Studies supported by the SPORE during the initial funding period demonstrated that immunostimulatory CpG ODN and IL-21 are synergistic in their ability to induce apoptosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells. One of the mechanisms responsible for this apoptosis is production of Granzyme B by the malignant B cells - a surprising finding given that B cells have not previously been shown to produce Granzyme B. IL-21 plus anti-B cell receptor antibody (Anti-BCR) also induce Granzyme B production by both CLL cells and other B cell populations. The identification of a potentially powerful new mechanism of anti-tumor activity opens up a number of new avenues for investigation. Studies are proposed to explore 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 such activity can be utilized therapeutically. Specifically, the effects of IL-21, CpG ODN, and anti-BCR, alone and in combination, on malignant and benign B cells will be determined to define the molecular changes induced by 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 how malignant B cells respond to other combinations of B cell activating agents. In the clinic, correlative studies will be done in conjunction with an ongoing phase I trial of CpG ODN in CLL to assess whether in vivo therapy with CpG ODN induces changes in CLL cells similar to those observed in vitro. Studies will be done to evaluate how clinical therapy with CpG ODN impacts on the response of CLL cells to IL-21, and other biological agents in vitro. Additional clinical trials of combinations of biologically active agents in CLL or other B cell malignancies will be tested based on the initial preclinical and clinical results. These studies, which will make extensive use of all of the SPORE shared 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097274-10
Application #
8302443
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
10
Fiscal Year
2011
Total Cost
$211,618
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Franqui-Machin, Reinaldo; Hao, Mu; Bai, Hua et al. (2018) Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. J Clin Invest 128:2877-2893
Ghahramani, Grant K; Goetz, Kirsten E; Liu, Vincent (2018) Dermoscopic characterization of cutaneous lymphomas: a pilot survey. Int J Dermatol 57:339-343
Hu, G; Dasari, S; Asmann, Y W et al. (2018) Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma. Leukemia 32:565-569
Moss, Jennifer L; Xiao, Qian; Matthews, Charles E (2018) Patterns of cancer-related health behaviors among middle-aged and older adults: Individual- and area-level socioeconomic disparities. Prev Med 115:31-38
Luchtel, Rebecca A; Dasari, Surendra; Oishi, Naoki et al. (2018) Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood 132:1386-1398
Oishi, Naoki; Brody, Garry S; Ketterling, Rhett P et al. (2018) Genetic subtyping of breast implant-associated anaplastic large cell lymphoma. Blood 132:544-547
Thompson, Carrie A; Yost, Kathleen J; Maurer, Matthew J et al. (2018) Quality of life at diagnosis predicts overall survival in patients with aggressive lymphoma. Hematol Oncol 36:749-756
Naik, Shruthi; Galyon, Gina D; Jenks, Nathan J et al. (2018) Comparative Oncology Evaluation of Intravenous Recombinant Oncolytic Vesicular Stomatitis Virus Therapy in Spontaneous Canine Cancer. Mol Cancer Ther 17:316-326
Thanarajasingam, Gita; Maurer, Matthew J; Farooq, Umar et al. (2018) Event-free survival at 24 months captures central nervous system relapse of systemic diffuse large B-cell lymphoma in the immunochemotherapy era. Br J Haematol 183:149-152
Kleinstern, Geffen; Maurer, Matthew J; Liebow, Mark et al. (2018) History of autoimmune conditions and lymphoma prognosis. Blood Cancer J 8:73

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