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Immunomodulatory gene therapy for haematological malignancies

The number of gene therapy clinical trials continues to grow. In September 2001, a total of 596 completed ongoing or pending trials world-wide have been identified, the majority being performed in the United States (The Journal of Gene Medicine, 2001). The USA accounts for approximately 75% of the world’s trials and patients. Since 1990, the majority of requests for trial approval have been in the area of oncology (Dranoff, 1998), accounting for over 50% of all patients participating in gene therapy trials world-wide, involving both gene marking studies and trials with therapeutic intent using a variety of strategies. The vast majority of immunomodulatory gene therapy studies for haematological malignancies are also taking place in the U.S.A., with only a small number in the U.K., Canada, France, Germany, Italy and other countries (Table I). Haematological malignancies in which human gene transfer has been performed are leukaemias, lymphomas, and cases with a graft-versus-host disease (GVHD) risk after allogeneic bone marrow transplantation (BMT) in leukaemia and multiple myeloma (Table I). About half of the patients treated with gene therapy undergo in vivo gene transfer, compared with only one third of those treated with gene immunotherapy (Anonymous, 2000). The vast majority of gene therapy clinical trials are currently in phase I or phase I ⁄ II. In terms of the numbers of protocols and patients, biological (viral) vector trials out-number physico-chemical (non-viral) methods by two to one. Retroviruses account for over half of all the biological agents used to date. Over half the patients entered into gene therapy protocols receive a gene encoding either a cytokine or an antigen (Anonymous, 1999). However, a relatively small number of protocols deal with the immunomodulatory gene therapy of haematological malignancies (Table I) [for a review on clinical gene therapy in haematology, especially gene transfer into human stem cells, the reader is referred to Richter & Karlsson (2001) and Brenner (2001]. There have been promising results when applied to in vitro cell cultures and to animal models, but clinical applications have been retarded by several factors. First, haematological malignancies are often systemic. This makes in vivo administration of vectors only possible if the vectors are highly selective for tumour cells. Second, most lymphoma and leukaemia patients have compromised immune systems, which is a hindrance for immune-based treatment strategies. Third, the ex vivo methods of gene transfer require specialized cell processing facilities and the transfer efficiencies have to be optimized for most haematological cells. But haematological malignancies also have advantages concerning gene transfer approaches. Leukaemic cells circulate in the blood, thus large numbers of tumour cells can be harvested and sorted for manipulation ex vivo. The efficiency of transduction can easily be monitored in vitro and simple blood tests can be used to monitor, for example, expression of the transgene. Gene therapy is a promising approach for the treatment of haematological malignancies because the molecular basis of these disorders is increasingly understood, therapeutic genes are available and alternative therapies are often lacking, e.g. for multiple myeloma. The cure rates for leukaemia and lymphoma are relatively high, but treatments remain toxic, expensive and ineffective for some patients. These conditions afflict a substantial number of individuals, often in their most productive years. There is evidence that the immune system has the potential to eradicate haematological malignancy, most apparent in the so-called graft-versus-leukaemia (GVL) effect (Porter & Antin, 1999). The poor immunogenicity of tumour cells results in part from their weak expression of major histocompatibility complex (MHC) antigens, adhesion molecules and co-stimulatory signals that could allow complete T-cell activation. Tumours may also secrete immunosuppressive molecules, such as interleukin 10 (IL-10), transforming growth factor-b (TGF-b) and prostaglandin E2 (PGE2), and they often fail to express cytokines that activate local immune responses (Leroy et al, 1998). One approach uses gene transfer to modify the malignant cell to make it more immunogenic. Another strategy is to effectively enhance the specificity or effector cell function of immune system cells, i.e. by infusion of tumour-specific cytotoxic T cells prepared ex vivo.