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TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice
- Source :
- Journal of Clinical Investigation. February 15, 2023, Vol. 133 Issue 4
- Publication Year :
- 2023
-
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.sup.+] 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 Fc[gamma]R and demonstrated that anti-TIGIT activity is dependent on Fc[gamma]R 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.sup.+] T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) [CD8.sup.+] 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.<br />Introduction Autologous stem cell transplantation (ASCT) is an effective and highly utilized consolidative therapy for multiple myeloma (MM) that prolongs progression-free survival (PFS). We have previously shown that T cell-dependent [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 133
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.738979371
- Full Text :
- https://doi.org/10.1172/JCI157907