Multiple myeloma is a largely incurable bone marrow (BM) resident plasma cell malignancy that is increasing in incidence. Autologous stem cell transplantation (ASCT) is a standard of care therapy that invokes durable progression free survival in a subset of patients that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape, and in both patients and preclinical models, myeloma progression is associated with T cell dysfunction and expression of multiple inhibitory receptors. The inhibitory receptor TIGIT represents a promising new immune checkpoint target as we’ve previously shown that TIGIT is a potent inhibitor of myeloma-specific immunity. Here we found high expression of TIGIT on activated CD8 T cells in mobilized peripheral blood stem cell grafts, which are used during ASCT, from patients with myeloma. These data suggest that combining TIGIT inhibition with ASCT may be a clinically tractable immunotherapy approach.
To guide clinical application of TIGIT inhibition, we evaluated identical TIGIT Abs that do or do not engage FcgR and demonstrated that anti-TIGIT activity is dependent on FcgR-binding. Notably, TIGIT inhibition did not protect against myeloma relapse in all mice and combinational approaches were required to target non-responders. Thus, we tested whether TIGIT blockade could be combined with immunomodulatory drugs (IMiDs) after ASCT. We used IMiD-sensitive CRBN mice to investigate the efficacy of anti-TIGIT in combination with an IMiD, lenalidomide, after transplantation. Notably, the combination provided synergistic, CD8 T cell-dependent, anti-myeloma activity. Analysis of BM-CD8 T cells by flow cytometry and single cell RNA sequencing demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Collectively, these data provide a logical rationale for combining TIGIT inhibition with IMiDs to prevent myeloma progression and as such, a Phase I/II clinical trial exploring this combination is currently enrolling patients with myeloma (NCT05289492).