridae
/ immunology
Spleen
/ immunology
Tumor Escape
Tumor Microenvironment
/ immunology
adaptive immunity
immunity
immunotherapy
innate immunity
oncolytic viruses
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
accepted:
17
02
2021
entrez:
20
3
2021
pubmed:
21
3
2021
medline:
18
12
2021
Statut:
ppublish
Résumé
Multiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported. This study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment. Using the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8 These data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.
Sections du résumé
BACKGROUND
Multiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.
METHODS
This study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.
RESULTS
Using the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8
CONCLUSION
These data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.
Identifiants
pubmed: 33741729
pii: jitc-2020-001803
doi: 10.1136/jitc-2020-001803
pmc: PMC7986878
pii:
doi:
Substances chimiques
Cytokines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Yorkshire Cancer Research
ID : L374RA
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C16708/A21855
Pays : United Kingdom
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: MC is affiliated with Oncolytics Biotec Inc.
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