Mechanisms of Serotherapy of B-Cell Malignancies

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Serotherapy of non-Hodgkin's lymphoma (NHL) using rituximab has revolutionized the use of naked antibodies in the treatment of cancer. Yet even with this success, there are still many questions about its mechanism of action that, if more were known, could aid in the improvement of or the development of similar relatively non-toxic approaches for treating this and other B-cell malignancies with rituximab or other antibodies. In this regard, we hypothesize that the anti-tumor activity of target-specific naked MAbs can be enhanced by one or more of the following means: (a) Stimulation of mononuclear cells and neutrophils using G-GSF or GM-CSF; (b) Natural killer (NK) cell activation via the concomitant use of immunomodulatory drugs (DvliDs); (c) Inhibition of the proteasome-ubiquitin system by PS341 (bortezimib); (d) Decreasing expression of Bcl-2 anti-apoptotic protein using antisense oligonucleotides (ASO). In addition, we hypothesize that the acquirement of resistant to rituximab is associated with: a) common gene expression profile changes between different rituximab-resistant cell lines and on primary lymphoma cells from patients demonstrating clinical rituximabresistance; b) structural changes in CD20 structure leads to abnormalities in CD20 antigen redistribution into lipid rafts and downstream signaling. These hypotheses serve as a basis for this project. An investigation of the mechanism of action of rituximab will be aided in part by the development of several rituximab-resistant cell lines. This undertaking is possible primarily because of the cooperation and collaboration of several investigators within this Program Project, including Roswell Park Cancer Center and at Fox Chase Cancer Center. Thus, this project is uniquely positioned to evaluate all of these issues with the intent to ultimately use the insights gained in this research to develop better treatment strategies that can be tested clinically, and which could lead to important changes in the way B-cell malignancies will be treated in the future.