Abstract
Immunotherapy for ovarian cancer is an area of intense investigation since the majority of women with relapsed disease develop resistance to conventional cytotoxic therapy. The paucity of safe and validated target antigens has limited the development of clinically relevant antibody-based immunotherapeutics for this disease. Although MUC16 expression is almost universal in High Grade Serous Ovarian Cancers, engagement of the shed circulating MUC16 antigen (CA-125) presents a theoretical risk of systemic activation and toxicity. We designed and evaluated a series of bispecific tandem single-chain variable fragments specific to the retained portion of human MUC16 ectodomain (MUC16ecto) and human CD3. These MUC16ecto- BiTEDs retain binding in the presence of soluble MUC16 (CA-125) and show cytotoxicity against a panel of ovarian cancer cells in vitro. MUC16ecto- BiTEDs delay tumor progression in vivo and significantly prolong survival in a xenograft model of ovarian peritoneal carcinomatosis. This effect was significantly enhanced by antiangiogenic (anti-VEGF) therapy and immune checkpoint inhibition (anti-PD1). However, the combination of BiTEDs with anti-VEGF was superior to combination with anti-PD1, based on findings of decreased peritoneal tumor burden and ascites with the former. This study shows the feasibility and efficacy of MUC16ecto- specific BiTEDs and provides a basis for the combination with anti-VEGF therapy for ovarian cancer.
Highlights
Epithelial Ovarian Cancer (EOC) continues to be a highly lethal disease [1]
Treatment of tumor-bearing mice with MUC16ecto- MUC16ecto bispecific tandem single-chain variable fragments (BiTEDs) increases in vivo cytokine secretion, substantially delays tumor progression, and increases overall survival in xenograft preclinical murine models of ovarian peritoneal carcinomatosis
The Single chain variable fragments (scFv) for MUC16ectoBiTEDs were derived from human phage display libraries, limiting the potential for human anti-mouse antibody (HAMA)
Summary
Epithelial Ovarian Cancer (EOC) continues to be a highly lethal disease [1]. This is due in large part to the evolution of a multidrug resistant phenotype in virtually all women with recurrent disease [2]. Immunotherapeutic modalities represent an opportunity to achieve durable clinical responses in this subset of patients. This could be accomplished by harnessing endogenous tumor-reactive cytotoxic T-cells. The presence of tumor-infiltrating T-cells (TILs) corresponded with a 5-year overall survival of 38% compared to 4% in patients without TILs [3]. There are ongoing efforts to harness the immune system against ovarian cancer using vaccine therapy [4], immune checkpoint blockade [5], adoptive cellular therapy [6], and antibody-drug conjugates [7]
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