A Novel Approach to the Immunotherapy of B Cell Malignancy

Principal Investigator: George Weiner, M.D., University of Iowa
Co-Principal Investigator: Clive Zent, M.D., Mayo Clinic

During the previous funding period, the University of Iowa/Mayo Clinic Lymphoma SPORE research team explored the potential of CpG oligonucleotides (ODN) as a treatment for B cell malignancy. The investigators demonstrated that CpG ODN and IL-21 are synergistic in their ability to induce apoptosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells, and that this apoptosis is independent of benign cells. Further studies demonstrated uniquely that one of the mechanisms responsible for this apoptosis is production of Granzyme B by the malignant B cells.

The researchers also found that other B cells can be induced to produce Granzyme B. Their studies demonstrated Granzyme B production by B cells can also be induced by IL-21 plus anti-B cell receptor antibody (anti-BCR). The identification of a potentially powerful new mechanism of anti-tumor activity resulted in myriad of new research opportunities. Further studies are needed to better understand the mechanisms responsible for induction of Granzyme B production by the B cells, how cells treated in such a manner mediate anti-tumor activity, and how this can be applied therapeutically.

Studies are also needed to evaluate whether Granzyme B-producing B cells undergo autolysis, function as cytotoxic cells, or both. In Project 1, these questions are addressed, and the researchers will assess the therapeutic potential for CLL and other B cell malignancies of treatments that induce these changes.

The research initiatives of Project 1, which will make extensive use of all of the Lymphoma SPORE Core Resources, will provide valuable information on how the unexpected immunologic finding that B cells can produce functional Granzyme B, can be applied to the treatment of Lymphoma and other B cell malignancies.

The specific aims of this project are:

1. Assess the effects of IL-21, CpG ODN, and other B cell activators, on malignant B cells in vitro
   • Define the molecular changes induced by IL-21, CpG ODN and anti-BCR, alone and in combination, and correlate these changes with the effect of therapy on malignant B cell viability and phenotype
   • Delineate the relative importance of autolysis, undirected cytotoxicity and antibody directed cellular cytotoxicity (ADCC) in the apoptosis of malignant B cells treated with IL-21 plus CpG ODN or IL-21 plus anti-BCR
   • Assess how malignant B cells respond to other combinations of B cell activating agents
2. Perform early phase clinical trials of biological therapy in subjects with CLL and assess the impact of treatment on the biology of CLL cells
   • Assess whether clinical therapy of CLL subjects with CpG ODN induces changes in CLL cells similar to those observed in vitro, and how dose and route of CpG ODN impact on this response
   • Evaluate how clinical therapy with CpG ODN impacts on the response of CLL cells to IL-21, and other biological agents in vitro
   • Conduct additional clinical trials of combinations of biologically active agents in CLL or other B cell malignancies based on the initial preclinical and clinical results