Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation

Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance anti-myeloma immunity after ASCT represents a major unmet need. Here, we demonstrate that patient mobilized stem cell grafts include high numbers of both effector CD8 T cells and immunosuppressive regulatory T cells (Treg). We show that BM residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit anti-myeloma immunity during SCM. We thus undertook ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells that dramatically enhanced myeloma control after ASCT. We thus explored clinically tractable translational approaches to mimic this scenario. Antibody based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic IL-2/IL-15 mimetic which stimulates the IL-2 receptor on CD8 T cells without binding to the high affinity IL-2Ra utilized by Treg, efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirm that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represents a clinically testable strategy to improve responses after ASCT.-