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

• Published in: The Journal of clinical investigation Vol. 133; no. 4; pp. 1 - 11
• Main Authors: Minnie, Simone A, Waltner, Olivia G, Ensbey, Kathleen S, Olver, Stuart D, Collinge, Alika D, Sester, David P, Schmidt, Christine R, Legg, Samuel Rw, Takahashi, Shuichiro, Nemychenkov, Nicole S, Sekiguchi, Tomoko, Driessens, Gregory, Zhang, Ping, Koyama, Motoko, Spencer, Andrew, Holmberg, Leona A, Furlan, Scott N, Varelias, Antiopi, Hill, Geoffrey R
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.02.2023
• Subjects: Analysis; Animals; Antibodies; Apheresis; Autografts; Biomedical research; Bone marrow; Care and treatment; CD8 antigen; Cell receptors; Cryopreservation; Drug synergism; Flow cytometry; Health aspects; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune response; Immunity - drug effects; Immunity - genetics; Immunological memory; Immunological research; Immunology; Immunomodulation; Immunosuppressive agents; Immunotherapy; Lenalidomide - pharmacology; Lymphocytes; Lymphocytes T; Memory cells; Mice; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Multiple Myeloma - therapy; Neoplasm Recurrence, Local; Oncology; Peripheral blood; Phenotypes; Receptors, IgG; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Stem cell transplantation; Stem Cell Transplantation - adverse effects; Stem cells; T cells; Targeted cancer therapy; Transplantation; Transplantation, Autologous; Tumor Microenvironment; Australia; Bone marrow transplantation; Oncology; Adaptive immunity; Immunology; Cancer immunotherapy
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI157907

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.