GM-CSF and IL-4 Derived Fusion Cytokine Reprograms Leukemic B-Cells to Anti-CLL Effectors

Abstract 4606

Fusion cytokines derived from GM-CSF and common γ-chain interleukins have potent gain-of-function properties to alter host immune response. Considering leukemic B cells from chronic lymphocytic leukemia (CLL) patients broadly express the IL-4 receptor, we generated a human GM-CSF and IL-4 derived fusokine GIFT4 to test its immune function on CLL-B cells. Unexpectedly, GIFT4 protein reprograms leukemic B cells into anti-CLL effectors with T-helper features. We show that GIFT4 recombinant protein led to IL4R-dependent hyper-phosphorylation of STAT5 in primary human CLL cells. GIFT4 treated CLL B-cells also up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86. These cells also secreted IL-1b, IL-6, ICAM1 and substantial IL-2. GIFT4-CLL B cells further propelled the expansion of IFN-g-producing CD314⁺ autologous cytotoxic NK and T cells in vitro. Administration of GIFT4 protein in NSG immune deficient mice decreased the survival of primary CLL cells from patients in murine circulation. Altogether, our data demonstrate that GIFT4 has potent anti-CLL immune function by reprograming leukemic B cells into anti-CLL helper cells. We propose that the newly bio-engineered fusokine GIFT4 could serve as a potential immunotherapeutic for CLL treatment.