Multiple myeloma is the second most common hematological malignancy and despite improved patient outcomes in the era of novel agents, it remains largely incurable. Clinical studies show that autologous stem cell transplantation (ASCT) remains an efficacious consolidation treatment for eligible patients and a subset of transplant recipients achieve long-term control of disease. Currently, the prolongation of plateau-phase induced by ASCT is attributed to the use of myeloablative chemotherapy and cytoreduction. However, ASCT generates inflammation and profound lymphodepletion, whilst disrupting the marrow microenvironment, all of which has the potential to induce anti-myeloma immunity. In our parent U01, we have utilized novel preclinical models to provide definitive evidence that ASCT invokes myeloma-specific Th1 immunity and the re-establishment of a state of immune equilibrium. Furthermore, we have demonstrated that disease progression after ASCT in these systems is a result of CD8 T cell exhaustion that is dependent on the accumulation of myeloid suppressive populations and the expression of multiple checkpoint molecules by CD8 T cells. This proposal will study the ability to invoke long term myeloma-specific immune control by optimizing the administration of a novel Th1 inducing synthetic cytokine, DR-18. DR-18 is a decoy resistant IL-18 that is not inactivated by the decoy IL-18 binding protein and preliminary data suggests it is highly effective in preventing myeloma progression. By working with the Ring/Bosenberg U01 that developed DR-18, the major focus of this supplementary award will be the optimization of this therapy for translation into the clinic in patients with myeloma over the next 1-2 years.
Myeloma is a common, largely incurable hematological malignancy of bone marrow plasma cells. Standard treatment approaches involve autologous stem cell transplantation (ASCT) in eligible patients that results in prolonged survival and which we have demonstrated can invoke myeloma-specific Th1 immunity. Despite this, the majority of patients eventually relapse. This proposal aims to prevent immune escape and relapse after ASCT by optimizing maintenance therapy with the synthetic Th1 inducing cytokine, Decoy Resistant IL-18.
