Stimulation of natural killer (NK) cell and macrophage infiltration in pancreatic cancer with virulizin (V), an immunotherapeutic agent.
M. Y. Cao, Y. Lee, D. Miao, S. Cadden, J. A. Wright, A. H. Young;
Lorus Therapeutics Inc., Toronto, ON, Canada; McGill University, Montreal, PQ, Canada
Abstract: Purpose: V is stimulates macrophages and monocytes in vitro and in vivo. Pancreatic cancer patients treated with V in phase I/II studies showed increased 6 and 12 months survival vs historical controls. V administration was associated with increased NK cell activity in patients showing the best response to V.
Hence, NK cell function may be a mediator of V anti-tumor activity. Methods: To determine if V induces NK cell infiltration into tumors, CD-1 nude mice with Capan-1 pancreatic tumor xenografts were treated with V; tumor samples were analyzed by flow cytometry using NK cell-specific antibodies.
Anti-tumor activity and NK cell infiltration were also evaluated in human tumor xenografts in CD-1 nude mice depleted of macrophages. Immunohistochemical staining of tumor xenografts was performed to further assess NK cell and macrophage activity.
Results: V increased NK cell infiltration of tumors (59.4 – 116.0%). Macrophage depletion reduced both NK cell infiltration of tumors, and anti-tumor activity of V (P=0.1632). V-treated mice showed a significant increase in infiltration of F4/80+ (macrophages) and NK1.1+ (NK) cells, vs saline treated controls.
Increased NK1.1+ cell infiltration occurred early in V treatment, and correlated with an early marker for tumor apoptosis. V treatment also resulted in a significant increase in the NK cell number in the spleen.
Conclusion: Macrophage-mediated NK cell activation/recruitment is implicated in the mechanism of action of V.. These results suggest that V mediates a sustained infiltration of NK cells and macrophages into tumors.
Low NK cell activity may be a risk factor for malignancy and metastases, and a negative prognostic indicator in pancreatic cancer.
NK cell function and other immune activities are being assessed as biologic markers of clinical response in a Phase III trial in pancreatic cancer as a first line combination therapy with gemcitabine.
NK cell function will be correlated with clinical response parameters.
Abstract No: 4257
Abstract # 4241
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