Lymphoproliferative disorders: prospects for gene therapy

The lymphoproliferative disorders represent a large group of diseases with a significant variation in presentation and clinical course. There has been a trend of increasing incidence for some of these disorders, and despite advances in therapies, a significant number of patients either respond poorly or have early relapses. For this reason there is a need to investigate novel therapies to be used either alone or as adjunct treatment in combination with conventional therapies. Gene therapy is a relatively new field that takes advantage of our increased understanding of molecular biology with the aim of treating a variety of diseases including cancer. It is defined as the introduction of genetic material into cells for therapeutic intent. Methods to improve gene delivery efficiency have been the focus of a large amount of research and to date the optimal procedure uses viruses such as oncoretroviruses, lentiviruses, adenoviruses, adeno-associated viruses and herpes simplex viruses. There are four main gene therapy strategies that might be used for the treatment of lymphoproliferative disorders. First, immunotherapy using tumour vaccines or techniques to enhance the function of immune effector cells has been investigated with some success in patients with B-cell malignancies. Second, the introduction of prodrug-activated 'suicide' genes into cells has been explored, in particular in patients with post-transplantation lymphoproliferative disease. Third, direct lysis of tumour cells using viruses shows some early promise, especially in the treatment of B-cell disorders by manipulating the measles virus to target the CD20 antigen. Finally, anti-gene strategies such as anti-sense therapy, ribozymes, and most recently RNA interference, could be used to suppress expression of specific target genes. RNA interference in particular has tremendous potential and has been studied in the context of anaplastic large cell lymphoma as well as Epstein-Barr virus-associated malignancies. Whilst we are still in the early days of this field and to date results have been modest, there is still a significant potential for gene therapy to play a role in the future treatment of these disorders.