Impaired immune mechanisms are a recognized characteristic of CLL and lead to increased autoimmunity against hematological targets and increased infections late in the disease course. The cause of these defects is poorly understood, but dysregulation of the T-cell compartment may play a role. Indeed, it is possible that the altered immunity in CLL may play a permissive role in the emergence of the malignant clone during the process of lymphomagenesis (46). Although investigators have recognized this factor as a potential barrier, they are developing and testing strategies to increase autoimmunity against the CLL cell. One area of active investigation is the CD40 pathway, which is involved in B-cell differentiation and activity; triggering of the CD40 pathway in germinal center B-cells results in inhibition of apoptosis, proliferation, differentiation with Ig isotype switch, and expression of activation antigens, including CD23, and Fas. In the allogeneic setting, CD40-stimulated B-CLL cells have been reported to activate CD8+ cytolytic T-cells against both untreated and CD40-stimulated B-CLL cells. When done in the autologous setting, however, the CD40-stimulated B-CLL cells could only activate CD4+ T-cells that lacked significant cytolytic activity (47). Whether the absence of autologous CD8+ T-cell expansion is owing to defects in the T-cell compartment of B-CLL needs to be explored, but this possibility presents a barrier to such strategies.
Using this theory, Kato et al. (48) transduced B-CLL leukemic cells with an adenovirus encoding the murine CD154 antigen (CD40 ligand) and showed increased expression of the CD80 and CD86 costimulatory molecules, as well as the generation of cytotoxic T-lymphocytes against unmodified autologous B-CLL cells. Moreover, they demonstrated the activation of noninfected bystander B-CLL cells. Results of a phase I trial using this approach were recently reported by the same group. Nine intermediate or high-risk B-CLL patients received escalating doses of CD154-transduced autologous B-CLL cells. The study demonstrated activation of circulating bystander leukemia cells, as well as reductions in absolute lymphocyte counts and lymph node sizes. Based on these promising results, further studies are planned.
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