Improving therapeutic efficacy of IL-12 intratumoral gene electrotransfer through novel plasmid design and modified parameters.

The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines results in serious, potentially life-threatening, adverse effects. By contrast, nucleic acid transfer via electroporation (EP) is a safe and effective method of delivering plasmid-encoded cytokines to tumors. Intratumoral delivery of IL-12 plasmid DNA by electroporation (IT-pIL12-EP) produced objective response rates in Phase 2 clinical trials in metastatic melanoma. However, only 17.9% of patients receiving IT-pIL12-EP show a complete therapeutic response. Here, we sought to improve the antitumor efficacy of our clinical IT-pIL12-EP plasmid electroporation platform. We evaluated multiple plasmid designs for IL-12 expression. IL-12 expression from a plasmid incorporating a picornavirus-derived co-translational P2A site was the most effective in expressing IL-12p70. In addition, modifying the electroporation parameters improved transfection efficiency and expression of plasmid-derived IL-12p70, as well as its downstream effector IFN-γ in vivo. Finally, using a murine melanoma model that is representative of the intended target patient population, we show that combining modified electroporation conditions with the pIL12-P2A plasmid expression enhances the systemic antitumor response. These improvements to the IT-pIL12-EP platform may improve patient clinical response rates and survival when translated to clinical trials.

Utility of the routine left lateral view in gated blood pool studies.

One hundred twenty-four sequential gated blood pool studies were examined by four observers in order to determine the impact on overall interpretation created by the addition of a routine left lateral view to supplement the standard LAO and RAO projections. Of these 124 studies, 114 studies in 87 patients were considered technically adequate. Forty-one of the 114 studies revealed differences in the perception of apex motion in the LAO as compared with the left lateral view. In seven of these 41 cases, the overall diagnostic impression was altered by the left lateral view. A 15-minute increase in technician time at an incremental cost of $3.00 is attributed to the added view. Approximately 6% of overall diagnostic impressions were altered because of this additional routine view.