Abstract PR09: An unexpectedly effective immunotherapy strategy for ovarian cancer
Authors: Jogender Tushir-Singh
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer (OvCa) is the most lethal of gynecologic diseases and is known for chemoresistance and frequent reoccurrence with no effective treatment available. Clinical data indicate that antibodies that kill tumor cells by activating the immune system are highly effective against blood and melanoma cancers. However, in the case of OvCa, antibody-based approaches have largely failed due to ineffective killing of tumor cells, below the tumor apoptotic clearance threshold by immune cells. This is mainly attributed to 1) the limited penetration of immune effector cell types into the solid tumor bed and 2) to the presence of large immune inhibitory glycoproteins such as Mucin 16. A long-term goal of research in our lab is to develop a safe and effective therapeutic antibody that achieves efficient clinical response against ovarian tumors despite the limitations of immune penetration and immune inhibitory proteins. Toward this goal, very recently we have engineered and tested a novel Bispecific-anchored Cytotoxicity-activator (BaCa) antibody. The BaCa antibody has dual specificity against: 1) the folate receptor alpha-1 (FOLR1), which is multiple-fold elevated in &amp;gt;80% OvCa patients, but has very minimal expression in healthy tissues; and 2) death receptor-5 (DR5/TRAIL-R2), an extrinsic agonist whose higher-order oligomerization drives apoptotic cell-death of tumor cells independently of immune effector function. We hypothesize that via a high-affinity anti-FOLR1 domain, the BaCa antibody finds a tumor anchor-dependent home to tightly bind to OvCa cells. This retains and selectively intensifies the cell death-inducing DR5 signaling of BaCa to the surface FOLR1-enriched OvCa cells and tumors. As a consequence, the DR5 receptor is exceedingly oligomerized and activated, resulting in a greatly superior apoptosis, well beyond the tumor clearance threshold (Cancer Cell 2018). When tested in OvCa tumor models including platinum-resistant patient-derived xenografts, the BaCa antibody was significantly efficacious over investigational clinical antibodies (Cancer Cell 2018), and was found to be &amp;gt;200 (IC50) and &amp;gt;500 (IC90) fold more effective over clinically tested antibodies in killing OvCa cells. Despite effective tumor clearance due to high-caliber DR5 receptor activation and signaling, two major questions still remain before realizing the true clinical potential of BaCa strategy: 1) Does BaCa antibody have added function to activate adaptive immune system for long-term response against OvCa? 2) Acquired tumor apoptotic resistance to clinical DR5 agonist therapies remains a limitation to their clinical success. Therefore, it is highly imperative to understand and test if amplified apoptotic output by BaCa antibody will differentially affect resistance to cell death. During this meeting I will present key preliminary data that support immunogenicity and effective therapeutic potential of OvCa-specific BaCa antibody. This abstract is also being presented as Poster B06. Citation Format: Jogender Tushir-Singh. An unexpectedly effective immunotherapy strategy for ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR09.