TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice
Simone A. Minnie, Olivia G. Waltner, Kathleen S. Ensbey, Stuart D. Olver, Alika D. Collinge, David P. Sester, Christine R. Schmidt, Samuel R.W. Legg, Shuichiro Takahashi, Nicole S. Nemychenkov, Tomoko Sekiguchi, Gregory Driessens, Ping Zhang, Motoko Koyama, Andrew Spencer, Leona A. Holmberg, Scott N. Furlan, Antiopi Varelias, Geoffrey R. Hill
Simone A. Minnie, Olivia G. Waltner, Kathleen S. Ensbey, Stuart D. Olver, Alika D. Collinge, David P. Sester, Christine R. Schmidt, Samuel R.W. Legg, Shuichiro Takahashi, Nicole S. Nemychenkov, Tomoko Sekiguchi, Gregory Driessens, Ping Zhang, Motoko Koyama, Andrew Spencer, Leona A. Holmberg, Scott N. Furlan, Antiopi Varelias, Geoffrey R. Hill
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Research Article Immunology Oncology

TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice

Abstract

Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell–dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.

Authors

Simone A. Minnie, Olivia G. Waltner, Kathleen S. Ensbey, Stuart D. Olver, Alika D. Collinge, David P. Sester, Christine R. Schmidt, Samuel R.W. Legg, Shuichiro Takahashi, Nicole S. Nemychenkov, Tomoko Sekiguchi, Gregory Driessens, Ping Zhang, Motoko Koyama, Andrew Spencer, Leona A. Holmberg, Scott N. Furlan, Antiopi Varelias, Geoffrey R. Hill

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Figure 6

αTIGIT and lenalidomide generate immunological memory that is highly dependent on CD8+ T cells in the donor graft.

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αTIGIT and lenalidomide generate immunological memory that is highly dep...
(A and B) B6 or CRBN recipients were transplanted with 10 × 106 BM with 2 × 106 T cells from B6 or CRBN donors and then treated with 100 μg of αTIGIT or cIg twice a week from day 0 and daily lenalidomide (50 mg/kg) or vehicle from day +14 until 5 weeks after SCT. (A) M-band in long-term survivors after αTIGIT + lenalidomide treatment that were rechallenged with Vk12653 compared to naive controls (n = 5–6/group). G/A, gamma/albumin ratio. (B) Modeled M-band and overall survival of recipients transplanted as above or with T cell–depleted BM (TCD) or treated with CD8-depleting antibodies (αCD8). Median survival analyzed with log-rank test and Benjamini-Hochberg correction for multiple comparisons. Tukey’s test was performed to correct for multiple comparisons for modeled M-bands. Mann-Whitney was used for comparison of 2 data sets. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.