A Balanced Decision? Regulatory Reaction to the “Third Case”
Authors: David A. Williams
Journal: Molecular Therapy (2005)

The Cellular, Tissue and Gene Therapies Advisory Committee of the U.S. FDA recently met to discuss new insights into the pathogenesis of insertional mutagenesis observed in clinical gene therapy trials and related animal models (http://www.fda.gov/ohrms/dockets/ac/cber05.html). The conference was triggered by a third case of leukemia in the pioneering SCID-X1 gene therapy trial conducted in Paris. The information available at the meeting was that the malignant clone in this third case carried at least three retroviral vector insertions. Meanwhile, the clinical investigators have disclosed in scientific conferences that two of these insertions were found to have upregulated potent cellular proto-oncogenes. While the precise pathogenesis of this and the former two cases of lymphoproliferative complications remain to be elucidated, the panel considered additional data from other ongoing clinical trials and animal models, leading to several important conclusions. Firstly, related clinical studies, including the London SCID-X1 and SCID-ADA trials, the Milan SCID-ADA trial, and the recent Frankfurt trial treating young adults with Chronic Granulomatous Disease have shown striking clinical success in the majority of over twenty patients without evidence of insertional complications. A second conclusion was that the interleukin 2-receptor gamma chain (IL2RG) transgene might be involved in the development of the lymphoproliferative complications. Studies with replication-competent retroviruses in mice strongly suggest that ectopic expression of endogenous Il2rg might collaborate with activated transcription factors—Lmo2 not being the only one—to increase the risk of induction of lymphoid malignancies via vector insertion. Thirdly, mouse models using other transgenes have shown that the risk of insertional leukemogenesis increases with the number of vector copies per cell. A fourth point was the observation of a “myeloid sarcoma” presenting over five years after a nonhuman primate received retrovirally modified CD34+ cells and was subsequently treated with one cycle of antifolates and hematopoietic growth factors. Of two vector insertions found in this clone, one was in proximity of an antiapoptotic gene. In contrast, over forty nonhuman primates under long-term observation have not shown evidence of insertional tumorigenesis, although only seven have been followed for greater than five years. Finally, gene marking studies in mice have revealed that single insertions in proto-oncogenes do not necessarily lead to the development of leukemia, but may give rise to clonal dominance in otherwise intact hematopoiesis. This could actually be therapeutically useful. Confronted with these provocative findings, the panel concluded that while insertional mutagenesis may occur with any type of integrating vector, tumorigenic complications are difficult to predict and are expected to depend strongly on the type of vector and the particular transgene, subsequent therapies that could accelerate oncogenesis such as chemotherapy, and the underlying disease. The panel strongly encouraged detailed studies addressing the underlying mechanisms, particularly considering the established curative potential of gene therapy for an increasing number of disorders. Finally, they concluded that SCID-X1 in particular should not be considered for gene therapy unless any alternative form of stem cell transplantation (SCT), including haploidentical or unrelated donor SCT, has failed to reconstitute the immune system. Having talked to several clinical experts, it appears that haploidentical or unrelated donor SCT might work in selected cases of SCID-X1. As with any therapy (including gene therapy), when transplantation works well, it is an excellent and life-saving therapy. However, it is still associated with a relatively high risk of procedure-related morbidity and mortality. Complications can arise from the need for conditioning therapy in some cases, graft rejection or incomplete immune reconstitution in other cases, and even chronic graft-versus-host disease. These challenges were and remain the impetus for the development of gene therapy. Therefore, these established but still unsatisfactory forms of SCT can hardly be considered a panacea for SCID-X1, and both disciplines (experimental SCT and gene therapy) are urgently awaiting progress in basic research to increase their therapeutic indices. The balance of risk and benefit in gene-based and other experimental therapies should rely on experience rather than expectations. While international meetings of clinical experts in both fields would be useful to continue the discussion of these issues, it should be anticipated that other regulatory bodies will allow continued gene therapy for SCID-X1 on a case-by-case basis. Christopher Baum Experimental Cell Therapy, Hannover Medical School, Germany, and Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA As described above, a new occurrence of leukemia in the French SCID-X1 trial has led to re-examination of the risks and benefits of gene transfer in this and other genetic diseases. As Dr. Baum points out, the track record emerging is of measurable clinical benefit for a group of patients (SCID-X1, SCID-ADA and Chronic Granulomatous Disease) with poor prognosis and no opportunity for a related HLA-matched transplantation procedure. While the FDA Cellular, Tissue and Gene Therapies Advisory Committee has commented that SCID-X1 patients should not be considered for gene therapy unless any alternative form of stem cell transplantation has failed to reconstitute the immune system, there may be a need to rethink this advice. As a practicing hematologist, I (and my patients and their families) are frequently faced with the reality of unrelated or haploidentical donor stem cell transplants as an option for life-threatening blood diseases. While certain centers claim high levels of success, the results often quoted are not widely obtained and represent (as noted by Dr. Baum) selected cases. For a “clean baby” with no infections and a family member donor who has a SCID phenotype likely to engraft without a preparative regimen, transplantation is clearly the preferable therapy. However, for those with less well-matched donors, the potential morbidity and mortality of such a transplantation should be the yardstick against which the risks and benefits of gene therapy are measured. These transplant modalities appear not to come under the same scrutiny as gene therapy trials, likely because they have become “accepted” forms of clinical therapy, in spite of their attendant risks. Studies that may help predict and minimize the risk of insertional mutagenesis are essential and will be key to improving the risk/benefit profile of gene therapy. However, gene therapy need not be free from any risk to be an attractive option compared to transplantation for those children with less well-matched donors. Thus, the idea that these experimental methods are preferred approaches to the treatment of SCID-X1 may need to be re-examined. The American Society of Gene Therapy (ASGT) organized an informative meeting in early April, 2005 in Washington, D.C. that brought together parties from regulatory agencies (FDA, RAC), academia and industry to discuss current barriers to progress in the gene therapy field (proceedings to be published in Molecular Therapy). It was clear from this meeting that remarkable progress has been accomplished in the field over the past 25 years. In many cases, the FDA was seen as a facilitator, but regulatory hurdles for those investigators trying to move the field into the clinic remain very high. The technology itself, while progressing at a rapid rate, needs ongoing improvement and the area of insertional mutagenesis requires additional focus to allow development of safer vectors. Finally, the study of insertional mutagenesis and stem cell behavior resulting from vector insertion clearly offers an opportunity to identify genes important for hematopoiesis and leukemogenesis. These topics will be covered in detail at the upcoming ASGT 8th Annual meeting (http://www.asgt.org/annualmeeting.shtml) and the 2nd Stem Cell Clonality and Genotoxicity meeting in St. Louis (http://www.cincinnatichildrens.org/research/div/exp-hematology/workshops/stemcellretreat/).