IL‐12 immunotherapy of murine leukaemia: comparison of systemic versus gene modified cell therapy

The ability of IL‐12 to initiate anti‐leukaemia immune responses has been well established; however clinical outcomes fail to recapitulate the therapeutic benefits observed in the laboratory. To address this, we compared two systems of IL‐12 therapy that elicit protective immune responses against the murine acute lymphoblastic leukaemia (ALL) cell line, 70Z/3. These systems differ in the method of IL‐12 administration and ultimately result in leukaemia clearance by distinct mechanisms, emphasizing the importance of treatment vehicle. Injecting low‐dose IL‐12 was sufficient to elicit long‐term protective immunity against an established leukaemia burden, mediated by both CD4 + and CD8 + T cells. These findings agree with the standard model of IL‐12 activity. We compared this protocol to a cell‐based approach in which a novel lentiviral vector (LV) expressing murine IL‐12 was created, 70Z/3 cells transduced, and clones selected that stably secrete different amounts of IL‐12. We found that only a small proportion (1%) of IL‐12 secreting cells were required for rejection but that the amount of IL‐12 produced per cell was critical for successful therapy. Importantly, the levels of IL‐12 required were found to be higher than the levels reported to date in the human clinical trial literature. We found that the cell‐based approach led to protective immunity that was both long‐term and specific but dependent primarily on a CD4 + cellular subset alone. Our results highlight that the mode of IL‐12 delivery has a distinct impact on the immune response initiated, leading to leukaemia clearance by disparate mechanisms. We also establish a new and critical parameter, IL‐12 production/cell, which may have significant implications for future therapeutic design.