Enhancing CAR T therapy in multiple myeloma

点击翻译按钮获取中文摘要

SUMMARY OF WORK Our long-term goal is to develop novel approaches to enhance the efficacy of chimeric antigen receptor (CAR) T therapy. CAR T cell therapy targeting B-cell maturation antigen (BCMA) has shown great promise in the treatment of relapsed and/or refractory (RR) multiple myeloma (MM). However, even with relatively short follow-up relapse eventually occurs in over half of all patients with a median progression-free survival of only 11.8 months (Raje et al. N Engl J Med 2019; 380:1726). A better understanding of the mechanisms of myeloma relapse and resistance to CAR T therapy is urgently needed and will lead to improved CAR T therapy. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells consisting of monocytic MDSCs and granulocytic MDSCs. MDSCs inhibit T cell function and are thought to play an important role in CAR T therapy resistance/relapse. The addition of MDSC depleting therapy increases CAR T efficacy in solid tumor models (Long et al. Cancer Immunol Res 2016; 4:869). Recently we have found that patients with RRMM had significantly elevated Gr-MDSCs. Additionally, we found that an increase of MDSCs correlated with the development of MM in a transplantable VK*MYC mouse myeloma model. Interestingly, compared to wild-type or sphingosine kinase 1 (SK1) knockout mice, sphingosine kinase 2 (SK2) knockout mice were completely free of myeloma after being injected with VK*MYC myeloma cells and showed significantly reduced numbers of MDSCs. Furthermore, treatment with a specific SK2 inhibitor (ABC294640, YELIVAÒ) eliminated both human and mouse MDSCs. ABC294640 showed an excellent safety profile in our recently completed phase I study in patients with RRMM (NCT02757326). The objective of this application is to determine the efficacy of combining SK2 inhibition with CAR T therapy in the treatment of MM. Our central hypothesis is that the combination of SK2 inhibitor and CAR T therapy will enhance the response and duration of the CAR T therapy by reducing the number of MDSCs. We have three specific aims. Aim 1 is to determine the efficacy of the combination of SK2 inhibitor (ABC294640) and CAR T therapy in vivo in a fully immunocompetent, syngeneic myeloma CAR T therapy mouse model. We will determine the efficacy of combining ABC294640 with mouse BCMA-targeted CAR T cell therapy in vivo. Aim 2 is to determine the mechanisms through which SK2 regulates MDSCs. We will determine the effects of SK2 on MDSC differentiation and function and on the S1P-STAT3/HDAC-1/2- ROR-gt pathway. Aim 3 is to measure the number and function of MDSCs over time in hematologic malignancy patients treated with CAR T therapy and determine the correlation between MDSCs and disease relapse/resistance to CAR T therapy. Our research is innovative, because it represents a new and substantive departure and significant advance from the status quo by understanding the roles of MDSCs and SK2 in CAR T therapy. Our study will fundamentally advance our knowledge of CAR T resistance and relapse, and have a positive translational impact on the care and outcomes of patients with MM.