Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model.
JCI Insight
; 52019 06 13.
Article
en En
| MEDLINE
| ID: mdl-31194697
ABSTRACT
Immunotherapy holds promise for multiple myeloma (MM) patients but little is known about how MM-induced immunosuppression influences response to therapy. Here, we investigated the impact of disease progression on immunotherapy efficacy in the Vk*MYC mouse model. Treatment with agonistic anti-CD137 (4-1BB) mAbs efficiently protected mice when administered early but failed to contain MM growth when delayed more than three weeks after Vk*MYC tumor cell challenge. The quality of CD8+ T cell response to CD137 stimulation was not altered by the presence of MM, but CD8+ T cell numbers were profoundly reduced at the time of treatment. Our data suggest that an insufficient ratio of CD8+ T cells over MM cells (CD8/MM) accounts for the loss of anti-CD137 mAb efficacy. We established serum M-protein levels prior to therapy as a predictive factor of response. Moreover, we developed an in silico model to capture the dynamic interactions between CD8+ T cells and MM cells. Finally, we explored two methods to improve the CD8/MM ratio anti-CD137 mAb immunotherapy combined with Treg-depletion or administered after chemotherapy treatment with cyclophosphamide or melphalan efficiently reduced MM burden and prolonged survival. Altogether, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ligando 4-1BB
/
Inmunoterapia
/
Anticuerpos Monoclonales
/
Mieloma Múltiple
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
JCI Insight
Año:
2019
Tipo del documento:
Article
País de afiliación:
Australia