2003; baxter - Supplements - Haematologica

112D. LillicrapFigure 1. A comparison of the host immune response withcoagulation protein delivery by either exogenous infusionor by gene therapy.Figure 2. Elements of the early, innate immune response followingadenoviral gene delivery and the later adaptive immunityinvolving cell-mediated and humoral responses to severalcomponents of the gene therapy protocol.transduction, using DNA microarray technology,it has been shown that the expression of severalhundreds of genes are altered, some of whichcorrespond to early response genes that are activatedunder acute-phase circumstances (unpublisheddata, Stilwell JL and Samulski RJ). In animalsand patients receiving adenoviral vectors,this early immune response is most often manifestthrough, transient hepatotoxicity (elevatedALT values), transient thrombocytopenia andelevations of the acute phase cytokines IL-6 andTNFα. These innate responses have been extensivelydocumented with early generation adenoviralvectors, and there is at least some evidenceto indicate that a similar, albeit reduced, innateresponse accompanies delivery of helper-dependentvectors. Whether this response to helperdependentvectors relates to factors such as themagnitude of helper virus contamination of thevector preparation remains to be resolved.Another feature of this early response which hasstill to be resolved is the potential for significantinter-individual variability in the magnitude ofthe response and the influence of pre-existinganti-adenoviral antibodies. 10,11 It is possible thatthese variables might significantly complicate theprediction of vector doses that are both effectiveand safe.Acquired immunity following adenoviralgene therapyThe second component of the immuneresponse following adenoviral gene deliveryinvolves an acquired cell mediated and humoralresponse. There is now good evidence to indicatethat these responses will differ for the earlyand later generations of adenoviral vectors. Thus,while residual viral transcription and presentationof virally-derived peptides will occur withearly generation vectors, in which a number ofadenoviral genes are preserved, this will not complicatethe delivery of helper-dependent adenoviralvectors. This has the consequence of minimizingthe risk of a subsequent cell-mediatedresponse following the delivery of helper-dependentvectors. In theory, this should serve to protecttransduced cells from immune attack andshould therefore enhance the likelihood of a positiveoutcome from adenoviral transgene delivery.In contrast, humoral responses to the viral capsidproteins will likely occur with equal frequencyfor the early generation and latest forms ofAdenovector.Immune responses to the transgeneproduct in adenoviral-mediatedhemophilia gene therapyThe development of neutralizing anti-clottingfactor antibodies (inhibitors) following hemophiliagene therapy remains a potential treatmentcomplication that requires further investigation.Clearly, the generation of inhibitors in a substantialproportion of individuals treated withgene therapy would represent a profound concernfor the continuation of this therapeuticapproach.As stated above, no inhibitors have been detectedin any of the 27 patients enrolled in the firstthree, phase I/II clinical trials. However,inhibitors have been documented, in manyinstances, in pre-clinical animal protocols forhemophilia gene therapy. Among the factors thatcontribute to this propensity are the use of heterologoustransgenes, the employment of pro-haematologica vol. 88(supplement n. 12):september 2003