Studies supported by the SPORE during the initial funding period demonstrated thatimmunostimulatory CpG ODN and IL-21 are synergistic in their ability to induce apoptosis of chroniclymphocytic leukemia/small lymphocytic lymphoma (CLL) cells. One of the mechanisms responsible for thisapoptosis is production of Granzyme B by the malignant B cells - a surprising finding given that B cells havenot previously been shown to produce Granzyme B. IL-21 plus anti-B cell receptor antibody (Anti-BCR) alsoinduce Granzyme B production by both CLL cells and other B cell populations. The identification of apotentially powerful new mechanism of anti-tumor activity opens up a number of new avenues forinvestigation. Studies are proposed to explore the mechanisms responsible for induction of Granzyme Bproduction by the B cells, how cells treated in such a manner mediate anti-tumor activity, and how suchactivity can be utilized therapeutically. Specifically, the effects of IL-21, CpG ODN, and anti-BCR, alone andin combination, on malignant and benign B cells will be determined to define the molecular changes inducedby therapy and correlate these changes with the effect of therapy on malignant B cell viability and phenotype.The relative importance of autolysis, undirected cytotoxicity and antibody directed cellular cytotoxicity (ADCC)in the apoptosis of malignant B cells treated with these agents will be determined. Studies will assess howmalignant B cells respond to other combinations of B cell activating agents. In the clinic, correlative studieswill be done in conjunction with an ongoing phase I trial of CpG ODN in CLL to assess whether in vivotherapy with CpG ODN induces changes in CLL cells similar to those observed in vitro. Studies will be doneto evaluate how clinical therapy with CpG ODN impacts on the response of CLL cells to IL-21, and otherbiological agents in vitro. Additional clinical trials of combinations of biologically active agents in CLL or otherB cell malignancies will be tested based on the initial preclinical and clinical results. These studies, which willmake extensive use of all of the SPORE shared resources, will provide valuable information on how theunexpected immunologic finding that B cells can produce functional Granzyme B, can be applied to thetreatment of Lymphoma and other B cell malignancies.
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