Ad-ISF35-transduced autologous cells promote in vitro and in vivo chemosensitization in patients with 17p-/P53-defective chronic lymphocytic leukemia

Abstract

e14552 Background: Transduction of chronic lymphocytic leukemia (CLL) cells with a replication-defective adenovirus (Ad) encoding recombinant CD154 (Ad-ISF35) induces expression of death receptors and Bid via a P53-independent pathway involving induction of P73. Induction of P73 significantly enhances the sensitivity of P53-defective CLL cells to “P53-dependent” drugs, such as Fludarabine (F-ara-A). Patients with P53-defective CLL who received iv infusions of autologous Ad-ISF35-transduced CLL cells were observed to achieve complete remissions (CR) with subsequent treatment using F-ara-A based treatment regimens, suggesting Ad-ISF35 could sensitize P53-defective CLL to chemotherapy. Methods: We examined patients with drug-resistant and/or P53-defective CLL before and after iv infusions of autologous Ad-ISF35-transduced CLL cells who were enrolled in a phase I study examining whether such treatment could sensitize patients to a truncated fludarabine, cyclophosphamide and rituximab (FCR) regimen. We examined CLL cells for sensitivity to F-ara-A in vitro, expression of CD95, DR5, Bid, and P73 and correlated these with the response to treatment in vivo. Results: P53-defective CLL cells were resistant to F-ara-A induced apoptosis with IC50 > 10μM prior to treatment. CLL cells collected from patients≥24 hours after IV infusion of autologous Ad-ISF35-trasduced CLL cells became sensitive to the cytotoxic effects of F-ara-A, with IC50 0.3–1 μM. Enhanced sensitivity to F-ara-A was associated with induced expression of Bid, DR5, CD95, and P73 by circulating CLL cells, an effect lasting≥2 weeks following iv infusion. Consistent with this, we observed complete resolution in lymphocytosis, lymphadenopathy and splenomegaly following 1 cycle of FCR administered 2 weeks after 3 biweekly infusions of Ad-ISF35- transduced CLL cells. Conclusions: IV infusion of autologous Ad-ISF35-transduced CLL cells can induce de novo, systemic expression of death receptors and Bid on bystander CLL cells, which is associated with enhanced sensitivity of P53-defective CLL to the cytotoxic effects of standard chemotherapy [Table: see text]