Covid 19: Improving CAR T Cell Function in CLL by Blocking Interleukin-10

Abstract T-cell immune therapies such as Chimeric Antigen Receptor (CAR) T-cell and Immune Checkpoint Blockade (ICB) have experienced limited success in B-cell Chronic Lymphocytic Leukemia (CLL). While anti-CD19 CAR T-cells are extremely effective in other B-cell malignancies, complete response rates remain low in CLL. T-cell dysfunctionality is well documented in CLL patients, and CLL cells play an active role in downregulating immune responses including the production of immune suppressive cytokines like Interleukin-10 (IL-10). In our recently submitted manuscript, we discovered that suppressing CLL-derived IL-10 greatly improves responses to ICB in a murine CLL model, and that reducing IL-10 levels restored T- cell functionality. Others have previously shown positive outcomes with CAR T-cell therapy in CLL may be linked to proinflammatory cytokine signals, such as IL-6. Therefore, we hypothesize that CLL-derived IL-10 plays an active role in decreasing CAR T-cell functionality, and we will test whether IL-10 blockade can restore CAR T-cell function. We will approach this by generating IL-10 receptor knockout anti-CD19 murine CAR T-cells, and test for increased functionality, reversal of exhaustion, and improved control of disease. These studies may greatly impact the treatment of hematologic malignancies, particularly those associated with immune dysfunction.