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Treatment of Mestastatic Breast Cancer by Photodynamic Therapy Induced Anti-Tumor Immunity in a Murine Model
Final rept. 1 Jul 2004-30 Nov 2005
MASSACHUSETTS GENERAL HOSPITAL BOSTON
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One in 8 women in the United States will develop breast cancer during her lifetime. Deaths are due to tumors that have metastasized. Photodynamic therapy PDT is a promising cancer treatment in which a photosensitizer PS accumulates in tumors and is subsequently activated by visible light of an appropriate wavelength. PDT produces cell death and tumor ablation. Mechanisms include cytotoxicity to tumor cells, shutting down of the tumor vasculature, and the induction of a host immune response. Mechanisms involved in the PDT-mediated induction of anti-tumor immunity are not yet understood. Potential contributing factors are alterations in the tumor microenvironment via stimulation of proinflammatory cytokines and direct effects of PDT on the tumor that increase immunogenicity. We have studied PDT of 410.4 variant 4T1 tumors growing in the mammary fat pad orthotopic in Balbc mice and which produce metastasis. We have shown that a PDT regimen that produces vascular shutdown and tumor necrosis leads to initial tumor ablation but the tumors recur at the periphery. We studied the combination of PDT with immunostimulating therapies. Low dose cyclophosphamide is a mechanism to deplete regulatory T cells these cells play a role in the immunosuppression activity of tumors. In combination with PDT, cyclophosphamide increases the survival. The second alternative therapy is the use of a novel combination of the immunostimulant CpG Oligodeoxynucleotides CpG-ODN and PDT. CpG-ODN directly or indirectly triggers B cells, NK cells, macrophages and dendritic cells to proliferate, mature and secrete cytokines, chemokines and immunoglobulins. Both these novel combinations gave significantly enhanced therapeutic benefit not seen with single treatments alone. We propose that a rational choice of immune stimulant is an ideal addition to PDT regimens.
APPROVED FOR PUBLIC RELEASE