Abstract
Simple SummaryOvarian cancer is one of the leading causes of cancer-related death among women in the United States. Overall survival of patients with advanced stage disease has not significantly changed despite improvements in treatment that have extended median survival. Photoimmunotherapy (PIT) using an antibody conjugated to a near infrared (NIR) dye constitutes an effective theranostic strategy to detect and selectively eliminate cell populations. The programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) signaling pathway is being extensively studied for immune checkpoint blockade. PD-L1 expression has been described across all major ovarian cancer histological subtypes and is commonly expressed by cancer cells and by tumor-associated macrophages (TAMs). Here, we used NIR-PIT to eliminate PD-L1-expressing TAMs and cancer cells in ovarian cancer xenografts. Overall, our findings support using NIR-PIT as a potential therapeutic option for ovarian cancer.(1) Background: Despite advances in surgical approaches and drug development, ovarian cancer is still a leading cause of death from gynecological malignancies. Patients diagnosed with late-stage disease are treated with aggressive surgical resection and chemotherapy, but recurrence with resistant disease is often observed following treatment. There is a critical need for effective therapy for late-stage ovarian cancer. Photoimmunotherapy (PIT), using an antibody conjugated to a near infrared (NIR) dye, constitutes an effective theranostic strategy to detect and selectively eliminate targeted cell populations. (2) Methods: Here, we are targeting program death ligand 1 (PD-L1) using NIR-PIT in a syngeneic mouse model of ovarian cancer. PD-L1 PIT-mediated cytotoxicity was quantified in RAW264.7 macrophages and ID8-Defb29-VEGF cells in culture, and in vivo with orthotopic ID8-Defb29-VEGF tumors. (3) Results: Treatment efficacy was observed both in vitro and in vivo. (4) Conclusions: Our data highlight the need for further investigations to assess the potential of using NIR-PIT for ovarian cancer therapy to improve the treatment outcome of ovarian cancer.
Highlights
Ovarian cancer is one of the leading causes of cancer-related deaths among women in the United States [1,2]
program death ligand 1 (PD-L1) PIT-mediated cytotoxicity was quantified in RAW264.7 macrophages and ID8-Defb29-VEGF cells in culture, and in vivo with orthotopic ID8-Defb29-VEGF tumors
near infrared (NIR)-PIT has direct cytotoxicity on cells targeted by the IRDye 700DX NHS ester (IR700)–antibody complex combined with light exposure, but it can have indirect effects on the tumor microenvironment
Summary
Ovarian cancer is one of the leading causes of cancer-related deaths among women in the United States [1,2]. RM-1929 PIT was associated with longer median overall survival (9.3 months), with four patients achieving complete responses (13%) [11] These early results suggest that NIR-PIT is superior to existing second- and third-line therapies for recurrent head and neck cancers [15]. Patients with recurrent or metastatic squamous cell cancer of the head and neck, or advanced or metastatic cutaneous squamous cell carcinoma will receive anti-PD1 therapy with an anti-EGFR antibody–dye conjugate, ASP-1929, followed by PIT. The ID8 cell line was further transformed to overexpress VEGF [23], and beta-defensin was added to the model to interact with VEGF, and further increase tumor vascularization [24] This modified cell line grows well orthotopically [25], and allows investigation into the effects of NIR-PIT on tumor progression in ovarian cancer in mice with an intact immune system. F4/80 is a widely used marker of murine macrophage populations, while CD11b is expressed on the surface of many leukocytes, including monocytes, granulocytes, macrophages, and natural killer cells
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