Effective Treatment of Human Lung Cancer by Targeting Tissue Factor with a Factor VII-Targeted Photodynamic Therapy

Abstract

Lung cancer is the leading cause of cancer death. Conventional photodynamic therapy (PDT) using a nontargeted photosensitizer (ntPDT) is a treatment option for central- and peripheral-type early-stage lung cancer. However, ntPDT can cause severe side effects for normal tissue due to its non-selective distribution. To improve the selectivity and effectiveness of ntPDT for human lung cancer, we hypothesized that tissue factor would be a common yet specific biomarker and a potential therapeutic target for both lung cancer cells and lung tumor vascular endothelial cells in factor VII-targeted PDT (fVII-tPDT), which uses the fVII-Sn(IV) chlorin e6 conjugate for the treatment of human lung cancer. We first identified that tissue factor is indeed expressed on the human non-small cell lung cancer (NSCLC) lines A549 and H460 as well as on tumor vascular endothelial cells of A549 tumor xenografts from nude mice, but it is not expressed by vascular endothelial cells in healthy mouse organs including the lungs. We then demonstrated that fVII-targeting in fVII-tPDT significantly enhanced (up to 25-fold) the in vitro effect of ntPDT on the destruction of A549 and H460 lung cancer cells via the rapid induction of apoptosis and necrosis. We further demonstrated that in vivo administration of fVIItPDT significantly inhibited or eliminated subcutaneous A549 and H460 tumor xenografts in an athymic nude (ATN) mouse model without any obvious side effects. We conclude that fVII-tPDT is effective and safe for the treatment of human lung cancer in preclinical studies and that this methodology holds therapeutic potential for lung cancer patients.

Dual-Targeting of Tumor Cells and Tumor Neovasculature by Tissue Factor- Targeted Photodynamic Therapy

“…Thus we conclude that TF is a common yet specific biomarker and therapeutic target molecule for both the tumor cells and tumor neovasculature [10][11][12]17,18]. By choosing the receptor TF as a target molecule and using its natural ligand, coagulation factor VII (fVII), as a targeting vehicle, we have successfully developed a novel dtPDT, namely fVII-targeted PDT (fVII-tPDT) using fVII-SnCe6 (activation wavelength at 635 nm) or fVII-VP (activation wavelength at 689 nm) conjugates, for treatment of human breast [12,17,18] and lung cancer [11] and wet macular degeneration [19] in preclinical studies. Our results showed that fVII-tPDT was selective and effective in vitro in killing angiogenic vascular endothelial cells and tumor cells that express TF as well as in vivo in treating breast and lung tumor xenografts in mouse models.…”

“…The bottleneck of development of such dtPDT is to identify a common yet specific biomarker on both tumor compartments [10]. We [11][12][13][14] and several other groups [15,16] showed that tissue factor (TF) was selectively expressed by tumor angiogenic vascular endothelial cells and was also overexpressed by many types of cancer cells in melanoma, breast, lung and brain tumors. Thus we conclude that TF is a common yet specific biomarker and therapeutic target molecule for both the tumor cells and tumor neovasculature [10][11][12]17,18].…”

“…We [11][12][13][14] and several other groups [15,16] showed that tissue factor (TF) was selectively expressed by tumor angiogenic vascular endothelial cells and was also overexpressed by many types of cancer cells in melanoma, breast, lung and brain tumors. Thus we conclude that TF is a common yet specific biomarker and therapeutic target molecule for both the tumor cells and tumor neovasculature [10][11][12]17,18]. By choosing the receptor TF as a target molecule and using its natural ligand, coagulation factor VII (fVII), as a targeting vehicle, we have successfully developed a novel dtPDT, namely fVII-targeted PDT (fVII-tPDT) using fVII-SnCe6 (activation wavelength at 635 nm) or fVII-VP (activation wavelength at 689 nm) conjugates, for treatment of human breast [12,17,18] and lung cancer [11] and wet macular degeneration [19] in preclinical studies.…”

“…Since TF is expressed by tumor angiogenic vascular endothelial cells and by cancer cells of human solid cancers and leukemia [18], we believe that TF-targeted therapeutics by using fVII as targeting vehicle, including fVII-tPDT that we recently developed [10][11][12]17,18] and fVII/IgG1 Fc (Icon immunotherapy) that we previously developed [13,14,20,21] could have broad therapeutic potential for solid cancer and leukemia.…”

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

“…The combination immunotherapy can target different molecules on some or all major tumor compartments, including but not limited to the cancer cells, tumor neovasculature, cancer stem cells, MDSC, Treg and TAM, or ideally, target the same molecule that is commonly expressed by these major tumor compartments. In this regard, we believe that tissue factor (also known as coagulation factor III or CD142) is one of few such promising and common target molecules as it is commonly yet selectively expressed on many types of solid cancer cells as well as leukemic cells (21,22), tumor angiogenic vascular endothelial cells in vitro (23) and in vivo (22,(24)(25)(26) and cancer stem cells (27).…”