The overall cancer death rates are down ~20% in past 25 years, however they remained unchanged for late stage ovarian cancer (OvCa) patients, making it the deadliest gynecological disease. Cancer immunotherapy makes use of antibody-based approaches to activate immune cells against the cancer cells and have proven effective in blood cancers and melanomas. Despite short-term positive responses, most OvCa specific antibodies have largely failed in clinical trials. This is attributed to limited infiltration of activated immune effector cells into the solid tumor bed. Therefore, it is highly important to generate efficacious therapies that have inbuilt capacity to turn OvCa against itself by exploiting inherent cancer properties. The proposed studies aim to investigate a novel and rationally combined dual-specificity antibody-based approach (called BaCa) that makes use of OvCa enriched surface antigen (FOLR1) and cancer inducible cell-death activator (DR5 or TRAIL-R2). Therapeutic antibodies individually against FOLR1 and DR5 have failed in clinical trials due to lack of efficacy. The BaCa approach combines these two targets in a single agent antibody with combined strength in the activity and selectivity. FOLR1 acts as an anchor to selectivity recruit, retain, and maintain anti-DR5 affinity in the ovarian tumor microenvironment. This results into a high level of DR5 receptor clustering, signaling and activation. As a consequence a highly superior cell death and cytotoxicity is instigated against ovarian tumors. We have already tested the feasibility of BaCa strategy in both ex vivo and in vivo OvCa models. Current application supported with comprehensive preliminary data aims to test the unique ability of BaCa strategy to engage host immune response for long-term immunogenicity against OvCa. If proved accurate and successful in vivo, this path has the inherent ?moon-shot? potential to selectively eliminate HGSOC cells, in a similar or improved fashion over FDA approved dual-specificity antibody called blinatumomab. Unlike chemotherapy, proposed biological therapy is safe and will significantly change the landscape of disease progression free survival of OvCa patients. Finally, this strategy has a great potential to be applicable for other solid cancer targeting.
Cancer immunotherapy makes use of antibody-based approaches to activate immune cells against the cancer cells. Although highly successful in blood cancers, it is not very effective in solid ovarian tumors. Here, we will evaluate a novel antibody-based symbiotic approach that drives apoptotic cell-death of tumors cells independent of limitedly tumor penetrated immune cells.
