Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model

Camille Guillerey (Corresponding author), Kyohei Nakamura, Andrea C. Pichler, Deborah Barkauskas, Sophie Krumeich, Kimberley Stannard, Kim Miles, Heidi Harjunpää, Yuan Yu, Mika Casey, Alina I. Doban, Mircea Lazar, Gunter Hartel, David Smith, Slavica Vuckovic, Michele W.L. Teng, P. Leif Bergsagel, Marta Chesi, Geoffrey R. Hill, Ludovic Martinet & 1 others Mark J. Smyth

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Immunotherapy holds promise for patients with multiple myeloma (MM), 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 3 weeks after Vk*MYC tumor cell challenge. The quality of the 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 to MM cells (CD8/MM ratio) 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. Together, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.

LanguageEnglish
Article numbere125932
Number of pages20
JournalJCI Insight
Volume4
Issue number14
DOIs
StatePublished - 25 Jul 2019

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Multiple Myeloma
Immunotherapy
Drug Therapy
T-Lymphocytes
Therapeutics
Melphalan
Computer Simulation
Cyclophosphamide
Immunosuppression
Disease Progression
Blood Proteins
Cell Count
Recurrence
Survival
Growth

Cite this

Guillerey, C., Nakamura, K., Pichler, A. C., Barkauskas, D., Krumeich, S., Stannard, K., ... Smyth, M. J. (2019). Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model. JCI Insight, 4(14), [e125932]. DOI: 10.1172/jci.insight.125932
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 W.L. ; Leif Bergsagel, P. ; Chesi, Marta ; Hill, Geoffrey R. ; Martinet, Ludovic ; Smyth, Mark J./ Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model. In: JCI Insight. 2019 ; Vol. 4, No. 14.
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title = "Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model",
abstract = "Immunotherapy holds promise for patients with multiple myeloma (MM), 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 3 weeks after Vk*MYC tumor cell challenge. The quality of the 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 to MM cells (CD8/MM ratio) 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. Together, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.",
author = "Camille Guillerey and Kyohei Nakamura and Pichler, {Andrea C.} and Deborah Barkauskas and Sophie Krumeich and Kimberley Stannard and Kim Miles and Heidi Harjunp{\"a}{\"a} and Yuan Yu and Mika Casey and Doban, {Alina I.} and Mircea Lazar and Gunter Hartel and David Smith and Slavica Vuckovic and Teng, {Michele W.L.} and {Leif Bergsagel}, P. and Marta Chesi and Hill, {Geoffrey R.} and Ludovic Martinet and Smyth, {Mark J.}",
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Guillerey, C, Nakamura, K, Pichler, AC, Barkauskas, D, Krumeich, S, Stannard, K, Miles, K, Harjunpää, H, Yu, Y, Casey, M, Doban, AI, Lazar, M, Hartel, G, Smith, D, Vuckovic, S, Teng, MWL, Leif Bergsagel, P, Chesi, M, Hill, GR, Martinet, L & Smyth, MJ 2019, 'Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model' JCI Insight, vol. 4, no. 14, e125932. DOI: 10.1172/jci.insight.125932

Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model. / Guillerey, Camille (Corresponding author); 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 W.L.; Leif Bergsagel, P.; Chesi, Marta; Hill, Geoffrey R.; Martinet, Ludovic; Smyth, Mark J.

In: JCI Insight, Vol. 4, No. 14, e125932, 25.07.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Guillerey,Camille

AU - Nakamura,Kyohei

AU - Pichler,Andrea C.

AU - Barkauskas,Deborah

AU - Krumeich,Sophie

AU - Stannard,Kimberley

AU - Miles,Kim

AU - Harjunpää,Heidi

AU - Yu,Yuan

AU - Casey,Mika

AU - Doban,Alina I.

AU - Lazar,Mircea

AU - Hartel,Gunter

AU - Smith,David

AU - Vuckovic,Slavica

AU - Teng,Michele W.L.

AU - Leif Bergsagel,P.

AU - Chesi,Marta

AU - Hill,Geoffrey R.

AU - Martinet,Ludovic

AU - Smyth,Mark J.

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N2 - Immunotherapy holds promise for patients with multiple myeloma (MM), 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 3 weeks after Vk*MYC tumor cell challenge. The quality of the 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 to MM cells (CD8/MM ratio) 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. Together, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.

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Guillerey C, Nakamura K, Pichler AC, Barkauskas D, Krumeich S, Stannard K et al. Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model. JCI Insight. 2019 Jul 25;4(14). e125932. Available from, DOI: 10.1172/jci.insight.125932