Fellowship for Rivas: Enhancing Antitumor Immunity in Chronic Lymphocytic Leukemia by Blocking Tumor Derived Interleukin

The proposed project aims to study the therapeutic potential of modulating anti-tumor immunity in B cell Chronic Lymphocytic Leukemia (CLL). CLL is the most common leukemia in the western world, with the number of cases expected to rise over the next decade. It is characterized by an accumulation of abnormal B cells in the blood and lymphoid organs and is often accompanied by serious complications such as anemia, immune dysfunction, and splenomegaly. In particular, it has become important to study immune suppression in CLL, as infection and secondary cancers are now the leading causes of morbidity and mortality. We and others have established that CLL cells produce the immunoregulatory cytokine Interleukin-10 (IL-10), and we found that eliminating IL-10 signaling increased anti-tumor T cell responses. Therefore, we propose investigating the blockade of IL-10 to reverse immunosuppression and harness the power of anti-tumor T cells. Many T-cell-based immunotherapies including CAR T-cells have experienced limited success in trials with CLL, and with no cure for this disease our approach may provide a new avenue for combination therapies. IL-10 production by primary human CLL cells as well as splenocytes from the Eì-TCL1 mouse model for CLL depends on the transcription factor Sp1, and we found that the Sp1 inhibitor mithramycin (MTM) is effective at suppressing IL-10 production. However, MTM is not well tolerated in vivo, so we synthesized MTM23, a novel analogue of MTM, which similarly suppresses IL- 10 production and is tolerated at 12-fold higher doses than MTM, with little to no effect on effector T cell cytokine production and viability. Preliminary studies show that MTM23 enhances anti-CLL immunity in vivo. Thus, MTM23 is a paradigm shifting approach to enhance anti-tumor immunity in CLL. We hypothesize that MTM23 in combination with checkpoint blockade or CAR T cells will be a potent enhancer of antitumor immunity in CLL and may be more potent at controlling disease than current strategies. The key focus of this project will be to determine the effect of MTM23 on antitumor immunity with and without combination therapies, with the specific aims of: 1) investigating MTM23 in a mouse model of CLL with and without checkpoint blockade and anti-CD19 CAR T cells, and 2) examining the outcome of MTM23 treatment on human and mouse T cells in the context of CLL.