Abstract 5221: A fusion toxin for the treatment of acute lymphoblastic leukemia
Authors: Reshmi Parameswaran, Min Yu, Mi-Ae Lyu, Michael Rosenblum, John Groffen, Nora Heisterkamp
Journal: Cancer Research (2012)

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Two major challenges in the therapy of B-lineage ALL are overcoming acquired drug resistance and treatment of relapse. The interaction of ALL cells with the bone marrow microenvironment is thought to assist the development of resistance to therapeutic drugs. Therefore, we are focusing on the bone marrow microenvironment as a possible target for treatment by investigating the interactions between cell surface receptors on the ALL cells that are engaged by factors produced in the bone marrow. Recently, we were the first to report that pre-B ALL cells express the B cell-activating factor receptor (BAFF-R). In the current study, we used a fusion protein, consisting of the toxin Gelonin (a plant toxin which inhibits protein synthesis by inactivating ribosomes) and the ligand for the BAFF-R, BAFF/BLys for selective killing of ALL cells. Gelonin cannot enter the cells by itself since it lacks the ability to bind to the cell surface. Here, we demonstrate that rGel/BLyS binds to ALL cells expressing BAFF-R and, upon internalization, it induces apoptosis of these cells and causes down-regulation of survival genes even in the presence of stromal protection. Further, we transplanted human leukemic cells into NSG mice and allowed the cells to proliferate for 6 days to form an appreciable tumor burden. Then 3.75 mg/kg rGel/BLyS was administered bi-weekly for 3 weeks. Mice not receiving treatment had to be sacrificed at around day 34 whereas mice treated with rGel/BLyS survived significantly (p&amp;lt;0.002) longer. Remarkably, FACS analysis of peripheral blood from mice treated with rGel/BLyS, using human CD19 and CD10 antibodies, showed that the treatment had eliminated virtually all circulating leukemia cells. However, the bone marrow (BM) of these mice clearly contained leukemic cells. We used AMD3100, a CXCR4 antagonist, to mobilize the ALL cells protected in the bone marrow microenvironment, in combination with rGel/BLyS. In the combination treatment group, mice were first treated with rGel/BLyS alone to reduce the overall leukemia burden. Then the combination treatment was initiated, with AMD3100 injected 5-6 hours before the rGel/BLyS was administered. This strategy was used to ensure the presence of ALL cells in circulation at the time when the toxin would also be in the circulation. The combination treatment resulted in a significant reduction of the tumor load in the bone marrow and complete eradication of ALL cells from the circulation. To conclude, rGel/BLyS is a very promising therapeutic agent for ALL with selective cytotoxicity mediated by its fusion to the ligand for the BAFF-R. Moreover, by combining this selective but toxic fusion protein with a non-toxic ALL mobilizing agent, we were able to significantly deplete the pool of malignant lymphoblasts in vivo that could form the basis for relapse in the bone marrow. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5221. doi:1538-7445.AM2012-5221