Immunogenetic therapy for B-cell malignancies.

Abstract

Neoplastic B cells are stealthlike in their ability to evade immune detection, even by allogeneic T cells of normal healthy donors. This stealthlike phenotype can be reversed by activating neoplastic B cells through ligation of CD40, a cell surface molecule that can interact with a ligand expressed on activated T cells. The gene encoding this ligand, CD154, can be transferred into neoplastic B cells ex vivo through infection with a modified adenovirus vector called Ad-CD154. This results in a dramatic change in the phenotype and function of the neoplastic B cells. Infected malignant B cells can stimulate T cells reactive with potential tumor antigens and induce autologous cytotoxic T cells capable of destroying the neoplastic B cells in vitro. This formed the basis for an immune gene therapy protocol in which patients were infused with Ad-CD154-transduced leukemic B cells. Treatment was well tolerated, without apparent long-term toxicity, and without a maximum tolerated dose. Biologic and clinical responses were observed, including significant reductions in leukemia cell counts and lymph node sizes after a single one-time infusion. Furthermore, preliminary data suggest that this approach can enhance antibody-dependent cellular cytotoxicity and thereby augment the activity of antitumor monoclonal antibody therapy. Development of such strategies may allow for effective immunogenetic therapy for B-cell malignancies.