Haematologica 2000;85:supplement to no. 10 - Supplements ...

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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 111 In conclusion, our current knowledge of inhibitor risk in association with hemophilia gene therapy protocols suggests that a number of host and delivery protocol characteristics have been documented to contribute to this potential complication. In initial trials of this novel therapeutic modality, extreme care must be exercised to take all of these factors into consideration in order to minimize the risk of inhibitor development. Only after a thorough evaluation of gene therapy has been undertaken in hemophiliacs without the development of inhibitors will it be acceptable to explore the exciting possibility of using this therapeutic modality to induce immune tolerance in patients with pre-existing inhibitors. REFERENCES 1. Schwaab R, Brackman HH, Meyer C, et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74:1402-6. 2. VandenDriessche T, Vanslembrouk V, Goovaerts I, et al. Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII deficient mice. Proc Natl Acad Sci USA 1999; 96:10379-84. 3. Jooss K, Yang Y, Fisher KJ, Wilson JM. Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers. J Virol 1998; 72:4212-23. 4. Pastore L, Morral N, Zhou H, et al. Use of a liver-specific promoter reduces immune responses to the transgene in adenoviral vectors. Hum Gene Ther 1999; 10: 1773-81. 5. Pittman DD, Alderman EM, Tomkinson KN, et al. Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII. Blood 1993; 81:2925-35. 6. Lusher J, Spira J, Rodriguez D, and the ReFacto PUP Study Group. A four year update of safety and efficacy of an albumin-free formulated, B-domain deleted factor VIII (BBDrFVIII, r-VIII SQ) in previously untreated severe hemophilia A patients. Thromb Haemost 1999; August (Suppl):1492a. 7. Kessler CM, Spira J, Fraunhofer A, ReFacto PTP Study Group. Safety and efficacy of an albumin-free formulated, B-domain deleted recombinant factor VIII (BBDrFVIII, r-VIII SQ) in previously treated patients (PTPs) [abstract]. A four year update. Thromb Haemost 1999; August (Suppl):1493a. 8. Arruda VR, Hagstrom JN, Herzog RW, et al. Biochemical and functional characterization of myotube synthesized factor IX. Thromb Haemost 1999; August (Suppl):84a. 9. Matzinger P. Tolerance, danger and the extended family. Ann Rev Immunol 1994; 12:991-1045. 10. Andrews A, Shirley P, Gallo-Penn AM, et al. Adenoviral vectors for the treatment of hemophilia A. Thromb Haemost 1999; August (Suppl):88a. 11. Herzog RW, Yang EY, Couto LB, et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 1999; 5:56-63. DISCUSSION 19 Gene therapy, factor VIII inhibitors and immune tolerance: hopes and concerns D. Lillicrap (Kingston, Canada) SAINT REMY: Dr. Lillicrap, I would like to ask you a question about the presence of CBG motifs in vectors; as far as I am aware most of the vectors used in gene therapy do contain such motifs. We know that such motifs would stimulate antigen-presenting cells and make them produce interferon gamma, activated T cells - the best environment to induce imunogenicity. Could you just summarize the evidence LILLICRAP: I think this is a very important issue and one that gene therapists are catching up on belatedly. There is no doubt that the CBG motifs are immuno-stimulatory and I believe that if you can modify those motifs or remove them from the vector background it is one of the factors which will reduce the likelihood of immunostimulation. People are belatedly taking a look at what they initially thought were innately neutral vector backgrounds. GARGALLO: If these protocols prove to be safe in the future I would like to know if the child is partially tolerized by a negative inhibitor in normal recovery but still has a short half-life could the child be a good candidate for gene therapy and would this depend upon the level of factor produced under gene therapy My second question is: if the child had developed an inhibitor against a certain recombinant product and was tolerized with that product, could he develop inhibitors a second time against that factor that he would produce in that it’s going to be a B domain deleted factor VIII LILLICRAP: I think the issue of patient choice for the initial gene therapy studies has occupied people’s minds a great deal in the last couple of years and will continue to do so. It’s very difficult to say definitively who should be the ideal candidates. The selection process is complex given that many of the hemophilia population already have inflammatory processes such as long term hepatitis C infection. This means that to get the right patient population early on will be tough. I don’t think that any of the things you said would exclude patients subsequently but they may not be the initial patients undergoing gene therapy. Haematologica vol. 85(supplement to n. 10):October 2000
112 D. Lillicrap DI MICHELE: I am a little concerned about your last statement about the tissue damage and inflammation because no matter how much you modify a vector you still have to get this gene in somehow. I can’t imagine not violating the body in some slight way to produce an inflammatory response in order to produce cellular uptake of this gene. I think the important question is really going to be how much tissue damage and inflammation is too much and I wonder how we might go about understanding that better because I think it’s a crucial issue. LILLICRAP: I don’t think we really know but I think we are likely to find out during meetings such as this one where clinicians, immunologists and others interested in gene delivery exchange ideas because I think that no one group can answer this complex question. The immunology of gene delivery is going to be very pertinent to individuals in this room and as we follow the immune tolerance protocols along with evolving gene therapy I think that the immunologists will be able to help both groups of individuals. Some of the new vectors as you are well aware do not really produce much inflammation and so I think there is an advantage both in the fact that this virus doesn’t transduce APCs and appears to be minimally inflammatory after delivery. Thus, we’re beginning to find vector systems which will produce advantages. Who knows if non-viral delivery, which should not be discounted, may be an advantage sometime in the near future. DI MICHELE: I would just like to say that our immune tolerance studies, as limited as they are, can help us in identifying not only inflammatory events but maybe again if people think about what we should be measuring in terms of inflammatory markers that might help us to further understand this process with respect to inhibitor development. ALEDORT: Dr: Lillicrap, I think you have given some balance with regard to some of the issues that we as clinicians are going to have to face in terms of recruiting people to studies. I think that we have to be really cautious in how therapeutically enthusiastic we should be at this point in entering people into the study. I think the death of this young man which has nothing to do with hemophilia but which certainly has to do with gene therapy is going to make recruitment into studies very different to what it was a week ago. As clinicians we need to reconsider informed consent because it is really a huge responsibility. We can be very enthusiastic or we can give some perspective to our patients on this new modality. LILLICRAP: I agree that getting the balance here is critical. It’s a time of great opportunity but we must be careful. Haematologica vol. 85(supplement to n. 10):October 2000
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28 P. Lollar these epitopes by site
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