To deliver the ISF35 molecule to target malignant B lymphocytes, we use a replication defective type 5 adenovirus. The adenovirus infects the leukemic cells, resulting in the stable expression of the ISF35 molecule on the cell surface. The adenoviral proteins trigger the immune system to attack infected malignant cells, and ISF35 augments this response, resulting in a localized full-force reaction against the treated cells. When the triggering antigen (adenoviral protein) disappears because the carrier adenovirus does not replicate, the treated cells undergo spontaneous apoptosis. ISF35 results in the rapid reduction of circulating and lymph node-bound leukemic cells, the up-regulation of pro-apoptotic proteins sensitizing these cells to standard treatments, and the generation of anti-leukemic immune responses that may have long term impact on disease progression. The adenovirus, containing the ISF35 molecule, can be used to infect leukemic cells ex vivo or by direct injection into tumor beds.
The treatment of CLL patients' disease with autologous ISF35-treated leukemic cells results in a reproducible reduction in circulating WBC concentrations and reduction in measured lymph node volumes. Repeat infusion of ISF35 augments the activity of this treatment and durable and long-lasting results can be achieved. Additionally, CLL B cell activation by ISF35 results in the up-regulation of a number of membrane-bound pro-apoptotic activator proteins such as CD95, DR5 and TNF receptor 1 and increased intracellular expression of a number of pro-apoptotic proteins including FADD, BID and p73. The activation of these factors increases the sensitivity of the patients' CLL cells to standard chemotherapy. For 17p- CLL patients, ISF35 treatment offers a potential therapeutic option for this form of the disease.