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.

Authors	Guillerey, Camille; Nakamura, Kyohei; Pichler, Andrea C; Barkauskas, Deborah; Krumeich, Sophie; Stannard, Kimberley; Miles, Kim; Harjunpää, Heidi; Yu, Yuan; Casey, Mika; Doban, Alina I; Lazar, Mircea; Hartel, Gunter; Smith, David; Vuckovic, Slavica; Teng, Michele Wl; Bergsagel, P Leif; Chesi, Marta; Hill, Geoffrey R; Martinet, Ludovic; Smyth, Mark J
Journal	JCI INSIGHT
Pages
Volume	5
Date	1/06/2019
Grant ID	1122183
Funding Body	Priority-driven Collaborative Cancer Research Scheme grant - Cancer Australia
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1172/jci.insight.125932
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