Molecular strategies to generate tumor vaccines for non-Hodgkin's lymphoma.
摘要
Despite the use of intensified chemotherapy and radiotherapy, the majority of patients with low grade non-Hodgkin's lymphoma remains incurable. The relatively low effectiveness of these modalities and their potential toxicity has inspired the search for alternative therapeutic strategies. One such approach attempts to utilize the immune system to target and eliminate lymphoma cells specifically. Lymphoma are unique in that they express tumor-specific antigens, the idiotypic determinants of the immunoglobulin variable regions. These offer the opportunity to create lymphoma-specific vaccines. However, the use of idiotypes (Id) for tumor vaccination has been hampered by the relatively low immunogenicity the Id sequences. Therefore, several strategies might enhance the efficacy of anti-Id vaccines: 1. Use of professional antigen-presenting cells (APCs) such as dendritic cells (DCs) loaded with Id peptide sequences; 2. gene transfer of cytokines or costimulatory molecules into lymphoma cells; 3. stimulation of CD40 present on most lymphoma cells by CD40 ligand (CD40L) which induces the up-regulation of costimulatory and MHC molecules on B cells. 4. Use of monoclonal or bispecific antibodies detecting lymphoma specific epitopes. It is open which of these strategies (or a combination thereof) will be optimal. Our group has developed simplified strategies for the isolation of lymphoma-specific idiotypes, and a vector system based on adeno-associated virus (AAV) allowing to express costimulatory B7 molecules on lymphoma cells. With this recombinant AAV vectors coding for human B7-1 and B7-2 genes, we transduced different lymphoma cell lines. B7-1 and B7-2 transduced tumor cell lines induced a strong anti-lymphoma T-cell response as shown by the enhanced proliferation, cytokine (IL-2) production and a cytotolytic T cell (CTL) response in vitro. Stimulation of freshly isolated lymphoma cells with CD40L also induced an up-regulation of many co-stimulatory molecules including B7-1 and B7-2, and stimulated a strong CTL response in vitro. These studies illustrate that lymphoma cells have apparent defects in costimulation which can be corrected to create a specific cytolytic T cell activity against the tumor.