Adoptive Immunotherapy of p53-Mutated B-CLL with a Trifunctional Antibody (Anti-CD3 x Anti-CD20) and Allogeneic Donor Lymphocyte Transfusion.

In most cases CLL patients with p53 aberrations are refractory to standard treatment approaches, even to allogeneic stem cell transplantation (ASCT). Here we report 3 patients with relapse after ASCT that were treated with the combination of the trifunctional antibody Bi20 and donor lymphocyte transfusions (DLT). The Bi20 antibody is trifunctional, it binds to CD20 and CD3 and activates phagocytosis of the leukemia cell by accessory cells via the Fc part. Bi20 was applied in escalating doses from 10 μg up to 640 μg and followed by DLT (1 x 10⁷/kg body weight). Patient 2 and 3 received repeated courses of antibody and DLT. In all cases we observed a prompt, dose-dependent decrease of B-CLL cells in the peripheral blood, which already started hours after application of the antibody infusion. Furthermore, in all cases the reduction of the enlarged lymph nodes and spleen went along with a significant improvement of the clinical symptoms like night sweat. Clinically, side effects were restricted to fever, chills and bone pain that could be easily controlled. These effects peaked at a concentration of 80 μg and did not increase or even decreased at higher concentrations. The cytokine profile was characterized by a transient increase of IL-6, IL-12 and IL-10. With respect to the transaminases, only a transient and modest increase of γGT was observed. HAMAs (human anti mouse antibodies) were not detectable; the absence allowed repeated transfusions of the trifunctional antibodies. Moreover, graft-versus-host disease (GVHD) was not observed. Unfortunately relapse of the disease occurred in all cases. In two cases repeated application of Bi20 and T-cells induced a repeated response. The overall survival was 47, 151 and 196 days. Bi20 can induce a prompt anti tumor response in B-CLL patients with a p53 mutation. The toxicity of treatment is not severe. However the response is of short duration and further studies are necessary to improve the outcome of patients by e.g. optimizing the application schedule.