Active and Adoptive Immunotherapy in Indolent Lymphoproliferative Diseases

Although monoclonal antibody (mAb) therapy has improved the outcome of low-grade B-cell non-Hodgkin lymphomas (B-NHL), they remain incurable diseases. The intimate relationship between immune cells and lymphomas for its maintenance and progression suggests that immunotherapy may represent a valuable strategy towards the control and eradication of these malignancies. Despite initial successes of anti-idiotype vaccination, its clinical benefits have not been definitely proven. New insights into the mechanisms whereby (i) tumour escape immunity, (ii) certain anticancer treatments exert immunogenic functions, (iii) microenvironment influences lymphoma growth should open new ways for immunotherapeutic intervention. Towards this goal, dendritic cells (DCs) loaded with autologous killed tumour cells were used to immunize indolent B-NHL patients against a wide spectrum of tumour antigens, thereby enhancing the possibility of a clinical success. A significant correlation was observed between clinical responses and both regulatory T cell frequency decrease and natural killer cell activation. These effects were positively associated with calreticulin and heat shock protein (HSP)90 surface expression in dying tumour cells used in the vaccine formulations. Therapeutic improvements might thus be accomplished by stimulating tumour release of "eat-me” signals. T-cell maturation and anti-lymphoma activation were also associated with a positive clinical outcome. A novel artificial expansion system was developed to boost these effects through the ex-vivo generation of functional, long-lasting polyclonal T cells and adoptive cell therapy. Finally, the investigation of tumour-restricted humoral immunity in clinical responders permitted the serological identification of HSP105 as a novel potential NHL immunodominant antigen. HSP105 expression correlated with B-NHL proliferation and aggressiveness. A specific neutralizing Ab significantly reduced lymphoma burden in xenotransplanted mice, thus laying the basis for a novel passive immunotherapy for B-NHL. Collectively, these results provide important information on mechanisms underlying anti-lymphoma immunity and open up the possibility of improving active and passive immunotherapy to the treatment of indolent B-NHLs